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1
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Liu R, Xu Y, Zhang N, Qu S, Zeng W, Li R, Dai Z. Nanotechnology for Enhancing Medical Imaging. Nanomedicine (Lond) 2023. [DOI: 10.1007/978-981-16-8984-0_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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2
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Shen H, Huang H, Jiang Z. Nanoparticle-based radiosensitization strategies for improving radiation therapy. Front Pharmacol 2023; 14:1145551. [PMID: 36873996 PMCID: PMC9977822 DOI: 10.3389/fphar.2023.1145551] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/03/2023] [Indexed: 02/18/2023] Open
Abstract
Radiotherapy remains the mainstay treatment for a variety of cancer forms. However, the therapeutic efficiency of radiation is significantly limited by several aspects, including high radiation resistance caused by low reactive oxygen species concentrations and a low absorption rate of radiation by tumor tissue, inappropriate tumor cell cycle and tumor cell apoptosis, and serious radiation damage to normal cells. In recent years, nanoparticles have been widely used as radiosensitizers due to their unique physicochemical properties and multifunctionalities for potentially enhancing radiation therapy efficacy. In this study, we systematically reviewed several nanoparticle-based radiosensitization strategies for radiation therapy use, including designing nanoparticles that upregulate the levels of reactive oxygen species, designing nanoparticles that enhance the radiation dose deposit, designing chemical drug-loaded nanoparticles for enhancing cancer cell sensitivity to radiation, designing antisense oligonucleotide gene-loaded nanoparticles, and designing nanoparticles using a unique radiation-activable property. The current challenges and opportunities for nanoparticle-based radiosensitizers are also discussed.
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Affiliation(s)
- Hongxin Shen
- Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Hong Huang
- Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Zhimei Jiang
- Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
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3
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Li Z, Lai M, Zhao S, Zhou Y, Luo J, Hao Y, Xie L, Wang Y, Yan F. Ultrasound Molecular Imaging for Multiple Biomarkers by Serial Collapse of Targeting Microbubbles with Distinct Acoustic Pressures. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2108040. [PMID: 35499188 DOI: 10.1002/smll.202108040] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/08/2022] [Indexed: 06/14/2023]
Abstract
Ultrasound molecular imaging (UMI) has shown promise for assessing the expression levels of biomarkers for the early detection of various diseases. However, it remains difficult to simultaneously image multiple biomarkers in a single systemic administration, which is important for the accurate diagnosis of diseases and for understanding the dynamic intermolecular mechanisms that drive their malignant progression. The authors develop an ultrasound molecular imaging method by serial collapse of targeting microbubbles with distinct acoustic pressures for the simultaneous detection of two biomarkers. To test this, αv β3 -targeting lipid microbubbles (L-MBα ) and VEGFR2-targeting lipid-PLGA microbubbles (LP-MBv ) are fabricated and simultaneously injected into tumor-bearing mice at 7 and 14 days, followed by the low-intensity acoustic collapse of L-MBα and high-intensity acoustic collapse of LP-MBv . The UMI signals of L-MBα and LP-MBv are obtained by subtracting the first post-burst signals from the first pre-burst signals, and subtracting the second post-burst signals from the first post-burst signals, respectively. Interestingly, the signal intensities from UMI agree with the immunohistochemical staining results for αv β3 and VEGFR2. Importantly, they find a better fit for the invasive behavior of MDA-MB-231 breast tumors by analyzing the ratio of αv β3 integrin to VEGFR2, but not the single αv β3 or VEGFR2 levels.
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Affiliation(s)
- Zhenzhou Li
- Department of Ultrasound, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518061, P. R. China
- Shenzhen University Health Science Center, Shenzhen, 518000, P. R. China
| | - Manlin Lai
- Department of Ultrasound, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518061, P. R. China
- Shenzhen University Health Science Center, Shenzhen, 518000, P. R. China
| | - Shuai Zhao
- Department of Ultrasound, Suzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province), Suzhou, 234000, P. R. China
| | - Yi Zhou
- Department of Ultrasound, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518061, P. R. China
- Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, P. R. China
| | - Jingna Luo
- Department of Ultrasound, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518061, P. R. China
- Shenzhen University Health Science Center, Shenzhen, 518000, P. R. China
| | - Yongsheng Hao
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
| | - Liting Xie
- Department of Ultrasound, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, P. R. China
| | - Yaru Wang
- Department of Radiology, Suzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province), Suzhou, 234000, P. R. China
| | - Fei Yan
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
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4
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Nanotechnology for Enhancing Medical Imaging. Nanomedicine (Lond) 2022. [DOI: 10.1007/978-981-13-9374-7_8-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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5
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DeNicola GM, Shackelford DB. Metabolic Phenotypes, Dependencies, and Adaptation in Lung Cancer. Cold Spring Harb Perspect Med 2021; 11:a037838. [PMID: 34127512 PMCID: PMC8559540 DOI: 10.1101/cshperspect.a037838] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Lung cancer is a heterogeneous disease that is subdivided into histopathological subtypes with distinct behaviors. Each subtype is characterized by distinct features and molecular alterations that influence tumor metabolism. Alterations in tumor metabolism can be exploited by imaging modalities that use metabolite tracers for the detection and characterization of tumors. Microenvironmental factors, including nutrient and oxygen availability and the presence of stromal cells, are a critical influence on tumor metabolism. Recent technological advances facilitate the direct evaluation of metabolic alterations in patient tumors in this complex microenvironment. In addition, molecular alterations directly influence tumor cell metabolism and metabolic dependencies that influence response to therapy. Current therapeutic approaches to target tumor metabolism are currently being developed and translated into the clinic for patient therapy.
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Affiliation(s)
- Gina M DeNicola
- Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - David B Shackelford
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California 90095, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, California 90095, USA
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6
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Xu S, He J, Imtiyaz Z, Agrawal AK, Woodle MC, Mixson AJ. Marked increase in tumor transfection with a truncated branched polymer. J Gene Med 2021; 24:e3396. [PMID: 34713552 PMCID: PMC8724455 DOI: 10.1002/jgm.3396] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 09/08/2021] [Accepted: 10/16/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND We previously determined that polyplexes formed by linear H2K peptides were more effective in transfecting tumors in vivo than polyplexes formed by branched H2K4b-20 peptides. Based on trypsin digest and salt displacement studies, the linear H2K polyplexes were less stable than the branched H2K4b-20 polyplexes. Because binding and release of the polymer and DNA from the H2K4b-20 polyplex may account for the ineffectiveness, we investigated whether four-branched histidine-lysine (HK) peptides with varying numbers of amino acids in their branches would be more effective in their ability to increase gene expression in tumors in vivo. METHODS Linear and branched peptides with multiple -KHHK- motifs were synthesized by solid-phase synthesis. The branched H2K4b-20, -18, -14 and 12 peptides had 20, 18, 14 and 12 amino acids in their branches, respectively. These peptides were examined for their ability to carry luciferase-expressing plasmids to human breast cancer xenografts in a mouse model. With gel retardation and in vivo transfection, the incorporation of a targeting ligand and an endosomal lysis peptide into these polyplexes was also examined. A blocking antibody was pre-injected prior to the polyplexes to determine the role of neuropilin 1 in the uptake of these polyplexes by the tumor. The size of the polyplexes was measured by dynamic light scattering. RESULTS Of the four negative surface-charge polyplexes formed by the branched carriers, the H2K4b-14 polyplex was determined to be the most effective plasmid delivery platform to tumors. The incorporation of a targeting ligand and an endosomal lysis peptide into H2K4b-14 polyplexes further enhanced their ability to transfect tumors in vivo. Furthermore, after pre-injecting tumor-bearing mice with a blocking antibody to the neuropilin-1 receptor (NRP-1), there was a marked reduction of tumor gene expression with the modified H2K4b-14 polyplexes, suggesting that NRP-1 mediated their transport into the tumor. CONCLUSIONS The present study established that branched peptides intermediate in length were very efficient in delivering plasmids to tumors in vivo.
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Affiliation(s)
- Songhui Xu
- Department of Pathology, University Maryland School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Jiaxi He
- Department of Pathology, University Maryland School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Zuha Imtiyaz
- Department of Pathology, University Maryland School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Atul K Agrawal
- Department of Pathology, University Maryland School of Medicine, University of Maryland, Baltimore, MD, USA
| | | | - A James Mixson
- Department of Pathology, University Maryland School of Medicine, University of Maryland, Baltimore, MD, USA
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7
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Guo D, Ji X, Luo J. Rational nanocarrier design towards clinical translation of cancer nanotherapy. Biomed Mater 2021; 16. [DOI: 10.1088/1748-605x/abe35a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/04/2021] [Indexed: 02/06/2023]
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8
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Ayala-Domínguez L, Pérez-Cárdenas E, Avilés-Salas A, Medina LA, Lizano M, Brandan ME. Quantitative Imaging Parameters of Contrast-Enhanced Micro-Computed Tomography Correlate with Angiogenesis and Necrosis in a Subcutaneous C6 Glioma Model. Cancers (Basel) 2020; 12:E3417. [PMID: 33217988 PMCID: PMC7698719 DOI: 10.3390/cancers12113417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/16/2020] [Accepted: 11/16/2020] [Indexed: 12/04/2022] Open
Abstract
The aim of this work was to systematically obtain quantitative imaging parameters with static and dynamic contrast-enhanced (CE) X-ray imaging techniques and to evaluate their correlation with histological biomarkers of angiogenesis in a subcutaneous C6 glioma model. Enhancement (E), iodine concentration (CI), and relative blood volume (rBV) were quantified from single- and dual-energy (SE and DE, respectively) micro-computed tomography (micro-CT) images, while rBV and volume transfer constant (Ktrans) were quantified from dynamic contrast-enhanced (DCE) planar images. CI and rBV allowed a better discernment of tumor regions from muscle than E in SE and DE images, while no significant differences were found for rBV and Ktrans in DCE images. An agreement was found in rBV for muscle quantified with the different imaging protocols, and in CI and E quantified with SE and DE protocols. Significant strong correlations (Pearson r > 0.7, p < 0.05) were found between a set of imaging parameters in SE images and histological biomarkers: E and CI in tumor periphery were associated with microvessel density (MVD) and necrosis, E and CI in the complete tumor with MVD, and rBV in the tumor periphery with MVD. In conclusion, quantitative imaging parameters obtained in SE micro-CT images could be used to characterize angiogenesis and necrosis in the subcutaneous C6 glioma model.
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Affiliation(s)
- Lízbeth Ayala-Domínguez
- Programa de Doctorado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico;
- Unidad de Investigación Biomédica en Cáncer INCan/UNAM, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico;
| | - Enrique Pérez-Cárdenas
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico;
| | - Alejandro Avilés-Salas
- Departamento de Patología, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico;
| | - Luis Alberto Medina
- Unidad de Investigación Biomédica en Cáncer INCan/UNAM, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico;
- Departamento de Física Experimental, Instituto de Física, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - Marcela Lizano
- Unidad de Investigación Biomédica en Cáncer INCan/UNAM, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico;
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - María-Ester Brandan
- Departamento de Física Experimental, Instituto de Física, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
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Børresen B, Hansen AE, Fliedner FP, Henriksen JR, Elema DR, Brandt-Larsen M, Kristensen LK, Kristensen AT, Andresen TL, Kjær A. Noninvasive Molecular Imaging of the Enhanced Permeability and Retention Effect by 64Cu-Liposomes: In vivo Correlations with 68Ga-RGD, Fluid Pressure, Diffusivity and 18F-FDG. Int J Nanomedicine 2020; 15:8571-8581. [PMID: 33173294 PMCID: PMC7646401 DOI: 10.2147/ijn.s239172] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 03/29/2020] [Indexed: 11/23/2022] Open
Abstract
Background The accumulation of liposome encapsulated chemotherapy in solid cancers is dependent on the presence of the enhanced permeability and retention (EPR) effect. Positron emission tomography (PET) imaging with a liposome encapsulated radioisotope, such as liposome encapsulated Cu-64 (64Cu-liposome) may help to identify tumors with high liposome accumulation, and thereby stratify patients based on expected benefit from liposomal chemotherapy. However, intravenous administration of liposomes without a cytotoxic content is complicated by the accelerated blood clearance (ABC) phenomenon for succeeding therapeutic liposome dosing. Alternative markers for assessing the tumor’s EPR level are therefore warranted. Materials and Methods To increase our understanding of EPR variations and to ultimately identify an alternative marker for the EPR effect, we investigated the correlation between 64Cu-liposome PET/CT (EPR effect) and 68Ga-RGD PET/CT (neoangiogenesis), 18F-FDG PET/CT (glycolysis), diffusion-weighted MRI (diffusivity) and interstitial fluid pressure in two experimental cancer models (CT26 and COLO 205). Results 64Cu-liposome and 68Ga-RGD SUVmax displayed a significant moderate correlation, however, none of the other parameters evaluated displayed significant correlations. These results indicate that differences in neoangiogenesis may explain some EPR variability, however, as correlations were only moderate and not observed for SUVmean, 68Ga-RGD is probably insufficient to serve as a stand-alone surrogate marker for quantifying the EPR effect and stratifying patients.
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Affiliation(s)
- Betina Børresen
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C 1870, Denmark
| | - Anders Elias Hansen
- Cluster for Molecular Imaging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N 2200, Denmark.,DTU Health Technology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Lyngby, Kgs 2800, Denmark
| | - Frederikke Petrine Fliedner
- Cluster for Molecular Imaging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N 2200, Denmark
| | - Jonas Rosager Henriksen
- DTU Health Technology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Lyngby, Kgs 2800, Denmark
| | - Dennis Ringkjøbing Elema
- DTU Health Technology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Lyngby, Kgs 2800, Denmark.,DTU Health Technology, The Hevesy Laboratory, Center for Nuclear Technologies, Technical University of Denmark, Roskilde, 4000, Denmark
| | - Malene Brandt-Larsen
- Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Copenhagen Ø 2100, Denmark
| | - Lotte Kellemann Kristensen
- Cluster for Molecular Imaging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N 2200, Denmark.,DTU Health Technology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Lyngby, Kgs 2800, Denmark.,DTU Health Technology, The Hevesy Laboratory, Center for Nuclear Technologies, Technical University of Denmark, Roskilde, 4000, Denmark.,Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Copenhagen Ø 2100, Denmark.,Minerva Imaging, Copenhagen N 2200, Denmark
| | - Annemarie Thuri Kristensen
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C 1870, Denmark.,Cluster for Molecular Imaging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N 2200, Denmark.,DTU Health Technology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Lyngby, Kgs 2800, Denmark.,DTU Health Technology, The Hevesy Laboratory, Center for Nuclear Technologies, Technical University of Denmark, Roskilde, 4000, Denmark.,Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Copenhagen Ø 2100, Denmark.,Minerva Imaging, Copenhagen N 2200, Denmark
| | - Thomas Lars Andresen
- DTU Health Technology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Lyngby, Kgs 2800, Denmark
| | - Andreas Kjær
- Cluster for Molecular Imaging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N 2200, Denmark.,Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Copenhagen Ø 2100, Denmark
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10
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Schreiber CL, Zhai C, Dempsey JM, McGarraugh HH, Matthews BP, Christmann CR, Smith B. Paired Agent Fluorescence Imaging of Cancer in a Living Mouse Using Preassembled Squaraine Molecular Probes with Emission Wavelengths of 690 and 830 nm. Bioconjug Chem 2020; 31:214-223. [PMID: 31756298 PMCID: PMC7768864 DOI: 10.1021/acs.bioconjchem.9b00750] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
New methods are described for the construction of targeted fluorescence probes for imaging cancer and the assessment of tumor targeting performance in a living mouse model. A novel noncovalent assembly process was used to fabricate a set of structurally related targeted fluorescent probes with modular differences in three critical assembly components: the emission wavelength of the squaraine fluorochrome, the number of cRGDfK peptide units that target the cancer cells, and the length of the polyethylene glycol chains as pharmacokinetic controllers. Selective targeting of cancer cells was proven by a series of cell microscopy experiments followed by in vivo imaging of subcutaneous tumors in living mice. The mouse imaging studies included a mock surgery that completely removed a fluorescently labeled tumor. Enhanced tumor accumulation due to probe targeting was first evaluated by conducting Single Agent Imaging (SAI) experiments that compared tumor imaging performance of a targeted probe and untargeted probe in separate mouse cohorts. Although there was imaging evidence for enhanced tumor accumulation of the targeted probe, there was moderate scatter in the data due to tumor-to-tumor variability of the vasculature structure and interstitial pressure. A subsequent Paired Agent Imaging (PAI) study coinjected a binary mixture of targeted probe (with emission at 690 nm) and untargeted probe (with emission at 830 nm) into the same tumor-burdened animal. The conclusion of the PAI experiment also indicated enhanced tumor accumulation of the targeted probe, but the statistical significance was much higher, even though the experiment required a much smaller cohort of mice. The imaging data from the PAI experiment was analyzed to determine the targeted probe's Binding Potential (BP) for available integrin receptors within the tumor tissue. In addition, pixelated maps of BP within each tumor indicated a heterogeneous spatial distribution of BP values. The results of this study show that the combination of fluorescent probe preassembly and PAI is a promising new way to rapidly develop targeted fluorescent probes for tumors with high BP and eventual use in clinical applications such as targeted therapy, image guided surgery, and personalized medicine.
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Affiliation(s)
- Cynthia L. Schreiber
- Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Canjia Zhai
- Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Janel M. Dempsey
- Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Hannah H. McGarraugh
- Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Braden P. Matthews
- Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Caroline R. Christmann
- Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Bradley Smith
- Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA
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Deh K, Zaman M, Vedvyas Y, Liu Z, Gillen KM, O' Malley P, Bedretdinova D, Nguyen T, Lee R, Spincemaille P, Kim J, Wang Y, Jin MM. Validation of MRI quantitative susceptibility mapping of superparamagnetic iron oxide nanoparticles for hyperthermia applications in live subjects. Sci Rep 2020; 10:1171. [PMID: 31980695 PMCID: PMC6981186 DOI: 10.1038/s41598-020-58219-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 01/10/2020] [Indexed: 02/06/2023] Open
Abstract
The use of magnetic fluid hyperthermia (MFH) for cancer therapy has shown promise but lacks suitable methods for quantifying exogenous irons such as superparamagnetic iron oxide (SPIO) nanoparticles as a source of heat generation under an alternating magnetic field (AMF). Application of quantitative susceptibility mapping (QSM) technique to prediction of SPIO in preclinical models has been challenging due to a large variation of susceptibility values, chemical shift from tissue fat, and noisier data arising from the higher resolution required to visualize the anatomy of small animals. In this study, we developed a robust QSM for the SPIO ferumoxytol in live mice to examine its potential application in MFH for cancer therapy. We demonstrated that QSM was able to simultaneously detect high level ferumoxytol accumulation in the liver and low level localization near the periphery of tumors. Detection of ferumoxytol distribution in the body by QSM, however, required imaging prior to and post ferumoxytol injection to discriminate exogenous iron susceptibility from other endogenous sources. Intratumoral injection of ferumoxytol combined with AMF produced a ferumoxytol-dose dependent tumor killing. Histology of tumor sections corroborated QSM visualization of ferumoxytol distribution near the tumor periphery, and confirmed the spatial correlation of cell death with ferumoxytol distribution. Due to the dissipation of SPIOs from the injection site, quantitative mapping of SPIO distribution will aid in estimating a change in temperature in tissues, thereby maximizing MFH effects on tumors and minimizing side-effects by avoiding unwanted tissue heating.
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Affiliation(s)
- Kofi Deh
- Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Marjan Zaman
- Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Yogindra Vedvyas
- Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Zhe Liu
- Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA
| | | | - Padraic O' Malley
- Department of Urology, University of Florida, Gainesville, FL, 32610, USA
| | | | - Thanh Nguyen
- Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Richard Lee
- Urology, Weill Cornell Medicine, New York, NY, 10065, USA
| | | | - Juyoung Kim
- Department of Advanced Materials Engineering, Kangwon National University, Samcheok, 245-711, South Korea
| | - Yi Wang
- Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA.,Department of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA
| | - Moonsoo M Jin
- Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. .,Department of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA.
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12
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Chen Z, Li Y, Airan R, Han Z, Xu J, Chan KWY, Xu Y, Bulte JWM, van Zijl PCM, McMahon MT, Zhou S, Liu G. CT and CEST MRI bimodal imaging of the intratumoral distribution of iodinated liposomes. Quant Imaging Med Surg 2019; 9:1579-1591. [PMID: 31667143 DOI: 10.21037/qims.2019.06.10] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background To develop liposomes loaded with iodinated agents as nanosized CT/MRI bimodal contrast agents for monitoring liposome-mediated drug delivery. Methods Rhodamine-labeled iodixanol (VisipaqueTM)-loaded liposomes (IX-lipo) were prepared and tested for their properties as a diamagnetic CEST contrast agent in vitro. Mice bearing subcutaneous CT26 colon tumors were injected i.v. with 1 g/kg (535 mg iodine/kg) IX-lipo, and in vivo CT and CEST MR images were acquired on day 3. CT and CEST MR images were also acquired for tumor-bearing mice co-injected with IX-lipo and tumor necrosis factor (TNF-α). Results In addition to CT contrast, IX-lipo exhibited a strong CEST contrast similar to its non-liposomal form, with a detectability of ~2 nM per liposome. Both CT imaging and CEST MRI showed that i.v. injection of IX-lipo resulted in a rim enhancement of CT26 tumors with a heterogeneous central distribution. In contrast, co-injection of TNF-α caused a significantly augmented CT/MRI contrast in the tumor center. The intratumoral biodistribution of IX-lipo correlated well to the rhodamine patterns observed with fluorescence microscopy. Conclusions We have developed a CT/MRI bimodal imaging approach for monitoring the delivery and biodistribution of liposomes by loading them with the clinically approved X-ray/CT contrast agent iodixanol. Our approach may be easily adapted for other-FDA approved iodinated agents and thus has great translational potential.
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Affiliation(s)
- Zelong Chen
- Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuguo Li
- Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA
| | - Raag Airan
- Department of Radiology, Stanford University Medical Center, Stanford, CA, USA
| | - Zheng Han
- Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA
| | - Jiadi Xu
- Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA
| | - Kannie W Y Chan
- Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA.,Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Yikai Xu
- Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jeff W M Bulte
- Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA.,Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Peter C M van Zijl
- Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA
| | - Michael T McMahon
- Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA
| | - Shibin Zhou
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Guanshu Liu
- Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA
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13
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Zhao N, Leng Q, Woodle MC, Mixson AJ. Enhanced tumor uptake and activity of nanoplex-loaded doxorubicin. Biochem Biophys Res Commun 2019; 513:242-247. [PMID: 30954222 DOI: 10.1016/j.bbrc.2019.03.190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 03/28/2019] [Indexed: 11/28/2022]
Abstract
Doxorubicin (Dox) has widespread use as a cancer chemotherapeutic agent, but Dox is limited by several side effects including irreversible cardiomyopathy. Although liposomal Dox formulations, such as Doxil, mitigate side effects, they do not prolong survival in many patients. As a result, efforts have continued to discover improved formulations of Dox. We previously found that a peptide-based nanoplex delivered plasmid DNA efficiently to tumors in murine models. Unlike the majority of nanoparticles that depend solely on enhanced permeability and retention (EPR) for their transport into the tumor, our peptide-based nanoplex has a potential advantage in that its uptake primarily depends on neuropilin-1 receptor targeting. Because Dox binds to DNA, we tested whether this delivery platform could effectively deliver Dox to tumors and reduce their size. The nanoplexes increased the levels of Dox in tumors by about 5.5-fold compared to aqueous (free) Dox controls. Consistent with enhanced levels in the tumor, the nanoplex-Dox treatment had significantly greater anti-tumor activity. Whereas low dose free Dox did not reduce the size of tumors compared to untreated controls, the low dose nanoplex-Dox reduced the size of tumors by nearly 55% (p < 0.001). The high dose nanoplex-Dox also inhibited the size of tumor significantly more than the comparable high-dose free Dox (p < 0.001). Furthermore, apoptosis and proliferation markers (Ki67) of tumors observed in the different treatment groups correlated with their ability to inhibit tumor size. This study shows the efficacy of an NRP-1 targeted nanoplexes to deliver Dox to tumors in vivo and lays the groundwork for more complex and effective formulations.
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Affiliation(s)
- Na Zhao
- Department of Pathology, University Maryland School of Medicine, Baltimore, MD, 21201, United States; Current Address-Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, 510300, China
| | - Qixin Leng
- Department of Pathology, University Maryland School of Medicine, Baltimore, MD, 21201, United States
| | - Martin C Woodle
- Aparna Biosciences Corp, 9119 Gaither Rd., Gaithersburg, MD, 20877, United States
| | - A James Mixson
- Department of Pathology, University Maryland School of Medicine, Baltimore, MD, 21201, United States.
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14
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Abstract
Cancer has been shown to negatively stimulate autophagy, leading to a decline in cardiac function. Although exercise is cardioprotective, its influence over autophagy-mediated tumor growth and cardiac function are not well defined. PURPOSE This study aimed to determine the effect of exercise on tumor morphology and cardiac function. METHODS Fisher 344 rats (n = 28) were assigned to one of four groups: 1) sedentary non-tumor bearing (SED), 2) sedentary tumor bearing (SED + T), 3) wheel run non-tumor bearing (WR), or 4) wheel run tumor bearing (WR + T). Rats remained sedentary or exercised for 6 wk. At week 4, rats in tumor groups were inoculated with MatBIII tumor cells. At week 6, cardiac function was measured. RESULTS SED + T animals exhibited significantly lower left ventricular developed pressure when compared with SED, WR, and WR + T (P < 0.05). This coincided with a significant increase in cardiac autophagy (increased LC3-II) in SED + T animals when compared with SED, WR, and WR + T (P < 0.05). Furthermore, SED + T hearts showed a significant increase in β-myosin heavy chain expression versus nontumor groups (P < 0.05). Tumor mass was significantly larger (P < 0.001) in SED + T animals when compared with WR + T animals, which was accompanied by a significant increase in tumor LC3-II protein expression (P < 0.05). CONCLUSION Nonexercised tumor-bearing rats showed severe cardiac dysfunction and excessive, maladaptive autophagy in the heart and tumors. Voluntary exercise preserved cardiac function and attenuated the autophagic response in heart and tumor tissues. This preservation may be related to the reduced tumor growth in aerobically exercised rats, to the improved regulation of autophagy by exercise, or both.
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Affiliation(s)
- Traci L Parry
- McAllister Heart Institute and Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC
| | - Reid Hayward
- School of Sport and Exercise Science, and the University of Northern Colorado Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO
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15
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Koç MM, Aslan N, Kao AP, Barber AH. Evaluation of X-ray tomography contrast agents: A review of production, protocols, and biological applications. Microsc Res Tech 2019; 82:812-848. [PMID: 30786098 DOI: 10.1002/jemt.23225] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/02/2019] [Accepted: 01/12/2019] [Indexed: 12/25/2022]
Abstract
X-ray computed tomography is a strong tool that finds many applications both in medical applications and in the investigation of biological and nonbiological samples. In the clinics, X-ray tomography is widely used for diagnostic purposes whose three-dimensional imaging in high resolution helps physicians to obtain detailed image of investigated regions. Researchers in biological sciences and engineering use X-ray tomography because it is a nondestructive method to assess the structure of their samples. In both medical and biological applications, visualization of soft tissues and structures requires special treatment, in which special contrast agents are used. In this detailed report, molecule-based and nanoparticle-based contrast agents used in biological applications to enhance the image quality were compiled and reported. Special contrast agent applications and protocols to enhance the contrast for the biological applications and works to develop nanoparticle contrast agents to enhance the contrast for targeted drug delivery and general imaging applications were also assessed and listed.
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Affiliation(s)
- Mümin Mehmet Koç
- School of Engineering, University of Portsmouth, Portsmouth, United Kingdom.,Department of Physics, Kirklareli University, Kirklareli, Turkey
| | - Naim Aslan
- Department of Metallurgical and Materials Engineering, Munzur University, Tunceli, Turkey
| | - Alexander P Kao
- School of Engineering, University of Portsmouth, Portsmouth, United Kingdom
| | - Asa H Barber
- School of Engineering, London South Bank University, London, United Kingdom
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16
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Xu J, Seung-Young Lee S, Seo H, Pang L, Jun Y, Zhang RY, Zhang ZY, Kim P, Lee W, Kron SJ, Yeo Y. Quinic Acid-Conjugated Nanoparticles Enhance Drug Delivery to Solid Tumors via Interactions with Endothelial Selectins. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2018; 14:e1803601. [PMID: 30411856 PMCID: PMC6361670 DOI: 10.1002/smll.201803601] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/11/2018] [Indexed: 05/26/2023]
Abstract
Current nanoparticle (NP) drug carriers mostly depend on the enhanced permeability and retention (EPR) effect for selective drug delivery to solid tumors. However, in the absence of a persistent EPR effect, the peritumoral endothelium can function as an access barrier to tumors and negatively affect the effectiveness of NPs. In recognition of the peritumoral endothelium as a potential barrier in drug delivery to tumors, poly(lactic-co-glycolic acid) (PLGA) NPs are modified with a quinic acid (QA) derivative, synthetic mimic of selectin ligands. QA-decorated NPs (QA-NP) interact with human umbilical vein endothelial cells expressing E-/P-selectins and induce transient increase in endothelial permeability to translocate across the layer. QA-NP reach selectin-upregulated tumors, achieving greater tumor accumulation and paclitaxel (PTX) delivery than polyethylene glycol-decorated NPs (PEG-NP). PTX-loaded QA-NP show greater anticancer efficacy than Taxol or PTX-loaded PEG-NP at the equivalent PTX dose in different animal models and dosing regimens. Repeated dosing of PTX-loaded QA-NP for two weeks results in complete tumor remission in 40-60% of MDA-MB-231 tumor-bearing mice, while those receiving control treatments succumb to death. QA-NP can exploit the interaction with selectin-expressing peritumoral endothelium and deliver anticancer drugs to tumors to a greater extent than the level currently possible with the EPR effect.
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Affiliation(s)
- Jun Xu
- Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA,
| | - Steve Seung-Young Lee
- Ludwig Center for Metastasis Research, The University of Chicago, 5758 South Maryland Avenue, MC 9006, and Department of Molecular Genetics and Cellular Biology, The University of Chicago, 929 East 57th Street, GCIS W519, Chicago, IL 60637, USA
| | - Howon Seo
- Graduate School of Nanoscience and Technology and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Liang Pang
- Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, People’s Republic of China
| | - Yearin Jun
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Ruo-Yu Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
| | - Pilhan Kim
- Graduate School of Nanoscience and Technology and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea; Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Wooin Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Stephen J. Kron
- Ludwig Center for Metastasis Research, The University of Chicago, 5758 South Maryland Avenue, MC 9006, and Department of Molecular Genetics and Cellular Biology, The University of Chicago, 929 East 57th Street, GCIS W519, Chicago, IL 60637, USA
| | - Yoon Yeo
- Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA, ; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
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17
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Gao X, Guo L, Li J, Thu HE, Hussain Z. Nanomedicines guided nanoimaging probes and nanotherapeutics for early detection of lung cancer and abolishing pulmonary metastasis: Critical appraisal of newer developments and challenges to clinical transition. J Control Release 2018; 292:29-57. [PMID: 30359665 DOI: 10.1016/j.jconrel.2018.10.024] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/17/2018] [Accepted: 10/19/2018] [Indexed: 01/13/2023]
Abstract
Lung cancer (LC) is the second most prevalent type of cancer and primary cause of mortality among both men and women, worldwide. The most commonly employed diagnostic modalities for LC include chest X-ray (CXR), magnetic-resonance-imaging (MRI), computed tomography (CT-scan), and fused-positron-emitting-tomography-CT (PET-CT). Owing to several limitations associated with the use of conventional diagnostic tools such as radiation burden to the patient, misleading diagnosis ("missed lung cancer"), false staging and low sensitivity and resolution, contemporary diagnostic regimen needed to be employed for screening of LC. In recent decades, nanotechnology-guided interventions have been transpired as emerging nanoimaging probes for detection of LC at advanced stages, while producing signal amplification, better resolution for surface and deep tissue imaging, and enhanced translocation and biodistribution of imaging probes within the cancerous tissues. Besides enormous potential of nanoimaging probes, nanotechnology-based advancements have also been evidenced for superior efficacy for treatment of LC and abolishing pulmonary metastasis (PM). The success of nanotherapeutics is due to their ability to maximise translocation and biodistribution of anti-neoplastic agents into the tumor tissues, improve pharmacokinetic profiles of anti-metastatic agents, optimise target-specific drug delivery, and control release kinetics of encapsulated moieties in target tissues. This review aims to overview and critically discuss the superiority of nanoimaging probes and nanotherapeutics over conventional regimen for early detection of LC and abolishing PM. Current challenges to clinical transition of nanoimaging probes and therapeutic viability of nanotherapeutics for treatment for LC and PM have also been pondered.
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Affiliation(s)
- Xiaoling Gao
- Department of Respiratory and Critical Care Medicine, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Lihua Guo
- Department of Nephrology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China
| | - Jianqiang Li
- Department of Respiratory and Critical Care Medicine, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Hnin Ei Thu
- Department of Pharmacology and Dental Therapeutics, Faculty of Dentistry, Lincoln University College, Jalan Stadium, SS 7/15, Kelana Jaya, 47301 Petaling Jaya, Selangor, Malaysia
| | - Zahid Hussain
- Department of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM) Selangor, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia.
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18
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Ayala-Domínguez L, Brandan ME. Quantification of tumor angiogenesis with contrast-enhanced x-ray imaging in preclinical studies: a review. Biomed Phys Eng Express 2018; 4. [DOI: 10.1088/2057-1976/aadc2d] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/22/2018] [Indexed: 01/01/2023]
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19
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Peiris PM, He F, Covarrubias G, Raghunathan S, Turan O, Lorkowski M, Gnanasambandam B, Wu C, Schiemann WP, Karathanasis E. Precise targeting of cancer metastasis using multi-ligand nanoparticles incorporating four different ligands. NANOSCALE 2018; 10:6861-6871. [PMID: 29620124 PMCID: PMC5908762 DOI: 10.1039/c8nr02513d] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Metastasis displays a highly heterogeneous cellular population with cancer cells continuously evolving. As a result, a single-ligand nanoparticle cannot account for the continuously changing expression of targetable biomarkers over time and space. To effectively direct nanoparticles to metastasis, we developed a multi-ligand nanoparticle by using four different types of ligands on the same nanoparticle that target biomarkers on the endothelium associated with metastatic disease. These vascular targets included αvβ3 integrin, P-selectin, EGFR and fibronectin. Using terminal and in vivo imaging studies, the targeting performance of the multi-ligand nanoparticles was compared to the single-ligand nanoparticle variants. All four single-ligand nanoparticle variants achieved significant targeting of lung metastasis in the 4T1 mouse model of breast cancer metastasis with about 2.5% of the injected dose being deposited into metastasis. A dual-ligand nanoparticle resulted in a nearly 2-fold higher deposition into lung metastases than its single-ligand counterparts. The multi-ligand nanoparticle significantly outperformed its targeting nanoparticle counterparts achieving a deposition of ∼7% of its injected nanoparticles into lung metastases. Using the high sensitivity of radionuclide imaging, PET imaging showed that a multi-ligand nanoparticle labeled with [18F]fluoride was able to precisely target metastatic disease at its very early stage of development in three different animal models of metastatic breast cancer.
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Affiliation(s)
- P M Peiris
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA.
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20
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Momcilovic M, Shackelford DB. Imaging Cancer Metabolism. Biomol Ther (Seoul) 2018; 26:81-92. [PMID: 29212309 PMCID: PMC5746040 DOI: 10.4062/biomolther.2017.220] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 11/11/2017] [Accepted: 11/13/2017] [Indexed: 12/23/2022] Open
Abstract
It is widely accepted that altered metabolism contributes to cancer growth and has been described as a hallmark of cancer. Our view and understanding of cancer metabolism has expanded at a rapid pace, however, there remains a need to study metabolic dependencies of human cancer in vivo. Recent studies have sought to utilize multi-modality imaging (MMI) techniques in order to build a more detailed and comprehensive understanding of cancer metabolism. MMI combines several in vivo techniques that can provide complementary information related to cancer metabolism. We describe several non-invasive imaging techniques that provide both anatomical and functional information related to tumor metabolism. These imaging modalities include: positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) that uses hyperpolarized probes and optical imaging utilizing bioluminescence and quantification of light emitted. We describe how these imaging modalities can be combined with mass spectrometry and quantitative immunochemistry to obtain more complete picture of cancer metabolism. In vivo studies of tumor metabolism are emerging in the field and represent an important component to our understanding of how metabolism shapes and defines cancer initiation, progression and response to treatment. In this review we describe in vivo based studies of cancer metabolism that have taken advantage of MMI in both pre-clinical and clinical studies. MMI promises to advance our understanding of cancer metabolism in both basic research and clinical settings with the ultimate goal of improving detection, diagnosis and treatment of cancer patients.
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Affiliation(s)
- Milica Momcilovic
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, Los Angeles, CA, 90095, USA
| | - David B Shackelford
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, Los Angeles, CA, 90095, USA
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21
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Yonucu S, Yιlmaz D, Phipps C, Unlu MB, Kohandel M. Quantifying the effects of antiangiogenic and chemotherapy drug combinations on drug delivery and treatment efficacy. PLoS Comput Biol 2017; 13:e1005724. [PMID: 28922358 PMCID: PMC5633204 DOI: 10.1371/journal.pcbi.1005724] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 10/09/2017] [Accepted: 08/14/2017] [Indexed: 11/18/2022] Open
Abstract
Tumor-induced angiogenesis leads to the development of leaky tumor vessels devoid of structural and morphological integrity. Due to angiogenesis, elevated interstitial fluid pressure (IFP) and low blood perfusion emerge as common properties of the tumor microenvironment that act as barriers for drug delivery. In order to overcome these barriers, normalization of vasculature is considered to be a viable option. However, insight is needed into the phenomenon of normalization and in which conditions it can realize its promise. In order to explore the effect of microenvironmental conditions and drug scheduling on normalization benefit, we build a mathematical model that incorporates tumor growth, angiogenesis and IFP. We administer various theoretical combinations of antiangiogenic agents and cytotoxic nanoparticles through heterogeneous vasculature that displays a similar morphology to tumor vasculature. We observe differences in drug extravasation that depend on the scheduling of combined therapy; for concurrent therapy, total drug extravasation is increased but in adjuvant therapy, drugs can penetrate into deeper regions of tumor.
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Affiliation(s)
- Sirin Yonucu
- Department of Physics, Bogazici University, Bebek, Istanbul, Turkey
- Center for Life Sciences and Technologies, Bogazici University, Bebek, Istanbul, Turkey
| | - Defne Yιlmaz
- Department of Physics, Bogazici University, Bebek, Istanbul, Turkey
- Center for Life Sciences and Technologies, Bogazici University, Bebek, Istanbul, Turkey
| | - Colin Phipps
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Mehmet Burcin Unlu
- Department of Physics, Bogazici University, Bebek, Istanbul, Turkey
- Center for Life Sciences and Technologies, Bogazici University, Bebek, Istanbul, Turkey
- * E-mail:
| | - Mohammad Kohandel
- Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada
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22
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Perry JL, Reuter KG, Luft JC, Pecot CV, Zamboni W, DeSimone JM. Mediating Passive Tumor Accumulation through Particle Size, Tumor Type, and Location. NANO LETTERS 2017; 17:2879-2886. [PMID: 28287740 PMCID: PMC5708115 DOI: 10.1021/acs.nanolett.7b00021] [Citation(s) in RCA: 186] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
As the enhanced permeation and retention (EPR) effect continues to be a controversial topic in nanomedicine, we sought to examine EPR as a function of nanoparticle size, tumor model, and tumor location, while also evaluating tumors for EPR mediating factors such as microvessel density, vascular permeability, lymphatics, stromal content, and tumor-associated immune cells. Tumor accumulation was evaluated for 55 × 60, 80 × 180, and 80 × 320 nm PRINT particles in four subcutaneous flank tumor models (SKOV3 human ovarian, 344SQ murine nonsmall cell lung, A549 human nonsmall cell lung, and A431 human epidermoid cancer). Each tumor model revealed specific particle accumulation trends with evident particle size dependence. Immuno-histochemistry staining revealed differences in tumor microvessel densities that correlated with overall tumor accumulation. Immunofluorescence images displayed size-mediated tumor penetration with signal from the larger particles concentrated close to the blood vessels, while signal from the smaller particle was observed throughout the tissue. Differences were also observed for the 55 × 60 nm particle tumor penetration across flank tumor models as a function of stromal content. The 55 × 60 nm particles were further evaluated in three orthotopic, metastatic tumor models (344SQ, A549, and SKOV3), revealing preferential accumulation in primary tumors and metastases over healthy tissue. Moreover, we observed higher tumor accumulation in the orthotopic lung cancer models than in the flank lung cancer models, whereas tumor accumulation was constant for both orthotopic and flank ovarian cancer models, further demonstrating the variability in the EPR effect as a function of tumor model and location.
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Affiliation(s)
- Jillian L. Perry
- Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Kevin G. Reuter
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - J. Christopher Luft
- UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Chad V. Pecot
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- Division of Hematology/Oncology, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - William Zamboni
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- Institute for Nanomedicine, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Joseph M. DeSimone
- Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- Institute for Nanomedicine, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina 27695, United States
- Corresponding Author:
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23
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Siddiqui S, Kadlecek S, Pourfathi M, Xin Y, Mannherz W, Hamedani H, Drachman N, Ruppert K, Clapp J, Rizi R. The use of hyperpolarized carbon-13 magnetic resonance for molecular imaging. Adv Drug Deliv Rev 2017; 113:3-23. [PMID: 27599979 PMCID: PMC5783573 DOI: 10.1016/j.addr.2016.08.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 08/25/2016] [Accepted: 08/27/2016] [Indexed: 02/06/2023]
Abstract
Until recently, molecular imaging using magnetic resonance (MR) has been limited by the modality's low sensitivity, especially with non-proton nuclei. The advent of hyperpolarized (HP) MR overcomes this limitation by substantially enhancing the signal of certain biologically important probes through a process known as external nuclear polarization, enabling real-time assessment of tissue function and metabolism. The metabolic information obtained by HP MR imaging holds significant promise in the clinic, where it could play a critical role in disease diagnosis and therapeutic monitoring. This review will provide a comprehensive overview of the developments made in the field of hyperpolarized MR, including advancements in polarization techniques and delivery, probe development, pulse sequence optimization, characterization of healthy and diseased tissues, and the steps made towards clinical translation.
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Affiliation(s)
- Sarmad Siddiqui
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Stephen Kadlecek
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mehrdad Pourfathi
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Electrical and Systems Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Yi Xin
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - William Mannherz
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hooman Hamedani
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicholas Drachman
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kai Ruppert
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Justin Clapp
- Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rahim Rizi
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
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24
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Yin XX, Hadjiloucas S, Chen JH, Zhang Y, Wu JL, Su MY. Tensor based multichannel reconstruction for breast tumours identification from DCE-MRIs. PLoS One 2017; 12:e0172111. [PMID: 28282379 PMCID: PMC5345763 DOI: 10.1371/journal.pone.0172111] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 01/31/2017] [Indexed: 11/18/2022] Open
Abstract
A new methodology based on tensor algebra that uses a higher order singular value decomposition to perform three-dimensional voxel reconstruction from a series of temporal images obtained using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is proposed. Principal component analysis (PCA) is used to robustly extract the spatial and temporal image features and simultaneously de-noise the datasets. Tumour segmentation on enhanced scaled (ES) images performed using a fuzzy C-means (FCM) cluster algorithm is compared with that achieved using the proposed tensorial framework. The proposed algorithm explores the correlations between spatial and temporal features in the tumours. The multi-channel reconstruction enables improved breast tumour identification through enhanced de-noising and improved intensity consistency. The reconstructed tumours have clear and continuous boundaries; furthermore the reconstruction shows better voxel clustering in tumour regions of interest. A more homogenous intensity distribution is also observed, enabling improved image contrast between tumours and background, especially in places where fatty tissue is imaged. The fidelity of reconstruction is further evaluated on the basis of five new qualitative metrics. Results confirm the superiority of the tensorial approach. The proposed reconstruction metrics should also find future applications in the assessment of other reconstruction algorithms.
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Affiliation(s)
- X. -X. Yin
- Centre for Applied Informatics School of Engineering and Science, Victoria University, Melbourne, Australia
- * E-mail: (XXY); (YZ); (JLW)
| | - S. Hadjiloucas
- School of Systems Engineering and Department of Bioengineering, University of Reading, Reading RG6 6AY, United Kingdom
| | - J. -H. Chen
- Tu & Yuen Center for Functional Onco-Imaging, Department of Radiological Sciences, University of California, Irvine, CA, United States of America
- Department of Radiology, EDa Hospital and I-Shou University, Kaohsiung, Taiwan
| | - Y. Zhang
- Centre for Applied Informatics School of Engineering and Science, Victoria University, Melbourne, Australia
- School of Computer Science, Fudan University, China
- * E-mail: (XXY); (YZ); (JLW)
| | - J. -L. Wu
- Department of Radiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
- * E-mail: (XXY); (YZ); (JLW)
| | - M. -Y. Su
- Tu & Yuen Center for Functional Onco-Imaging, Department of Radiological Sciences, University of California, Irvine, CA, United States of America
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25
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Ramanathan RK, Korn RL, Raghunand N, Sachdev JC, Newbold RG, Jameson G, Fetterly GJ, Prey J, Klinz SG, Kim J, Cain J, Hendriks BS, Drummond DC, Bayever E, Fitzgerald JB. Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study. Clin Cancer Res 2017; 23:3638-3648. [PMID: 28159813 DOI: 10.1158/1078-0432.ccr-16-1990] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 01/19/2017] [Accepted: 01/20/2017] [Indexed: 11/16/2022]
Abstract
Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI).Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2* signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI.Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman ρ = 0.7824; P = 0.0016).Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors. Clin Cancer Res; 23(14); 3638-48. ©2017 AACR.
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Affiliation(s)
- Ramesh K Ramanathan
- Virginia G Piper Cancer Center, Honor Healthcare, Scottsdale, Arizona. .,Translational Genomics Research Institute, Phoenix, Arizona
| | - Ronald L Korn
- Virginia G Piper Cancer Center, Honor Healthcare, Scottsdale, Arizona.,Imaging Endpoints, Scottsdale, Arizona
| | | | - Jasgit C Sachdev
- Virginia G Piper Cancer Center, Honor Healthcare, Scottsdale, Arizona
| | - Ronald G Newbold
- Virginia G Piper Cancer Center, Honor Healthcare, Scottsdale, Arizona.,Imaging Endpoints, Scottsdale, Arizona
| | - Gayle Jameson
- Virginia G Piper Cancer Center, Honor Healthcare, Scottsdale, Arizona
| | | | - Joshua Prey
- Roswell Park Cancer Institute, Buffalo, New York
| | | | - Jaeyeon Kim
- Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts
| | - Jason Cain
- Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts
| | | | | | - Eliel Bayever
- Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts
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26
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Ngoune R, Peters A, von Elverfeldt D, Winkler K, Pütz G. Accumulating nanoparticles by EPR: A route of no return. J Control Release 2016; 238:58-70. [PMID: 27448444 DOI: 10.1016/j.jconrel.2016.07.028] [Citation(s) in RCA: 152] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 07/13/2016] [Accepted: 07/17/2016] [Indexed: 11/26/2022]
Abstract
Nanoparticle-based drug delivery to ease anticancer therapy relies primarily on the enhanced permeability and retention effect (EPR). The leaky vascular structure in tumors allows extravasation of nanoparticles, often termed passive targeting. Long term retention of nanoparticles is attributed to the lack of lymphatic drainage, and unidirectional extravasation has been implied. Fluorescent liposomes with a plasma half-life of 29h were injected into tumor-bearing rats, and biodistribution in tumor, skin, paws and ears was monitored via in vivo fluorescence measurements. To calculate tissue accumulation, an algorithm was developed to subtract the blood signal from the total fluorescence recorded. Accumulation in tumor tissue was much higher than that in other tissues monitored, initially exhibiting very rapid accumulation followed by a long plateau phase with little change. Discontinuous plasmapheresis was established that was as effective as highly sophisticated clinical plasmapheresis. We observed no difference in the tumor tissue's accumulation when plasmapheresis was performed 22h after liposome injection. In contrast, plasmapheresis led to a significant inhibition of further accumulation in other tissues. When the liposomes' blood concentration was rapidly lowered, we detected no drop in tumor fluorescence. Thus extravasation via EPR is most likely a route of no return. These data support the emerging view of a more dynamic model of EPR, where gaps or entire vessels may open and close over time, or accumulated liposomes become entangled within the pores, hampering further accumulation.
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Affiliation(s)
- Romeo Ngoune
- University Freiburg Medical Center, Institute for Clinical Chemistry, Freiburg, Germany.
| | - Annette Peters
- University Freiburg Medical Center, Institute for Clinical Chemistry, Freiburg, Germany.
| | - Dominik von Elverfeldt
- University Freiburg Medical Center, Department of Diagnostic Radiology Medical Physics, Freiburg, Germany.
| | - Karl Winkler
- University Freiburg Medical Center, Institute for Clinical Chemistry, Freiburg, Germany.
| | - Gerhard Pütz
- University Freiburg Medical Center, Institute for Clinical Chemistry, Freiburg, Germany.
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27
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Wang D, Fu J, Shi Y, Peng D, Yuan L, He B, Dai W, Zhang H, Wang X, Tian J, Zhang Q. The modulation of tumor vessel permeability by thalidomide and its impacts on different types of targeted drug delivery systems in a sarcoma mouse model. J Control Release 2016; 238:186-196. [PMID: 27422610 DOI: 10.1016/j.jconrel.2016.07.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Revised: 06/20/2016] [Accepted: 07/09/2016] [Indexed: 02/08/2023]
Abstract
The transport of nanocarriers is supposed to be based on EPR effect which is affected by diverse factors, so the modulation of EPR effect seems very significant for nanocarriers including targeted drug delivery systems (TDDSs). Besides, it is extremely unclear how the EPR effect impacts the fate of different types of TDDSs. To make the most advantage of EPR effect for TDDSs, it is definitely necessary to clarify these key issues. Here, we construct and characterize various TDDSs, including sterically-stabilized liposomes (SSL), RGD functionalized SSL (RGD-SSL) and novel 7PEP functionalized SSL (7PEP-SSL), loaded with doxorubicin (DOX), DIR or DID. Here, we modulate the permeability of tumor vessels by thalidomide (THD) in a sarcoma-bearing EPR mouse model via monitoring endogenous deoxygenated hemoglobin in circulation, and then we confirm the effect of THD on tumor vessel permeability by vessel density, vessel maturity, VEGF expression and so on. Importantly, we investigate and find the impacts of EPR effect on the antitumor efficacy, in vivo distribution and intratumoral microdistribution of the three TDDSs. Interestingly, the EPR effects affect different TDDSs differently. The elevated EPR effect enhances the tumor accumulation of SSL and RGD-SSL but fails to increase their efficacy. The RGD-SSL exhibits the best efficacy with the least fluctuation, demonstrating the advantage of angiogenesis targeted systems. 7PEP-SSL seems the biggest beneficiary of EPR effect, suggesting the significance of EPR modulation for cells targeted systems. Generally, this study demonstrates the feasibility of modulating EPR effect bidirectionally by THD as well as the impacts of EPR effect on different type of testing TDDSs based on this animal model. It certainly provides novel insight into the design and potential use of TDDSs.
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Affiliation(s)
- Dan Wang
- Beijing Key Laboratory of Molecular Pharmaceutics and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
| | - Jijun Fu
- Beijing Key Laboratory of Molecular Pharmaceutics and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
| | - Yujie Shi
- Beijing Key Laboratory of Molecular Pharmaceutics and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
| | - Dong Peng
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Lan Yuan
- Medical and Healthy Analytical Center, Peking University, Beijing 100191, China
| | - Bing He
- Beijing Key Laboratory of Molecular Pharmaceutics and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
| | - Wenbing Dai
- Beijing Key Laboratory of Molecular Pharmaceutics and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
| | - Hua Zhang
- Beijing Key Laboratory of Molecular Pharmaceutics and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
| | - Xueqing Wang
- Beijing Key Laboratory of Molecular Pharmaceutics and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
| | - Jie Tian
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Qiang Zhang
- Beijing Key Laboratory of Molecular Pharmaceutics and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
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28
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Abstract
Aggressive surgical resection is the primary therapy for glioma. However, aggressive resection may compromise functional healthy brain tissue. Currently, there are no objective cues for surgeons to distinguish healthy tissue from tumor and determine tumor borders; surgeons skillfully rely on subjective means such as tactile feedback. This often results in incomplete resection and recurrence. The objective of the present study was to design, develop, and evaluate, in vitro and in vivo, a nanoencapsulated visible dye for intraoperative, visual delineation of tumor margins in an invasive tumor model. Liposomal nanocarriers containing Evans blue dye (nano-EB) were developed, characterized, and tested for safety in vitro and in vivo. 3RT1RT2A glioma cells were implanted into brains of Fischer 344 rats. Nano-EB or EB solution was injected via tail vein into tumor-bearing animals. To assess tumor staining, tissue samples were analyzed visibly and using fluorescence microscopy. Area, perimeter ratios, and Manders overlap coefficients were calculated to quantify extent of staining. Nano-EB clearly marked tumor margins in the invasive tumor model. Area ratio of nano-EB staining to tumor was 0.89 ± 0.05, perimeter ratio was 0.94 ± 0.04, Manders R was 0.51 ± 0.08, and M1 was 0.97 ± 0.06. Microscopic tumor border inspection under high magnification verified that nano-EB did not stain healthy tissue. Nano-EB clearly aids in distinguishing tumor tissue from healthy tissue in an invasive tumor model, while injection of unencapsulated EB results in false identification of healthy tissue as tumor due to diffusion of dye from the tumor into healthy tissue.
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29
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Parry TL, Hayward R. Exercise training does not affect anthracycline antitumor efficacy while attenuating cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol 2015; 309:R675-83. [PMID: 26246505 DOI: 10.1152/ajpregu.00185.2015] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 08/03/2015] [Indexed: 11/22/2022]
Abstract
Highly effective anthracyclines, like doxorubicin (DOX), have limited clinical use due to protracted cardiotoxic effects. While exercise is known to be cardioprotective, it is unclear whether exercise compromises chemotherapy treatment efficacy. To determine the effect of exercise training on DOX antitumor efficacy as well as DOX-induced cardiotoxicity, female Fisher 344 rats were randomly assigned to sedentary + saline (SED+SAL), SED+DOX, wheel run exercise training + SAL (WR+SAL), or WR+DOX. On week 11, animals were inoculated with 1×10(6) MatBIII tumor cells. Once tumors reached ∼1 cm in diameter, animals were treated with 12 mg/kg of DOX or SAL. Animals were killed 1, 3, or 5 days following treatment. Tumor growth and cardiac function were measured at each interval. DOX accumulation and multidrug resistance protein (MRP) expression were quantified in tumor and heart tissue. No significant difference (P > 0.05) existed between DOX-treated SED and WR groups for tumor measurements. Exercise preserved cardiac function up to 5 days following DOX treatment. Exercise reduced ventricular DOX accumulation and upregulated ventricular MPR1 and MPR2. In contrast, no differences were observed in DOX accumulation or MRP expression in tumors of SED and WR animals. Endurance exercise had no effect on DOX antitumor efficacy as evidenced by a definitive DOX-induced reduction in tumor growth in both the SED and WR groups. Although exercise did not affect the antitumor efficacy of DOX, it still provided protection against cardiac dysfunction. These effects may be mediated by the degree of DOX tissue accumulation secondary to the regulation of MRP expression.
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Affiliation(s)
- Traci L Parry
- School of Sport and Exercise Science, University of Northern Colorado, Greeley, Colorado; and Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, Colorado
| | - Reid Hayward
- School of Sport and Exercise Science, University of Northern Colorado, Greeley, Colorado; and Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, Colorado
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30
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Zhao YJ, Han HZ, Liang Y, Shi CZ, Zhu QC, Yang J. Alternative splicing of VEGFA, APP and NUMB genes in colorectal cancer. World J Gastroenterol 2015; 21:6550-60. [PMID: 26074693 PMCID: PMC4458765 DOI: 10.3748/wjg.v21.i21.6550] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Revised: 02/10/2015] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate alternative splicing in vascular endothelial growth factor A (VEGFA), amyloid beta precursor protein (APP), and Numb homolog (NUMB) in colorectal cancer (CRC). METHODS Real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and PCR-restriction fragment length polymorphism analyses were performed to detect the expression of VEGFA, APP, and NUMB mRNA in 20 CRC tissues and matched adjacent normal tissues, as well as their alternative splicing variants. RESULTS qRT-PCR analysis revealed that the expression of APP, NUMB, and VEGFA165b mRNA were significantly downregulated, while VEGFA mRNA was upregulated, in CRC tissues (all P < 0.05). PCR-restriction fragment length polymorphism analysis revealed that the expression of VEGFA165a/b in CRC tissues was significantly higher than in adjacent normal tissues (P < 0.05). Compared with adjacent normal tissues, the expression of NUMB-PRR(S) in CRC tissues was significantly decreased (P < 0.05), and the expression of NUMB-PRR(L) was increased (P < 0.05). CONCLUSION Alternative splicing of VEGFA, APP, and NUMB may regulate the development of CRC, and represent new targets for its diagnosis, prognosis, and treatment.
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31
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Ekdawi SN, Stewart JM, Dunne M, Stapleton S, Mitsakakis N, Dou YN, Jaffray DA, Allen C. Spatial and temporal mapping of heterogeneity in liposome uptake and microvascular distribution in an orthotopic tumor xenograft model. J Control Release 2015; 207:101-11. [DOI: 10.1016/j.jconrel.2015.04.006] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Revised: 03/21/2015] [Accepted: 04/04/2015] [Indexed: 01/01/2023]
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32
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Toy R, Bauer L, Hoimes C, Ghaghada KB, Karathanasis E. Targeted nanotechnology for cancer imaging. Adv Drug Deliv Rev 2014; 76:79-97. [PMID: 25116445 PMCID: PMC4169743 DOI: 10.1016/j.addr.2014.08.002] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 07/26/2014] [Accepted: 08/04/2014] [Indexed: 02/02/2023]
Abstract
Targeted nanoparticle imaging agents provide many benefits and new opportunities to facilitate accurate diagnosis of cancer and significantly impact patient outcome. Due to the highly engineerable nature of nanotechnology, targeted nanoparticles exhibit significant advantages including increased contrast sensitivity, binding avidity and targeting specificity. Considering the various nanoparticle designs and their adjustable ability to target a specific site and generate detectable signals, nanoparticles can be optimally designed in terms of biophysical interactions (i.e., intravascular and interstitial transport) and biochemical interactions (i.e., targeting avidity towards cancer-related biomarkers) for site-specific detection of very distinct microenvironments. This review seeks to illustrate that the design of a nanoparticle dictates its in vivo journey and targeting of hard-to-reach cancer sites, facilitating early and accurate diagnosis and interrogation of the most aggressive forms of cancer. We will report various targeted nanoparticles for cancer imaging using X-ray computed tomography, ultrasound, magnetic resonance imaging, nuclear imaging and optical imaging. Finally, to realize the full potential of targeted nanotechnology for cancer imaging, we will describe the challenges and opportunities for the clinical translation and widespread adaptation of targeted nanoparticles imaging agents.
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Affiliation(s)
- Randall Toy
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lisa Bauer
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Physics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Christopher Hoimes
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA; University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Ketan B Ghaghada
- Edward B. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA; Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Radiology, Case Western Reserve University, Cleveland, OH 44106, USA.
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Wang L, Fan Z, Zhang J, Changyi Y, Huang C, Gu Y, Xu Z, Tang Z, Lu W, Wei X, Li C. Evaluating tumor metastatic potential by imaging intratumoral acidosisviapH-activatable near-infrared fluorescent probe. Int J Cancer 2014; 136:E107-16. [DOI: 10.1002/ijc.29153] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 08/12/2014] [Accepted: 08/15/2014] [Indexed: 12/16/2022]
Affiliation(s)
- Lu Wang
- Key Laboratory of Smart Drug Delivery; Ministry of Education, School of Pharmacy, Fudan University; Shanghai 201203 China
| | - Zhichao Fan
- Med-X Research Institute and School of Biomedical Engineering; Shanghai Jiao Tong University; Shanghai 200030 China
| | - Jingye Zhang
- Key Laboratory of Smart Drug Delivery; Ministry of Education, School of Pharmacy, Fudan University; Shanghai 201203 China
| | - Yinzhi Changyi
- Key Laboratory of Smart Drug Delivery; Ministry of Education, School of Pharmacy, Fudan University; Shanghai 201203 China
| | - Cuiyun Huang
- Key Laboratory of Smart Drug Delivery; Ministry of Education, School of Pharmacy, Fudan University; Shanghai 201203 China
| | - Yanjuan Gu
- Department of Applied Biology and Chemical Technology; The Hong Kong Polytechnic University, Hung Hom; Kowloon Hong Kong China
| | - Ziyao Xu
- Key Laboratory of Smart Drug Delivery; Ministry of Education, School of Pharmacy, Fudan University; Shanghai 201203 China
| | - Zhijia Tang
- Key Laboratory of Smart Drug Delivery; Ministry of Education, School of Pharmacy, Fudan University; Shanghai 201203 China
| | - Weiyue Lu
- Key Laboratory of Smart Drug Delivery; Ministry of Education, School of Pharmacy, Fudan University; Shanghai 201203 China
| | - Xunbin Wei
- Med-X Research Institute and School of Biomedical Engineering; Shanghai Jiao Tong University; Shanghai 200030 China
| | - Cong Li
- Key Laboratory of Smart Drug Delivery; Ministry of Education, School of Pharmacy, Fudan University; Shanghai 201203 China
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Toy R, Peiris PM, Ghaghada KB, Karathanasis E. Shaping cancer nanomedicine: the effect of particle shape on the in vivo journey of nanoparticles. Nanomedicine (Lond) 2014; 9:121-34. [PMID: 24354814 DOI: 10.2217/nnm.13.191] [Citation(s) in RCA: 393] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Recent advances in nanoparticle technology have enabled the fabrication of nanoparticle classes with unique sizes, shapes and materials, which in turn has facilitated major advancements in the field of nanomedicine. More specifically, in the last decade, nanoscientists have recognized that nanomedicine exhibits a highly engineerable nature that makes it a mainstream scientific discipline that is governed by its own distinctive principles in terms of interactions with cells and intravascular, transvascular and interstitial transport. This review focuses on the recent developments and understanding of the relationship between the shape of a nanoparticle and its navigation through different biological processes. It also seeks to illustrate that the shape of a nanoparticle can govern its in vivo journey and destination, dictating its biodistribution, intravascular and transvascular transport, and, ultimately, targeting of difficult to reach cancer sites.
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Affiliation(s)
- Randall Toy
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
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Ogawara KI, Abe S, Un K, Yoshizawa Y, Kimura T, Higaki K. Determinants for in vivo antitumor effect of angiogenesis inhibitor SU5416 formulated in PEGylated emulsion. J Pharm Sci 2014; 103:2464-9. [PMID: 24985750 DOI: 10.1002/jps.24071] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Revised: 05/13/2014] [Accepted: 06/10/2014] [Indexed: 11/06/2022]
Abstract
Angiogenesis, the sprouting of capillaries from preexisting ones, is essential for the sustained growth of solid tumors. In this study, we used SU5416, a hydrophobic molecule with potent tyrosine kinase inhibitor of type 2 receptor for vascular endothelial growth factor (VEGF), as PEGylated emulsion (SU5416-PE), and evaluated the antitumor potency of this formulation in Lewis lung cancer (LLC), Colon-26 (C26), and B16BL6 melanoma (B16) tumor-bearing mice. Intravenous injection of SU5416-PE into tumor-bearing mice significantly suppressed the growth of C26 and B16 tumors, but had no effect on the growth of LLC tumors. MTT assay revealed that SU5416 inhibited the proliferation of human umbilical vein endothelial cells in a concentration-dependent manner but did not show such an inhibitory effect on all types of tumor cells examined, demonstrating the specificity of SU5416 for endothelial cells. Considering that VEGF levels within C26 and B16 tumors were found to be about 10-fold and 20-fold higher than that in LLC tumors, respectively, it was suggested that SU5416-PE would inhibit angiogenesis in certain types of tumor tissue such as C26 and B16 where VEGF plays a major role for promoting angiogenesis, leading to the suppression of in vivo tumor growth.
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Affiliation(s)
- Ken-Ichi Ogawara
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, 700-8530, Japan
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Ashton JR, Clark DP, Moding EJ, Ghaghada K, Kirsch DG, West JL, Badea CT. Dual-energy micro-CT functional imaging of primary lung cancer in mice using gold and iodine nanoparticle contrast agents: a validation study. PLoS One 2014; 9:e88129. [PMID: 24520351 PMCID: PMC3919743 DOI: 10.1371/journal.pone.0088129] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 01/06/2014] [Indexed: 11/19/2022] Open
Abstract
Purpose To provide additional functional information for tumor characterization, we investigated the use of dual-energy computed tomography for imaging murine lung tumors. Tumor blood volume and vascular permeability were quantified using gold and iodine nanoparticles. This approach was compared with a single contrast agent/single-energy CT method. Ex vivo validation studies were performed to demonstrate the accuracy of in vivo contrast agent quantification by CT. Methods Primary lung tumors were generated in LSL-KrasG12D; p53FL/FL mice. Gold nanoparticles were injected, followed by iodine nanoparticles two days later. The gold accumulated in tumors, while the iodine provided intravascular contrast. Three dual-energy CT scans were performed–two for the single contrast agent method and one for the dual contrast agent method. Gold and iodine concentrations in each scan were calculated using a dual-energy decomposition. For each method, the tumor fractional blood volume was calculated based on iodine concentration, and tumor vascular permeability was estimated based on accumulated gold concentration. For validation, the CT-derived measurements were compared with histology and inductively-coupled plasma optical emission spectroscopy measurements of gold concentrations in tissues. Results Dual-energy CT enabled in vivo separation of gold and iodine contrast agents and showed uptake of gold nanoparticles in the spleen, liver, and tumors. The tumor fractional blood volume measurements determined from the two imaging methods were in agreement, and a high correlation (R2 = 0.81) was found between measured fractional blood volume and histology-derived microvascular density. Vascular permeability measurements obtained from the two imaging methods agreed well with ex vivo measurements. Conclusions Dual-energy CT using two types of nanoparticles is equivalent to the single nanoparticle method, but allows for measurement of fractional blood volume and permeability with a single scan. As confirmed by ex vivo methods, CT-derived nanoparticle concentrations are accurate. This method could play an important role in lung tumor characterization by CT.
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Affiliation(s)
- Jeffrey R. Ashton
- Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina, United States of America
- Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America
| | - Darin P. Clark
- Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina, United States of America
- Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America
| | - Everett J. Moding
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Ketan Ghaghada
- The Edward B. Singleton Department of Pediatric Radiology, Texas Children’s Hospital, Houston, Texas, United States of America
| | - David G. Kirsch
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Jennifer L. West
- Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America
| | - Cristian T. Badea
- Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina, United States of America
- * E-mail:
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Lee N, Choi SH, Hyeon T. Nano-sized CT contrast agents. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2013; 25:2641-60. [PMID: 23553799 DOI: 10.1002/adma.201300081] [Citation(s) in RCA: 420] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Indexed: 05/20/2023]
Abstract
Computed tomography (CT) is one of the most widely used clinical imaging modalities. In order to increase the sensitivity of CT, small iodinated compounds are used as injectable contrast agents. However, the iodinated contrast agents are excreted through the kidney and have short circulation times. This rapid renal clearance not only restricts in vivo applications that require long circulation times but also sometimes induces serious adverse effects related to the excretion pathway. In addition, the X-ray attenuation of iodine is not efficient for clinical CT that uses high-energy X-ray. Due to these limitations, nano-sized iodinated CT contrast agents have been developed that can increase the circulation time and decrease the adverse effects. In addition to iodine, nanoparticles based on heavy atoms such as gold, lanthanides, and tantalum are used as more efficient CT contrast agents. In this review, we summarize the recent progresses made in nano-sized CT contrast agents.
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Affiliation(s)
- Nohyun Lee
- Center for Nanoparticle Research, Institute for Basic Science and School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744 South Korea
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Toy R, Hayden E, Camann A, Berman Z, Vicente P, Tran E, Meyers J, Pansky J, Peiris PM, Hu H, Exner A, Wilson D, Ghaghada KB, Karathanasis E. Multimodal in vivo imaging exposes the voyage of nanoparticles in tumor microcirculation. ACS NANO 2013; 7:3118-29. [PMID: 23464827 PMCID: PMC3640526 DOI: 10.1021/nn3053439] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Tumors present numerous biobarriers to the successful delivery of nanoparticles. Decreased blood flow and high interstitial pressure in tumors dictate the degree of resistance to extravasation of nanoparticles. To understand how a nanoparticle can overcome these biobarriers, we developed a multimodal in vivo imaging methodology, which enabled the noninvasive measurement of microvascular parameters and deposition of nanoparticles at the microscopic scale. To monitor the spatiotemporal progression of tumor vasculature and its vascular permeability to nanoparticles at the microcapillary level, we developed a quantitative in vivo imaging method using an iodinated liposomal contrast agent and a micro-CT. Following perfusion CT for quantitative assessment of blood flow, small animal fluorescence molecular tomography was used to image the in vivo fate of cocktails containing liposomes of different sizes labeled with different NIR fluorophores. The animal studies showed that the deposition of liposomes depended on local blood flow. Considering tumor regions of different blood flow, the deposition of liposomes followed a size-dependent pattern. In general, the larger liposomes effectively extravasated in fast flow regions, while smaller liposomes performed better in slow flow regions. We also evaluated whether the tumor retention of nanoparticles is dictated by targeting them to a receptor overexpressed by the cancer cells. Targeting of 100 nm liposomes showed no benefits at any flow rate. However, active targeting of 30 nm liposomes substantially increased their deposition in slow flow tumor regions (∼12-fold increase), which suggested that targeting prevented the washout of the smaller nanoparticles from the tumor interstitium back to blood circulation.
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Affiliation(s)
- Randall Toy
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
| | - Elliott Hayden
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
| | - Andrew Camann
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
| | - Zachary Berman
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
| | - Peter Vicente
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
| | - Emily Tran
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
| | - Joseph Meyers
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
| | - Jenna Pansky
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
| | - Pubudu M. Peiris
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
| | - Hanping Hu
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
| | - Agata Exner
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106
| | - David Wilson
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106
| | - Ketan B. Ghaghada
- Edward B. Singleton Department of Pediatric Radiology, Texas Children’s Hospital, Houston, Texas 77030
- Department of Radiology, Baylor College of Medicine, Houston, Texas 77030
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio 44106
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106
- Author to whom correspondence should be addressed: Efstathios Karathanasis, Wickenden Bldg. MS 7207, 10900 Euclid Ave, Cleveland, Ohio 44106, United States of America, Phone: 216.844.5281; Fax: 216.844.4987;
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Long J, Wang S, Zhang Y, Liu X, Zhang H, Wang S. The therapeutic effect of vascular endothelial growth factor gene- or heme oxygenase-1 gene-modified endothelial progenitor cells on neovascularization of rat hindlimb ischemia model. J Vasc Surg 2013; 58:756-65.e2. [PMID: 23562340 DOI: 10.1016/j.jvs.2012.11.096] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2012] [Revised: 11/21/2012] [Accepted: 11/25/2012] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To explore the therapeutic potential of endothelial progenitor cells (EPCs) transfected with vascular endothelial growth factor A (VEGFA) and heme oxygenase-1 (HO-1) on rat hindlimb ischemia model. METHODS Eukaryotic expression vectors encoding VEGFA or HO-1 were constructed and introduced into EPCs isolated from rat bone marrow. In total, 150 Sprague Dawley rat hindlimb ischemia models were established and randomized into five groups which were injected via tail vein with phosphate-buffered saline (PBS), nontransfected EPCs, VEGFA-modified EPCs, HO-1-modified EPCs, and both VEGFA- and HO-1-modified EPCs, respectively. The microvessel density, the expressions of VEGFA and HO-1 in the ischemic limbs, the recovery of blood flow as evaluated by laser-Doppler perfusion imaging, and the rate of limb salvage were compared among different groups. RESULTS Transplantation of both VEGFA- and HO-1-modified EPCs in recipient rats significantly increased the microvessel density (expressed as capillaries/m(2) at day 21 after operation, group vascular endothelial growth factor (VEGF)+HO-1, 357 ± 14.1; group VEGF, 253.7 ± 9.9; group HO-1, 255.5 ± 12.5; group EPC, 210.7 ± 10.3; group PBS, 144.3 ± 9.3; P < .001), the expressions of VEGFA and HO-1 in ischemic tissue, the recovery of blood flow (at day 21, VEGF+HO-1 group, 85.4 ± 17.8%; VEGF group, 51.2 ± 13.2%; HO-1 group, 50.4 ± 12.9%; EPC group, 39.9 ± 8.5%; PBS group, 28.3 ± 7.8%; P < .001), and the rate of limb salvage (VEGF+HO-1 group, 94.4%; VEGF group or HO-1 group, 63.6%; EPC group, 50.0%; PBS group, 11.1%), compared with transplantation of either VEGFA- or HO-1-modified EPCs alone, or of nontransfected EPCs, or PBS injection. The order of therapeutic effectiveness on ischemic limbs was VEGFA- + HO-1-modifed EPC > either VEGFA- or HO-1-modified EPC alone > nontransfected EPC > PBS. CONCLUSIONS VEGFA-modified EPC and HO-1-modified EPC synergized with each other in promoting angiogenesis in ischemic limbs of rat hindlimb ischemia model. In addition to VEGF, the introduction of HO-1 in EPC-based transplantation may serve as a novel and useful therapeutic strategy for ischemic disease of lower extremity.
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Affiliation(s)
- Jianting Long
- Department of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
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Cho EJ, Holback H, Liu KC, Abouelmagd SA, Park J, Yeo Y. Nanoparticle characterization: state of the art, challenges, and emerging technologies. Mol Pharm 2013; 10:2093-110. [PMID: 23461379 DOI: 10.1021/mp300697h] [Citation(s) in RCA: 202] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nanoparticles have received enormous attention as a promising tool to enhance target-specific drug delivery and diagnosis. Various in vitro and in vivo techniques are used to characterize a new system and predict its clinical efficacy. These techniques enable efficient comparison across nanoparticles and facilitate a product optimization process. On the other hand, we recognize their limitations as a prediction tool, due to inadequate applications and overly simplified test conditions. We provide a critical review of in vitro and in vivo techniques currently used for evaluation of nanoparticles and introduce emerging techniques and models that may be used complementarily.
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Affiliation(s)
- Eun Jung Cho
- Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA
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41
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Affiliation(s)
- Hrvoje Lusic
- Boston University, Departments of Biomedical Engineering and Chemistry, Metcalf Center for Science and Engineering, 590 Commonwealth Ave., Boston, MA 02215. Fax: 617-358-3186; Tel: 617-353-3871
| | - Mark W. Grinstaff
- Boston University, Departments of Biomedical Engineering and Chemistry, Metcalf Center for Science and Engineering, 590 Commonwealth Ave., Boston, MA 02215. Fax: 617-358-3186; Tel: 617-353-3871
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Annapragada AV, Hoffman E, Divekar A, Karathanasis E, Ghaghada KB. High-resolution CT vascular imaging using blood pool contrast agents. Methodist Debakey Cardiovasc J 2012; 8:18-22. [PMID: 22891106 DOI: 10.14797/mdcj-8-1-18] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
While the evolution of computed tomography imaging in the last 2 decades has been driven almost exclusively by improvements in the instrumentation and processing algorithms, there have been comparatively modest advances in contrast agent technology.A notable change in the last decade has been the development of blood pool contrast agents based on nanoparticle technology.While not yet ready for clinical use, the stable and uniform opacification provided by these agents in normal vasculature and controlled extravasation in compromised vasculature enables novel techniques for imaging and diagnosis of pathologies. This manuscript presents preclinical examples demonstrating cardiovascular pathologies and tumor characterization by high-resolution computed tomography imaging.
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Affiliation(s)
- Ananth V Annapragada
- Singleton Department of Pediatric Radiology, Texas Children’s Hospital, Houston, TX, USA
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Peiris PM, Toy R, Doolittle E, Pansky J, Abramowski A, Tam M, Vicente P, Tran E, Hayden E, Camann A, Mayer A, Erokwu BO, Berman Z, Wilson D, Baskaran H, Flask CA, Keri RA, Karathanasis E. Imaging metastasis using an integrin-targeting chain-shaped nanoparticle. ACS NANO 2012; 6:8783-95. [PMID: 23005348 PMCID: PMC3487383 DOI: 10.1021/nn303833p] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
While the enhanced permeability and retention effect may promote the preferential accumulation of nanoparticles into well-vascularized primary tumors, it is ineffective in the case of metastases hidden within a large population of normal cells. Due to their small size, high dispersion to organs, and low vascularization, metastatic tumors are less accessible to targeted nanoparticles. To tackle these challenges, we designed a nanoparticle for vascular targeting based on an α(v)β(3) integrin-targeted nanochain particle composed of four iron oxide nanospheres chemically linked in a linear assembly. The chain-shaped nanoparticles enabled enhanced "sensing" of the tumor-associated remodeling of the vascular bed, offering increased likelihood of specific recognition of metastatic tumors. Compared to spherical nanoparticles, the chain-shaped nanoparticles resulted in superior targeting of α(v)β(3) integrin due to geometrically enhanced multivalent docking. We performed multimodal in vivo imaging (fluorescence molecular tomography and magnetic resonance imaging) in a non-invasive and quantitative manner, which showed that the nanoparticles targeted metastases in the liver and lungs with high specificity in a highly aggressive breast tumor model in mice.
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Affiliation(s)
- Pubudu M. Peiris
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Randall Toy
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Elizabeth Doolittle
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Jenna Pansky
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Aaron Abramowski
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Morgan Tam
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Peter Vicente
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Emily Tran
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Elliott Hayden
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Andrew Camann
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Aaron Mayer
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Bernadette O. Erokwu
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Zachary Berman
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - David Wilson
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Harihara Baskaran
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
- Department of Chemical Engineering, Case Western Reserve University, Cleveland, Ohio
| | - Chris A. Flask
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Ruth A. Keri
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
- Author to whom correspondence should be addressed: Efstathios Karathanasis, Wickenden Bldg. MS 7207, 10900 Euclid Ave, Cleveland, Ohio 44106, United States of America, Phone: 216.844.5281; Fax: 216.844.4987;
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Park S, Kang S, Chen X, Kim EJ, Kim J, Kim N, Kim J, Jin MM. Tumor suppression via paclitaxel-loaded drug carriers that target inflammation marker upregulated in tumor vasculature and macrophages. Biomaterials 2012; 34:598-605. [PMID: 23099063 DOI: 10.1016/j.biomaterials.2012.10.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2012] [Accepted: 10/03/2012] [Indexed: 12/18/2022]
Abstract
Clinically approved chemotherapeutic nanoparticles may provide advantages over free drugs by achieving slower clearance and preferential accumulation in tumors. However, the lack of leaky vasculatures can create barriers to the permeation of ~100 nm-sized nanoparticles in solid tumors. We hypothesized that nanoparticles designed to target both tumor and tumor stroma would penetrate deeper into the tumors. To construct such comprehensive drug carriers, we utilized cross-linked amphiphilic polymer nanoparticles and functionalized them to target ICAM-1, a biomarker prevalent in various tumors and inflamed tumor stroma. The targeting moiety was derived from the modular domain present in α(L) integrin, which was engineered for high affinity and cross-reactivity with human and murine ICAM-1. ICAM-1-selective delivery of paclitaxel produced potent tumor suppression of not only ICAM-1-positive cervical cancer cells but also ICAM-1-negative tumors, presumably by causing cytotoxicity in tumor-associated endothelium (CD31(+)) and macrophages (CD68(+)) over-expressing ICAM-1. Contrary to the strategies of targeting only the tumor or specific tumor stromal constituents, we present a strategy in delivering therapeutics to the major cellular components of solid tumors. Drug carriers against inflammation-biomarkers may be effective against many different types of tumors, while being less susceptible to the highly mutable nature of tumor markers.
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Affiliation(s)
- Spencer Park
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
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Hale JS, Li M, Sinyuk M, Jahnen-Dechent W, Lathia JD, Silverstein RL. Context dependent role of the CD36--thrombospondin--histidine-rich glycoprotein axis in tumor angiogenesis and growth. PLoS One 2012; 7:e40033. [PMID: 22808089 PMCID: PMC3393734 DOI: 10.1371/journal.pone.0040033] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Accepted: 06/03/2012] [Indexed: 11/19/2022] Open
Abstract
The angiogenic switch is a promising therapeutic target in cancer. Work by our laboratory and others has described an important endogenous anti-angiogenic pathway mediated by interactions of CD36, a receptor on microvascular endothelial cells, with proteins containing thrombospondin (TSP) type I repeat domains (TSR). Recent studies revealed that circulating Histidine Rich Glycoprotein (HRG) inhibits the anti-angiogenic potential of the CD36-TSR pathway by functioning as a decoy receptor that binds and sequesters TSR proteins. As tumors of different origin display variable expression profiles of numerous targets, we hypothesized that the TSP-CD36-HRG axis regulates vascularization and growth in the tumor microenvironment in a context, or tumor type, dependent manner. Growth of Lewis Lung Carcinoma (LL2) and B16F1 Melanoma tumor cell implants in syngeneic wild type (WT), hrg, or cd36 null mice were used as a model to interrogate this signaling axis. LL2 tumor volumes were greater in cd36 null mice and smaller in hrg null mice compared to WT. Immunofluorescent staining showed increased vascularity in cd36 null vs. WT and WT vs. hrg null mice. No differences in tumor growth or vascularity were observed with B16F1 implants, consistent with lack of expression of TSP-1 in B16F1 cells. When TSR expression was induced in B16F1 cells by cDNA transfection, tumor growth and vascularity were similar to that seen with LL2 cells. These data show a role for CD36-mediated anti-angiogenic activity in the tumor microenvironment when TSR proteins are available and demonstrate that HRG modulates this activity. Further, they suggest a mechanism by which tumor microenvironments may regulate sensitivity to TSR containing proteins.
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MESH Headings
- Animals
- CD36 Antigens/deficiency
- CD36 Antigens/genetics
- Carcinoma, Lewis Lung/blood supply
- Carcinoma, Lewis Lung/genetics
- Carcinoma, Lewis Lung/metabolism
- Carcinoma, Lewis Lung/pathology
- Cell Line, Tumor
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Gene Expression Regulation, Neoplastic
- Male
- Melanoma, Experimental/blood supply
- Melanoma, Experimental/genetics
- Melanoma, Experimental/metabolism
- Melanoma, Experimental/pathology
- Mice
- Mice, Knockout
- Neovascularization, Pathologic
- Organ Specificity
- Protein Binding
- Proteins/genetics
- Proteins/metabolism
- RNA, Small Interfering/genetics
- Signal Transduction
- Skin Neoplasms/blood supply
- Skin Neoplasms/genetics
- Skin Neoplasms/metabolism
- Skin Neoplasms/pathology
- Thrombospondin 1/genetics
- Thrombospondin 1/metabolism
- Tumor Burden/genetics
- Tumor Microenvironment/genetics
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Affiliation(s)
- James Scott Hale
- Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio, United States of America
- Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America
| | - Meizhang Li
- Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America
| | - Maksim Sinyuk
- Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America
| | - Willi Jahnen-Dechent
- Helmholtz Institute for Biomedical Engineering, Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, Aachen, Germany
| | - Justin Durla Lathia
- Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America
| | - Roy Lee Silverstein
- Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio, United States of America
- Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- * E-mail:
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46
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Peiris PM, Bauer L, Toy R, Tran E, Pansky J, Doolittle E, Schmidt E, Hayden E, Mayer A, Keri RA, Griswold MA, Karathanasis E. Enhanced delivery of chemotherapy to tumors using a multicomponent nanochain with radio-frequency-tunable drug release. ACS NANO 2012; 6:4157-68. [PMID: 22486623 PMCID: PMC3358486 DOI: 10.1021/nn300652p] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
While nanoparticles maximize the amount of chemotherapeutic drug in tumors relative to normal tissues, nanoparticle-based drugs are not accessible to the majority of cancer cells because nanoparticles display patchy, near-perivascular accumulation in tumors. To overcome the limitations of current drugs in their molecular or nanoparticle form, we developed a nanoparticle based on multicomponent nanochains to deliver drug to the majority of cancer cells throughout a tumor while reducing off-target delivery. The nanoparticle is composed of three magnetic nanospheres and one doxorubicin-loaded liposome assembled in a 100 nm long chain. These nanoparticles display prolonged blood circulation and significant intratumoral deposition in tumor models in rodents. Furthermore, the magnetic particles of the chains serve as a mechanical transducer to transfer radio frequency energy to the drug-loaded liposome. The defects on the liposomal walls trigger the release of free drug capable of spreading throughout the entire tumor, which results in a widespread anticancer effect.
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Affiliation(s)
- Pubudu M. Peiris
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Lisa Bauer
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
- Department of Physics, Case Western Reserve University, Cleveland, Ohio
| | - Randall Toy
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Emily Tran
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Jenna Pansky
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Elizabeth Doolittle
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Erik Schmidt
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Elliott Hayden
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Aaron Mayer
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Ruth A. Keri
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Mark A. Griswold
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
- Author to whom correspondence should be addressed: Efstathios Karathanasis, Wickenden Bldg. MS 7207, 10900 Euclid Ave, Cleveland, Ohio 44106, United States of America, Phone: 216.844.5281; Fax: 216.844.4987;
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Valmikinathan CM, Mukhatyar VJ, Jain A, Karumbaiah L, Dasari M, Bellamkonda RV. Photocrosslinkable chitosan based hydrogels for neural tissue engineering. SOFT MATTER 2012; 8:1964-1976. [PMID: 29805470 PMCID: PMC5969809 DOI: 10.1039/c1sm06629c] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Hydrogel based scaffolds for neural tissue engineering can provide appropriate physico-chemical and mechanical properties to support neurite extension and facilitate transplantation of cells by acting as 'cell delivery vehicles'. Specifically, in situ gelling systems such as photocrosslinkable hydrogels can potentially conformally fill irregular neural tissue defects and serve as stem cell delivery systems. Here, we report the development of a novel chitosan based photocrosslinkable hydrogel system with tunable mechanical properties and degradation rates. A two-step synthesis of amino-ethyl methacrylate derivitized, degradable, photocrosslinkable chitosan hydrogels is described. When human mesenchymal stem cells were cultured in photocrosslinkable chitosan hydrogels, negligible cytotoxicity was observed. Photocrosslinkable chitosan hydrogels facilitated enhanced neurite differentiation from primary cortical neurons and enhanced neurite extension from dorsal root ganglia (DRG) as compared to agarose based hydrogels with similar storage moduli. Neural stem cells (NSCs) cultured within photocrosslinkable chitosan hydrogels facilitated differentiation into tubulin positive neurons and astrocytes. These data demonstrate the potential of photocrosslinked chitosan hydrogels, and contribute to an increasing repertoire of hydrogels designed for neural tissue engineering.
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Affiliation(s)
- Chandra M. Valmikinathan
- Neurological Biomaterials and Cancer Therapeutics Laboratory, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, 3108, UA Whitaker Building, 313 Ferst Drive, Atlanta, Georgia, 30332-0535, USA
| | - Vivek J. Mukhatyar
- Neurological Biomaterials and Cancer Therapeutics Laboratory, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, 3108, UA Whitaker Building, 313 Ferst Drive, Atlanta, Georgia, 30332-0535, USA
| | - Anjana Jain
- Neurological Biomaterials and Cancer Therapeutics Laboratory, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, 3108, UA Whitaker Building, 313 Ferst Drive, Atlanta, Georgia, 30332-0535, USA
| | - Lohitash Karumbaiah
- Neurological Biomaterials and Cancer Therapeutics Laboratory, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, 3108, UA Whitaker Building, 313 Ferst Drive, Atlanta, Georgia, 30332-0535, USA
| | - Madhuri Dasari
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, 3108, UA Whitaker Building, 313 Ferst Drive, Atlanta, Georgia, 30332-0535, USA
| | - Ravi V. Bellamkonda
- Neurological Biomaterials and Cancer Therapeutics Laboratory, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, 3108, UA Whitaker Building, 313 Ferst Drive, Atlanta, Georgia, 30332-0535, USA
- ; Fax: +1 404 385 5044; Tel: +1 404 385 5038
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Abstract
The field of radiation oncology has evolved, especially in the past 20 years. Advances in technology, particularly in computing power, software, and imaging, have fueled contributions to cancer care. It is currently fashionable to say that many of these advances have only served to increase costs of care without clear evidence of benefit, and certainly, efforts to evaluate the value of radiation oncology treatments are needed. However, it is undeniable that the future of radiation oncology depends on discovering such advances and to demonstrate that these increase the therapeutic index of treatment. Across the global radiation oncology community, investigations are proceeding in which innovative means are being used to achieve this goal. We review some of these novel methods to improve the therapeutic index of radiation therapy.
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Karumbaiah L, Anand S, Thazhath R, Zhong Y, McKeon RJ, Bellamkonda RV. Targeted downregulation of N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase significantly mitigates chondroitin sulfate proteoglycan-mediated inhibition. Glia 2011; 59:981-96. [PMID: 21456043 PMCID: PMC3077466 DOI: 10.1002/glia.21170] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Accepted: 02/23/2011] [Indexed: 01/17/2023]
Abstract
Chondroitin sulfate-4,6 (CS-E) glycosaminoglycan (GAG) upregulation in astroglial scars is a major contributor to chondroitin sulfate proteoglycan (CSPG)-mediated inhibition [Gilbert et al. (2005) Mol Cell Neurosci 29:545–558]. However, the role of N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S6ST) catalyzed sulfation of CS-E, and its contribution to CSPG-mediated inhibition of CNS regeneration remains to be fully elucidated. Here, we used in situ hybridization to show localized upregulation of GalNAc4S6ST mRNA after CNS injury. Using in vitro spot assays with immobilized CS-E, we demonstrate dose-dependent inhibition of rat embryonic day 18 (E18) cortical neurons. To determine whether selective downregulation of CS-E affected the overall inhibitory character of extracellular matrix produced by reactive astrocytes, single [against (chondroitin 4) sulfotransferase 11 (C4ST1) or GalNAc4S6ST mRNA] or double [against C4ST1 and GalNAc4S6ST mRNA] siRNA treatments were conducted and assayed using quantitative real-time polymerase chain reaction and high-performance liquid chromatography to confirm the specific downregulation of CS-4S GAG (CS-A) and CS-E. Spot and Bonhoeffer stripe assays using astrocyte-conditioned media from siRNA-treated rat astrocytes showed a significant decrease in inhibition of neuronal attachment and neurite extensions when compared with untreated and TGF-treated astrocytes. These findings reveal that selective attenuation of CS-E via siRNA targeting of GalNAc4S6ST significantly mitigates CSPG-mediated inhibition of neurons, potentially offering a novel intervention strategy for CNS injury.
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Affiliation(s)
- Lohitash Karumbaiah
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA 30332
| | - Sanjay Anand
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA 30332
| | - Rupal Thazhath
- Department of Biology, Georgia Institute of Technology, Atlanta, GA 30332
| | - Yinghui Zhong
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA 30332
| | | | - Ravi V. Bellamkonda
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA 30332
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50
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Tugues S, Koch S, Gualandi L, Li X, Claesson-Welsh L. Vascular endothelial growth factors and receptors: anti-angiogenic therapy in the treatment of cancer. Mol Aspects Med 2011; 32:88-111. [PMID: 21565214 DOI: 10.1016/j.mam.2011.04.004] [Citation(s) in RCA: 163] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2011] [Accepted: 04/27/2011] [Indexed: 12/21/2022]
Abstract
Vascular endothelial growth factors (VEGFs) are critical regulators of vascular and lymphatic function during development, in health and in disease. There are five mammalian VEGF ligands and three VEGF receptor tyrosine kinases. In addition, several VEGF co-receptors that lack intrinsic catalytic activity, but that indirectly modulate the responsiveness to VEGF contribute to the final biological effect. This review describes the molecular features of VEGFs, VEGFRs and co-receptors with focus on their role in the treatment of cancer.
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Affiliation(s)
- Sònia Tugues
- Uppsala University, Dept. of Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjöldsv. 20, 751 85 Uppsala, Sweden
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