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Habibollahi P, Gurevich A, Hui JZ, Weinfurtner K, McClung G, Adler J, Soulen MC, Kaplan DE, Nadolski GJ, Hunt SJ, Tsourkas A, Gade TP. Integrated Imaging Probe and Bispecific Antibody Development Enables In Vivo Targeting of Glypican-3-Expressing Hepatocellular Carcinoma. Mol Cancer Ther 2024; 23:1815-1826. [PMID: 39312187 PMCID: PMC11726262 DOI: 10.1158/1535-7163.mct-23-0470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 06/07/2024] [Accepted: 09/16/2024] [Indexed: 01/15/2025]
Abstract
Glypican-3 (GPC3) is a proteoglycan with high sensitivity and specificity for hepatocellular carcinoma (HCC). We describe the integrated development and validation of a GPC3-targeting optical imaging probe and T cell-redirecting antibody (TRAB) as a theranostic strategy for the detection and treatment of HCC. A novel TRAB targeting GPC3 on HCC tumor cells and the CD3 T-cell receptor as well as a distinct GPC3-specific optical imaging probe were developed from a short peptide. The efficacy of GPC3/CD3 TRAB was evaluated in vitro using IFNγ release and calcein-AM assays. Patient-derived xenografts were used to assess the in vivo efficacy of GPC3/CD3 TRAB and the GPC3 imaging probe for the detection of GPC3+ HCC. GPC3/CD3 TRAB caused a dose-dependent escalation in IFNγ release from inactive peripheral blood T cells (P = 0.001) and higher tumor-cell lysis (P = 0.01) compared with controls in vitro. Intratumorally injected GPC3/CD3 TRAB resulted in significant prolongation of tumor doubling time in the GPC3+ tumors, with an associated reduction of tumor fluorescent signal from the HiLyte 488-conjugated GPC3-specific peptide on optical imaging. These data demonstrate that HCC cell targeting using a GPC3/CD3 TRAB derived from a small peptide enabled effective T-cell activation and induction of a cytotoxic response toward GPC3+ HCC tumor cells both in vitro and in vivo. GPC3-specific optical imaging enabled the detection of the GPC3+ HCC cells and noninvasive monitoring of tumor response to adoptive immunotherapy. The integrated development of a targeted therapeutic and molecular imaging probe provides a promising paradigm for the development of cancer theranostics.
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Affiliation(s)
- Peiman Habibollahi
- Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center; Houston, TX
| | - Alexey Gurevich
- Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - James Z. Hui
- Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA
- Center for Targeted Therapeutics and Translational Nanomedicine, University of Pennsylvania, Philadelphia, PA
| | - Kelly Weinfurtner
- Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - George McClung
- Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Justin Adler
- Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Michael C. Soulen
- Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - David E. Kaplan
- Department of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Gregory J. Nadolski
- Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Stephen J. Hunt
- Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Andrew Tsourkas
- Center for Targeted Therapeutics and Translational Nanomedicine, University of Pennsylvania, Philadelphia, PA
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
| | - Terence P. Gade
- Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA
- Center for Targeted Therapeutics and Translational Nanomedicine, University of Pennsylvania, Philadelphia, PA
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA
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Xing L, Chen Y, Zheng T. Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma. Open Life Sci 2024; 19:20220932. [PMID: 39220591 PMCID: PMC11365471 DOI: 10.1515/biol-2022-0932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 09/04/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most common malignant liver tumors. Despite progress in anticancer drugs and surgical approaches, early detection of HCC remains challenging, often leading to late-stage diagnosis where rapid disease progression precludes surgical intervention, leaving chemotherapy as the only option. However, the systemic toxicity, low bioavailability, and significant adverse effects of chemotherapy drugs often lead to resistance, rendering treatments ineffective for many patients. This article outlines how nanoparticles, following functional modification, offer high sensitivity, reduced drug toxicity, and extended duration of action, enabling precise targeting of drugs to HCC tissues. Combined with other therapeutic modalities and imaging techniques, this significantly enhances the diagnosis, treatment, and long-term prognosis of HCC. The advent of nanomedicine provides new methodologies and strategies for the precise diagnosis and integrated treatment of HCC.
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Affiliation(s)
- Lijun Xing
- Shenzhen Key Laboratory for Drug Addiction and Medication Safety, Department of Hubei University of Medicine, Institute of Ultrasonic Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, P. R. China
| | - Yun Chen
- Shenzhen Key Laboratory for Drug Addiction and Medication Safety, Department of Ultrasound, Institute of Ultrasonic Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, P. R. China
| | - Tingting Zheng
- Shenzhen Key Laboratory for Drug Addiction and Medication Safety, Department of Ultrasound, Institute of Ultrasonic Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, P. R. China
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Varlamova EG. Molecular Mechanisms of the Therapeutic Effect of Selenium Nanoparticles in Hepatocellular Carcinoma. Cells 2024; 13:1102. [PMID: 38994955 PMCID: PMC11240755 DOI: 10.3390/cells13131102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/10/2024] [Accepted: 06/21/2024] [Indexed: 07/13/2024] Open
Abstract
This review describes and summarizes, for the first time, the molecular mechanisms of the cytotoxic effect of selenium nanoparticles of various origins on hepatocellular carcinoma cells. The text provides information from recent years indicating the regulation of various signaling pathways and endoplasmic reticulum stress by selenium nanoparticles; the pathways of cell death of liver cancer cells as a result of exposure to selenium nanoparticles are considered. Particular attention is paid to the participation of selenoproteins and selenium-containing thioredoxin reductases and glutathione peroxidases in these processes. Previously, there were no reviews that fully reflected the cytotoxic effects of selenium nanoparticles specifically in hepatocellular carcinoma, despite the fact that many reviews and experimental articles have been devoted to the causes of this disease and the molecular mechanisms of regulation of cytotoxic effects by other agents. The relevance of this review is primarily explained by the fact that despite the development of various drugs and approaches for the treatment and prevention of hepatocellular carcinoma, this disease is still the fourth leading cause of death in the world. For this reason, a complete understanding of the latest trends in the treatment of oncology of various etiologies, especially hepatocellular carcinoma, is extremely important.
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Affiliation(s)
- Elena G Varlamova
- Institute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", 142290 Pushchino, Russia
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Kong Y, Xu L, Cao J. Preparation of a Novel Multifunctional Cationic Liposome Drug-carrying System and its Functional Study on Lung Cancer. Anticancer Agents Med Chem 2024; 24:1085-1095. [PMID: 38803174 DOI: 10.2174/0118715206294695240522075454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/16/2024] [Accepted: 04/09/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUND Low-dose chemotherapy is a promising treatment strategy that may be improved by controlled delivery. OBJECTIVE This study aimed to design polyethylene glycol-stabilized bilayer-decorated magnetic Cationic Liposomes (CLs) as a drug delivery system for integrated functional studies of lung cancer cell therapy and imaging. METHODS A novel multifunctional folic acid targeting magnetic CLs docetaxel drug-loading system (FA-CLs-Fe- DOC) was prepared and tested for its physical properties, encapsulation rate and drug release performance. The feasibility of FA-CLs-Fe-DOC ability to inhibit tumor cells and act as an MRI contrast agent was investigated in vitro, and the target recognition and therapeutic ability of FA-CLs-Fe-DOC was studied in vivo. RESULTS FA-CLs-Fe-DOC had a particle size of 221.54 ± 6.42 nm and a potential of 28.64 ± 3.56 mv, with superparamagnetic properties and better stability. The encapsulation rate was 95.36 ± 1.63%, and the drug loading capacity was 9.52 ± 0.22%, which possessed the drug slow-release performance and low cytotoxicity and could effectively inhibit the proliferation of lung cancer cells, promoting apoptosis of lung cancer cells. MRI showed that it had the function of tracking and localization of lung cancer cells. In vivo experiments confirmed the targeted recognition property and therapeutic function of lung cancer cells. CONCLUSION In this study, we successfully prepared an FA-CLs-Fe-DOC capable of specifically targeting lung cancer cells with integrated functions of efficient lung cancer cell killing and imaging localization. This targeted drug packaging technology may provide a new strategy for the design of integrated carriers for targeted cancer therapy and imaging.
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Affiliation(s)
- Yi Kong
- The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha 410013, Hunan Province, P.R. China
| | - Li Xu
- The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha 410013, Hunan Province, P.R. China
| | - Jun Cao
- The First Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, 410013, Hunan Province, P.R. China
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Escutia-Gutiérrez R, Sandoval-Rodríguez A, Zamudio-Ojeda A, Guevara-Martínez SJ, Armendáriz-Borunda J. Advances of Nanotechnology in the Diagnosis and Treatment of Hepatocellular Carcinoma. J Clin Med 2023; 12:6867. [PMID: 37959332 PMCID: PMC10647688 DOI: 10.3390/jcm12216867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/20/2023] [Accepted: 10/22/2023] [Indexed: 11/15/2023] Open
Abstract
Nanotechnology has emerged as a promising technology in the field of hepatocellular carcinoma (HCC), specifically in the implementation of diagnosis and treatment strategies. Nanotechnology-based approaches, such as nanoparticle-based contrast agents and nanoscale imaging techniques, have shown great potential for enhancing the sensitivity and specificity of HCC detection. These approaches provide high-resolution imaging and allow for the detection of molecular markers and alterations in cellular morphology associated with HCC. In terms of treatment, nanotechnology has revolutionized HCC therapy by enabling targeted drug delivery, enhancing therapeutic efficacy, and minimizing off-target effects. Nanoparticle-based drug carriers can be functionalized with ligands specific to HCC cells, allowing for selective accumulation of therapeutic agents at the tumor site. Furthermore, nanotechnology can facilitate combination therapy by co-encapsulating multiple drugs within a single nanoparticle, allowing for synergistic effects and overcoming drug resistance. This review aims to provide an overview of recent advances in nanotechnology-based approaches for the diagnosis and treatment of HCC. Further research is needed to optimize the design and functionality of nanoparticles, improve their biocompatibility and stability, and evaluate their long-term safety and efficacy. Nonetheless, the integration of nanotechnology in HCC management holds great promise and may lead to improved patient outcomes in the future.
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Affiliation(s)
- Rebeca Escutia-Gutiérrez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, Guadalajara 44340, Mexico; (R.E.-G.); (A.S.-R.)
| | - Ana Sandoval-Rodríguez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, Guadalajara 44340, Mexico; (R.E.-G.); (A.S.-R.)
| | - Adalberto Zamudio-Ojeda
- Department of Physics, Exact Sciences and Engineering University Center, University of Guadalajara, Guadalajara 44340, Mexico;
| | - Santiago José Guevara-Martínez
- Department of Physics, Exact Sciences and Engineering University Center, University of Guadalajara, Guadalajara 44340, Mexico;
| | - Juan Armendáriz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, Guadalajara 44340, Mexico; (R.E.-G.); (A.S.-R.)
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Zapopan 45201, Mexico
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Liu T, Liu L, Li L, Cai J. Exploiting targeted nanomedicine for surveillance, diagnosis, and treatment of hepatocellular carcinoma. Mater Today Bio 2023; 22:100766. [PMID: 37636988 PMCID: PMC10457457 DOI: 10.1016/j.mtbio.2023.100766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/26/2023] [Accepted: 08/05/2023] [Indexed: 08/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the cancers that has the highest morbidity and mortality rates. In clinical practice, there are still many limitations in surveilling, diagnosing, and treating HCC, such as the poor detection of early HCC, the frequent post-surgery recurrence, the low local tumor control rate, the therapy resistance and side effects. Therefore, improved, or innovative modalities are urgently required for early diagnosis as well as refined and effective management. In recent years, nanotechnology research in the field of HCC has received great attention, with various aspects of diagnosis and treatment including biomarkers, ultrasound, diagnostic imaging, intraoperative imaging, ablation, transarterial chemoembolization, radiotherapy, and systemic therapy. Different from previous reviews that discussed from the perspective of nanoparticles' structure, design and function, this review systematically summarizes the methods and limitations of diagnosing and treating HCC in clinical guidelines and practices, as well as nanomedicine applications. Nanomedicine can overcome the limitations to improve diagnosis accuracy and therapeutic effect via enhancement of targeting, biocompatibility, bioavailability, controlled releasing, and combination of different clinical treatment modalities. Through an in-depth understanding of the logic of nanotechnology to conquer clinical limitations, the main research directions of nanotechnology in HCC are sorted out in this review. It is anticipated that nanomedicine will play a significant role in the future clinical practices of HCC.
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Affiliation(s)
- Tingting Liu
- Department of Medical Imaging, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510000, China
| | - Li Liu
- Department of Ultrasound, Peking University Shenzhen Hospital, Shenzhen, 518000, China
| | - Li Li
- Department of Medical Imaging, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510000, China
| | - Jing Cai
- Department of Medical Imaging, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510000, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510000, PR China
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Qi YM, Xiao EH. Advances in application of novel magnetic resonance imaging technologies in liver disease diagnosis. World J Gastroenterol 2023; 29:4384-4396. [PMID: 37576700 PMCID: PMC10415971 DOI: 10.3748/wjg.v29.i28.4384] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/03/2023] [Accepted: 07/07/2023] [Indexed: 07/26/2023] Open
Abstract
Liver disease is a major health concern globally, with high morbidity and mor-tality rates. Precise diagnosis and assessment are vital for guiding treatment approaches, predicting outcomes, and improving patient prognosis. Magnetic resonance imaging (MRI) is a non-invasive diagnostic technique that has been widely used for detecting liver disease. Recent advancements in MRI technology, such as diffusion weighted imaging, intravoxel incoherent motion, magnetic resonance elastography, chemical exchange saturation transfer, magnetic resonance spectroscopy, hyperpolarized MR, contrast-enhanced MRI, and ra-diomics, have significantly improved the accuracy and effectiveness of liver disease diagnosis. This review aims to discuss the progress in new MRI technologies for liver diagnosis. By summarizing current research findings, we aim to provide a comprehensive reference for researchers and clinicians to optimize the use of MRI in liver disease diagnosis and improve patient prognosis.
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Affiliation(s)
- Yi-Ming Qi
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha 410000, Hunan Province, China
| | - En-Hua Xiao
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha 410000, Hunan Province, China
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Sobhani T, Shahbazi-Gahrouei D, Zahraei M, Hejazi SH, Dousti F, Rostami M. Novel MR imaging nanoprobe for hepatocellular carcinoma detection based on manganese-zinc ferrite nanoparticles: in vitro and in vivo assessments. J Cancer Res Clin Oncol 2023; 149:4939-4957. [PMID: 36309602 DOI: 10.1007/s00432-022-04427-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 10/16/2022] [Indexed: 10/31/2022]
Abstract
PURPOSE Achieving new contrast enhancer agents that can produce high-resolution images in magnetic resonance imaging (MRI) with a minimum dose and side effects has always been important. METHODS Herein, the pegylated curcumin-coated manganese-zinc ferrite nanoparticles (MZF@CA-PEG-CUR NPs) have been reported as an MR imaging nanoprobe in hepatocellular carcinoma detection in the murine model for the first time. In vitro studies were done on HEPA 1-6 cancer cells and L929 as normal cells, and in vivo studies were done on hepatocellular carcinoma (HCC) using xenograft models of HCC. RESULTS The prepared NP had a diameter of 105 nm with narrow size distribution and was superparamagnetic with a saturated magnetization (Ms) of 39 emu/g. The NP was biocompatible without any significant hemolysis and cytotoxicity. Prussian blue staining showed more cellular uptake of HEPA 1-6 compared to L929 control cells after incubation (P < 0.05). The concentration of Fe in mice blood confirmed the plasma half-life of about 3 h; it seems the PEGylation increased the circulation time. ICP-OES of Fe showed the highest tumor localization for MZF@CA-CUR-PEG NPs, due to passive accumulation, compared to the other mice studied organs. The r2 relaxivity of NPs was 134.89 mM- 1 s- 1, and in vitro MRI demonstrated better effects in HEPA 1-6 cells than in L929 (P < 0.05). Also, in vivo MR images showed signal enhancement efficacy in tumor-bearing mice. CONCLUSION This study demonstrated that the MZF@CA-CUR-PEG nanoprobe could be a promising candidate as an MR imaging agent in hepatocellular carcinoma early detection.
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Affiliation(s)
- Tayebe Sobhani
- Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Daryoush Shahbazi-Gahrouei
- Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Zahraei
- Department of Materials Engineering, Isfahan University of Technology, Isfahan, Iran
| | - Seyed Hossein Hejazi
- Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Dousti
- Novel Drug Delivery Systems Research Centre and Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahboubeh Rostami
- Novel Drug Delivery Systems Research Centre and Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
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Zhang Y, Wu X, Zhu H, Cong Y. Development and in functional study of a bi-specific sustained release drug-loaded nano-liposomes for hepatocellular carcinoma. J Biomater Appl 2023:8853282231179313. [PMID: 37243614 DOI: 10.1177/08853282231179313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
BACKGROUND Lenvatinib (LEN) is a first-line therapy for patients with hepatocellular carcinoma (HCC), but has a larger adverse effect profile. In this study, we developed a liposome with drug-carrying function and magnetic resonance imaging (MRI) imaging function to investigate the targeted drug-carrying function and MRI tracing ability of liposome for HCC. METHODS Magnetic nano-liposomes (MNL) with dual targeting function of epithelial cell adhesion molecule (EpCAM) and vimentin and capable of encapsulating LEN drugs were prepared. The characterization performance, drug loading efficiency and cytotoxicity of EpCAM/vimentin-LEN-MNL were tested, and the dual-targeting slow release drug loading function and MRI tracing ability were investigated in cellular and animal models. RESULTS EpCAM/vimentin-LEN-MNL has a mean particle size of 218.37 ± 5.13 nm and a mean potential of 32.86 ± 4.62 mV, and is spherical in shape and can be uniformly dispersed in solution. The encapsulation rate was 92.66 ± 0.73% and the drug loading rate was 9.35 ± 0.16%. It has low cytotoxicity, can effectively inhibit HCC cell proliferation and promote HCC cell apoptosis, and has specific targeting function and MRI tracing ability for HCC cells. CONCLUSIONS In this study, an HCC-specific dual-targeted sustained-release drug delivery liposome with dual-targeted recognition and sensitive MRI tracer was successfully prepared, which provides an important scientific basis for maximizing the multiple effects of nano-carriers in tumor diagnosis and treatment.
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Affiliation(s)
- Yufei Zhang
- Shanghai Seventh People's Hospital, Shanghai, China
| | - Xiaoxiong Wu
- Shanghai Seventh People's Hospital, Shanghai, China
| | - Hongfan Zhu
- Shanghai Seventh People's Hospital, Shanghai, China
| | - Yun Cong
- Shanghai Seventh People's Hospital, Shanghai, China
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Song Y, Zhang YY, Yu Q, Chen T, Wei CG, Zhang R, Hu W, Qian XJ, Zhu Z, Zhang XW, Shen JK. A nomogram based on LI-RADS features, clinical indicators and quantitative contrast-enhanced MRI parameters for predicting glypican-3 expression in hepatocellular carcinoma. Front Oncol 2023; 13:1123141. [PMID: 36824129 PMCID: PMC9941525 DOI: 10.3389/fonc.2023.1123141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/26/2023] [Indexed: 02/10/2023] Open
Abstract
Purpose Noninvasively assessing the tumor biology and microenvironment before treatment is greatly important, and glypican-3 (GPC-3) is a new-generation immunotherapy target for hepatocellular carcinoma (HCC). This study investigated the application value of a nomogram based on LI-RADS features, quantitative contrast-enhanced MRI parameters and clinical indicators in the noninvasive preoperative prediction of GPC-3 expression in HCC. Methods and materials We retrospectively reviewed 127 patients with pathologically confirmed solitary HCC who underwent Gd-EOB-DTPA MRI examinations and related laboratory tests. Quantitative contrast-enhanced MRI parameters and clinical indicators were collected by an abdominal radiologist, and LI-RADS features were independently assessed and recorded by three trained intermediate- and senior-level radiologists. The pathological and immunohistochemical results of HCC were determined by two senior pathologists. All patients were divided into a training cohort (88 cases) and validation cohort (39 cases). Univariate analysis and multivariate logistic regression were performed to identify independent predictors of GPC-3 expression in HCC, and a nomogram model was established in the training cohort. The performance of the nomogram was assessed by the area under the receiver operating characteristic curve (AUC) and the calibration curve in the training cohort and validation cohort, respectively. Results Blood products in mass, nodule-in-nodule architecture, mosaic architecture, contrast enhancement ratio (CER), transition phase lesion-liver parenchyma signal ratio (TP-LNR), and serum ferritin (Fer) were independent predictors of GPC-3 expression, with odds ratios (ORs) of 5.437, 10.682, 5.477, 11.788, 0.028, and 1.005, respectively. Nomogram based on LI-RADS features (blood products in mass, nodule-in-nodule architecture and mosaic architecture), quantitative contrast-enhanced MRI parameters (CER and TP-LNR) and clinical indicators (Fer) for predicting GPC-3 expression in HCC was established successfully. The nomogram showed good discrimination (AUC of 0.925 in the training cohort and 0.908 in the validation cohort) and favorable calibration. The diagnostic sensitivity and specificity were 76.9% and 92.3% in the training cohort, 76.8% and 93.8% in the validation cohort respectively. Conclusion The nomogram constructed from LI-RADS features, quantitative contrast-enhanced MRI parameters and clinical indicators has high application value, can accurately predict GPC-3 expression in HCC and may help noninvasively identify potential patients for GPC-3 immunotherapy.
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Affiliation(s)
- Yan Song
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China,Department of Radiology, Jieshou City People’s Hospital, Fuyang, China
| | - Yue-yue Zhang
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Qin Yu
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China,Department of Radiology, Dongtai City People’s Hospital, Yancheng, China
| | - Tong Chen
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Chao-gang Wei
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Rui Zhang
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Wei Hu
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xu-jun Qian
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhi Zhu
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xue-wu Zhang
- Department of Infectious Diseases, Jieshou City People’s Hospital, Fuyang, China
| | - Jun-kang Shen
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China,Institute of Imaging Medicine, Soochow University, Suzhou, China,*Correspondence: Jun-kang Shen,
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Chong H, Gong Y, Zhang Y, Dai Y, Sheng R, Zeng M. Radiomics on Gadoxetate Disodium-enhanced MRI: Non-invasively Identifying Glypican 3-Positive Hepatocellular Carcinoma and Postoperative Recurrence. Acad Radiol 2023; 30:49-63. [PMID: 35562264 DOI: 10.1016/j.acra.2022.04.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/30/2022] [Accepted: 04/09/2022] [Indexed: 11/01/2022]
Abstract
RATIONALE AND OBJECTIVES To investigate the impact of preoperative gadoxetate disodium (EOB) MRI-based radiomics on predicting glypican 3 (GPC3)-positive expression and the relevant recurrence-free survival (RFS) of HCC ≤ 5 cm. MATERIALS AND METHODS Between January 2014 and October 2018, 259 patients with solitary HCC ≤ 5 cm who underwent hepatectomy and preoperative EOB-MRI were retrieved. Multivariate logistic regression was implemented to identify independent predictors for GPC3. By combining five feature selection strategies and three classifiers, 15 GPC3-oriented radiomics models could be constructed, the best of which with independent clinicoradiologic predictors was integrated into the comprehensive nomogram. RESULTS GPC3 was an independent risk factor of postoperative recrudescence for HCC. Alpha-fetoprotein >20 ng/mL, homogenous T2 signal and hypointensity on hepatobiliary phase were independently related to GPC3-positive expression in the clinicoradiologic model. With 10 features selected by support vector machines-recursive feature elimination, logistic regression-based classifier achieved the best performance among 15 radiomics models. After five-fold cross-validation, our comprehensive nomogram acquired better average area under receiver operating characteristic curves (training and validation cohorts: 0.931 vs. 0.943) than the clinicoradiologic algorithm (0.738 vs. 0.739) and the optimal radiomics model (0.943 vs. 0.931). Net reclassification indexes further demonstrated the superiority of GPC3 nomogram over clinicoradiologic and radiomics algorithms (46.54%, p < 0.001; 7.84%, p = 0.207). Meanwhile, higher radiomics score significantly shortened the median RFS (from >77.9 to 48.2 months, p = 0.044), which was analogue to that of the histological GPC3-positive phenotype (from >73.9 to 43.2 months, p < 0.001). CONCLUSIONS Preoperative EOB-MRI radiomics-based nomogram satisfactorily distinguished GPC3 status and outcomes of solitary HCC ≤ 5 cm.
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Affiliation(s)
- Huanhuan Chong
- Department of Radiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Yuda Gong
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Yunfei Zhang
- Central Research Institute, United Imaging Healthcare, Shanghai, China
| | - Yongming Dai
- Central Research Institute, United Imaging Healthcare, Shanghai, China
| | - Ruofan Sheng
- Department of Radiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China; Department of Medical Imaging, Shanghai Medical College, Fudan University, 130 Dongan Road, Shanghai, China; Shanghai Institute of Medical Imaging, 180 Fenglin Road, Shanghai, China.
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12
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Chen Y, Qin Y, Wu Y, Wei H, Wei Y, Zhang Z, Duan T, Jiang H, Song B. Preoperative prediction of glypican-3 positive expression in solitary hepatocellular carcinoma on gadoxetate-disodium enhanced magnetic resonance imaging. Front Immunol 2022; 13:973153. [PMID: 36091074 PMCID: PMC9453305 DOI: 10.3389/fimmu.2022.973153] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
Purpose As a coreceptor in Wnt and HGF signaling, glypican-3 (GPC-3) promotes the progression of tumor and is associated with a poor prognosis in hepatocellular carcinoma (HCC). GPC-3 has evolved as a target molecule in various immunotherapies, including chimeric antigen receptor T cell. However, its evaluation still relies on invasive histopathologic examination. Therefore, we aimed to develop an easy-to-use and noninvasive risk score integrating preoperative gadoxetic acid–enhanced magnetic resonance imaging (EOB-MRI) and clinical indicators to predict positive GPC-3 expression in HCC. Methods and materials Consecutive patients with surgically-confirmed solitary HCC who underwent preoperative EOB-MRI between January 2016 and November 2021 were retrospectively included. EOB-MRI features were independently evaluated by two masked abdominal radiologists and the expression of GPC-3 was determined by two liver pathologists. On the training dataset, a predictive scoring system for GPC-3 was developed against pathology via logistical regression analysis. Model performances were characterized by computing areas under the receiver operating characteristic curve (AUCs). Results A total of 278 patients (training set, n=156; internal validation set, n=39; external validation set, n=83) with solitary HCC (208 [75%] with positive GPC-3 expression) were included. Serum alpha-fetoprotein >10 ng/ml (AFP, odds ratio [OR]=2.3, four points) and five EOB-MR imaging features, including tumor size >3.0cm (OR=0.5, -3 points), nonperipheral “washout” (OR=3.0, five points), infiltrative appearance (OR=9.3, 10 points), marked diffusion restriction (OR=3.3, five points), and iron sparing in solid mass (OR=0.2, -7 points) were significantly associated with positive GPC-3 expression. The optimal threshold of scoring system for predicting GPC-3 positive expression was 5.5 points, with AUC 0.726 and 0.681 on the internal and external validation sets, respectively. Conclusion Based on serum AFP and five EOB-MRI features, we developed an easy-to-use and noninvasive risk score which could accurately predict positive GPC-3 HCC, which may help identify potential responders for GPC-3-targeted immunotherapy.
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Affiliation(s)
- Yidi Chen
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Yun Qin
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuanan Wu
- Big Data Research Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Hong Wei
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Wei
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhen Zhang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Duan
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Hanyu Jiang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Hanyu Jiang, ; Bin Song,
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
- Department of Radiology, Sanya People’s Hospital, Sanya, China
- *Correspondence: Hanyu Jiang, ; Bin Song,
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13
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Huang Z, Li F, Zhang J, Shi X, Xu Y, Huang X. Research on the Construction of Bispecific-Targeted Sustained-Release Drug-Delivery Microspheres and Their Function in Treatment of Hepatocellular Carcinoma. ACS OMEGA 2022; 7:22003-22014. [PMID: 35785307 PMCID: PMC9244910 DOI: 10.1021/acsomega.2c02584] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/01/2022] [Indexed: 06/01/2023]
Abstract
Lenvatinib (LEN) is approved as one of the commonly used drugs in the treatment of hepatocellular carcinoma (HCC). It is recognized to be a novel therapeutic choice for the direct and targeted delivery of effective drugs to HCC tumor sites. The key to the proposed method lies in the requirement for efficient targeted drug delivery carriers with targeting performance to deliver effective drugs directly and safely to tumor lesions. Methods: Here, magnetic liposomes (MLs) were modified by phosphatidylinositol proteoglycan 3 (GPC3) and epithelial cell adhesion molecules (EpCAMs). Subsequently, bispecific-targeted sustained-release drug-loaded microspheres containing LEN (GPC3/EpCAM-LEN-MLs) were constructed. In addition, both cytotoxicity and magnetic resonance imaging (MRI) analyses were performed to establish a mouse model and further perform corresponding performance assessments. Results: The corresponding results showed that GPC3/EpCAM-LEN-MLs were spherical-shaped and evenly dispersed. The encapsulation and drug-loading efficiencies were 91.08% ± 1.83% and 8.22% ± 1.24%, respectively. Meanwhile, GPC3/EpCAM-LEN-MLs showed a high inhibition rate on the proliferation of HCC cells and significantly increased their apoptosis. Furthermore, MRI revealed that the system possessed the function of tracking and localizing tumor cells, and animal experiments verified that it could exert the function of disease diagnosis. Conclusions: Our experiments successfully constructed a safe and efficient bispecific-targeted sustained-release drug delivery system for HCC tumor cells. It provides a useful diagnostic and therapeutic scheme for the clinical diagnosis and targeted therapy of HCC. Moreover, it can be used as a potential tumor-specific MRI contrast agent for the localization and diagnosis of malignant tumors.
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Affiliation(s)
- Zi−Li Huang
- Department
of General Surgery, Shanghai Jiaotong University
Affiliated Sixth People’s Hospital, No. 600, Yishan RD., Shanghai 200233, PR China
- Department
of Radiology, Xuhui District Central Hospital of Zhongshan Hospital, Fudan University, No. 966, Huaihai Middle RD., Shanghai 200031, PR China
| | - Feng Li
- School
of Materials of Science and Engineering, Shanghai Jiao Tong University, No. 800, Dongchuan RD., Shanghai 200240, PR China
| | - Jun−Tao Zhang
- Institute
of Microsurgery on Extremities, Shanghai
Jiao Tong University Affiliated Sixth People’s Hospital, No. 600, Yishan RD., Shanghai 200233, PR China
| | - Xiang−Jun Shi
- Department
of General Surgery, Shanghai Jiaotong University
Affiliated Sixth People’s Hospital, No. 600, Yishan RD., Shanghai 200233, PR China
| | - Yong−Hua Xu
- Department
of Radiology, Xuhui District Central Hospital of Zhongshan Hospital, Fudan University, No. 966, Huaihai Middle RD., Shanghai 200031, PR China
| | - Xiu−Yan Huang
- Department
of General Surgery, Shanghai Jiaotong University
Affiliated Sixth People’s Hospital, No. 600, Yishan RD., Shanghai 200233, PR China
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Graur F, Puia A, Mois EI, Moldovan S, Pusta A, Cristea C, Cavalu S, Puia C, Al Hajjar N. Nanotechnology in the Diagnostic and Therapy of Hepatocellular Carcinoma. MATERIALS (BASEL, SWITZERLAND) 2022; 15:3893. [PMID: 35683190 PMCID: PMC9182427 DOI: 10.3390/ma15113893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/20/2022] [Accepted: 05/24/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is the most common liver malignancy and is among the top five most common cancers. Despite the progress of surgery and chemotherapy, the results are often disappointing, in part due to chemoresistance. This type of tumor has special characteristics that allow the improvement of diagnostic and treatment techniques used in clinical practice, by combining nanotechnology. This article presents a brief review of the literature focused on nano-conditioned diagnostic methods, targeted therapy, and therapeutic implications for the pathology of hepatocellular carcinoma. Within each subdomain, several modern technologies with significant impact were highlighted: serological, imaging, or histopathological diagnosis; intraoperative detection; carrier-type nano-conditioned therapy, thermal ablation, and gene therapy. The prospects offered by nanomedicine will strengthen the hope of more efficient diagnoses and therapies in the future.
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Affiliation(s)
- Florin Graur
- Department of Surgery, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania; (F.G.); (C.P.); (N.A.H.)
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400394 Cluj-Napoca, Romania;
| | - Aida Puia
- Department of General Practitioner, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400347 Cluj-Napoca, Romania
| | - Emil Ioan Mois
- Department of Surgery, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania; (F.G.); (C.P.); (N.A.H.)
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400394 Cluj-Napoca, Romania;
| | - Septimiu Moldovan
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400394 Cluj-Napoca, Romania;
| | - Alexandra Pusta
- Department of Analytical Chemistry, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400347 Cluj-Napoca, Romania; (A.P.); (C.C.)
| | - Cecilia Cristea
- Department of Analytical Chemistry, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400347 Cluj-Napoca, Romania; (A.P.); (C.C.)
| | - Simona Cavalu
- Department of Medical Biophysics, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania;
| | - Cosmin Puia
- Department of Surgery, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania; (F.G.); (C.P.); (N.A.H.)
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400394 Cluj-Napoca, Romania;
| | - Nadim Al Hajjar
- Department of Surgery, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania; (F.G.); (C.P.); (N.A.H.)
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400394 Cluj-Napoca, Romania;
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15
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Zhao D, Cao J, Zhang L, Zhang S, Wu S. Targeted Molecular Imaging Probes Based on Magnetic Resonance Imaging for Hepatocellular Carcinoma Diagnosis and Treatment. BIOSENSORS 2022; 12:bios12050342. [PMID: 35624643 PMCID: PMC9138815 DOI: 10.3390/bios12050342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/09/2022] [Accepted: 05/11/2022] [Indexed: 11/30/2022]
Abstract
Hepatocellular carcinoma (HCC) is the sixth most commonly malignant tumor and the third leading cause of cancer-related death in the world, and the early diagnosis and treatment of patients with HCC is core in improving its prognosis. The early diagnosis of HCC depends largely on magnetic resonance imaging (MRI). MRI has good soft-tissue resolution, which is the international standard method for the diagnosis of HCC. However, MRI is still insufficient in the diagnosis of some early small HCCs and malignant nodules, resulting in false negative results. With the deepening of research on HCC, researchers have found many specific molecular biomarkers on the surface of HCC cells, which may assist in diagnosis and treatment. On the other hand, molecular imaging has progressed rapidly in recent years, especially in the field of cancer theranostics. Hence, the preparation of molecular imaging probes that can specifically target the biomarkers of HCC, combined with MRI testing in vivo, may achieve the theranostic purpose of HCC in the early stage. Therefore, in this review, taking MR imaging as the basic point, we summarized the recent progress regarding the molecular imaging targeting various types of biomarkers on the surface of HCC cells to improve the theranostic rate of HCC. Lastly, we discussed the existing obstacles and future prospects of developing molecular imaging probes as HCC theranostic nanoplatforms.
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Affiliation(s)
- Dongxu Zhao
- Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China;
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jian Cao
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou 215006, China;
| | - Lei Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China
- Correspondence: (L.Z.); (S.Z.); (S.W.)
| | - Shaohua Zhang
- Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China;
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Correspondence: (L.Z.); (S.Z.); (S.W.)
| | - Song Wu
- Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China;
- Department of Urology, The Affiliated South China Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China
- Correspondence: (L.Z.); (S.Z.); (S.W.)
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16
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Peserico A, Di Berardino C, Russo V, Capacchietti G, Di Giacinto O, Canciello A, Camerano Spelta Rapini C, Barboni B. Nanotechnology-Assisted Cell Tracking. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:1414. [PMID: 35564123 PMCID: PMC9103829 DOI: 10.3390/nano12091414] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 02/06/2023]
Abstract
The usefulness of nanoparticles (NPs) in the diagnostic and/or therapeutic sector is derived from their aptitude for navigating intra- and extracellular barriers successfully and to be spatiotemporally targeted. In this context, the optimization of NP delivery platforms is technologically related to the exploitation of the mechanisms involved in the NP-cell interaction. This review provides a detailed overview of the available technologies focusing on cell-NP interaction/detection by describing their applications in the fields of cancer and regenerative medicine. Specifically, a literature survey has been performed to analyze the key nanocarrier-impacting elements, such as NP typology and functionalization, the ability to tune cell interaction mechanisms under in vitro and in vivo conditions by framing, and at the same time, the imaging devices supporting NP delivery assessment, and consideration of their specificity and sensitivity. Although the large amount of literature information on the designs and applications of cell membrane-coated NPs has reached the extent at which it could be considered a mature branch of nanomedicine ready to be translated to the clinic, the technology applied to the biomimetic functionalization strategy of the design of NPs for directing cell labelling and intracellular retention appears less advanced. These approaches, if properly scaled up, will present diverse biomedical applications and make a positive impact on human health.
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Affiliation(s)
- Alessia Peserico
- Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy; (C.D.B.); (V.R.); (G.C.); (O.D.G.); (A.C.); (C.C.S.R.); (B.B.)
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17
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Ma XH, Chen K, Wang S, Liu SY, Li DF, Mi YT, Wu ZY, Qu CF, Zhao XM. Bi-specific T1 positive-contrast-enhanced magnetic resonance imaging molecular probe for hepatocellular carcinoma in an orthotopic mouse model. World J Gastrointest Oncol 2022; 14:858-871. [PMID: 35582105 PMCID: PMC9048532 DOI: 10.4251/wjgo.v14.i4.858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/31/2021] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. HCC-targeted magnetic resonance imaging (MRI) is an effective noninvasive diagnostic method that involves targeting clinically-related HCC biomarkers, such as alpha-fetoprotein (AFP) or glypican-3 (GPC3), with iron oxide nanoparticles. However, in vivo studies of HCC-targeted MRI utilize single-target iron oxide nanoprobes as negative (T2) contrast agents, which might weaken their future clinical applications due to tumor heterogeneity and negative MRI contrast. Ultra-small superparamagnetic iron oxide (USPIO) nanoparticles (approximately 5 nm) are potential optimal positive (T1) contrast agents. We previously verified the efficiency of AFP/GPC3-double-antibody-labeled iron oxide MR molecular probe in vitro.
AIM To validate the effectiveness of a bi-specific probe in vivo for enhancing T1-weighted positive contrast to diagnose the early-stage HCC.
METHODS The single- and double-antibody-conjugated 5-nm USPIO probes, including anti-AFP-USPIO (UA), anti-GPC3-USPIO (UG), and anti-AFP-USPIO-anti-GPC3 (UAG), were synthesized. T1- and T2-weighted MRI were performed on day 10 after establishment of the orthotopic HCC mouse model. Following intravenous injection of U, UA, UG, and UAG probes, T1- and T2-weighted images were obtained at 12, 12, and 32 h post-injection. At the end of scanning, mice were euthanized, and a histologic analysis was performed on tumor samples.
RESULTS T1- and T2-weighted MRI showed that absolute tumor-to-background ratios in UAG-treated HCC mice peaked at 24 h post-injection, with the T1- and T2-weighted signals increasing by 46.7% and decreasing by 11.1%, respectively, relative to pre-injection levels. Additionally, T1-weighted contrast in the UAG-treated group at 24 h post-injection was enhanced 1.52-, 2.64-, and 4.38-fold compared to those observed for single-targeted anti-GPC3-USPIO, anti-AFP-USPIO, and non-targeted USPIO probes, respectively. Comparison of U-, UA-, UG-, and UAG-treated tumor sections revealed that UAG-treated mice exhibited increased stained regions compared to those observed in UG- or UA-treated mice.
CONCLUSION The bi-specific T1-positive contrast-enhanced MRI probe (UAG) for HCC demonstrated increased specificity and sensitivity to diagnose early-stage HCC irrespective of tumor size and/or heterogeneity.
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Affiliation(s)
- Xiao-Hong Ma
- Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Kun Chen
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
| | - Shuang Wang
- Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Si-Yun Liu
- GE Healthcare (China), Beijing 100176, China
| | - Deng-Feng Li
- Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Tao Mi
- Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhi-Yuan Wu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
| | - Chun-Feng Qu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
| | - Xin-Ming Zhao
- Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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18
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Yi B, Wu T, Zhu N, Huang Y, Yang X, Yuan L, Wu Y, Liang X, Jiang X. The clinical significance of CTC enrichment by GPC3-IML and its genetic analysis in hepatocellular carcinoma. J Nanobiotechnology 2021; 19:74. [PMID: 33726759 PMCID: PMC7962223 DOI: 10.1186/s12951-021-00818-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/27/2021] [Indexed: 12/15/2022] Open
Abstract
Background This research was to develop a special method for enriching Circulating tumor cells (CTCs) of Hepatocellular carcinoma (HCC) by Glypican-3 immunoliposomes (GPC3-IML), and to analyze the correlation between the CTCs count and tumor malignancy, as well as to investigate the mutation characteristics of CTC-derived NGS. Results In this study characterization of physical parameters was performed with the preparation of GPC3-IML. CTCs in peripheral blood of HCC patients were further separated and identified. Immunofluorescence was used to identify CTCs for further counting. By this means, the correlation between CTCs count and clinicopathological features was analyzed, and the genetic mutation characteristics of NGS derived from CTCs were investigated and compared with that of tissue NGS. Results showed that compared with EpCAM and vimentin, GPC-3 had a stronger CTCs separation ability. There was a correlation between "positive" count of CTCs (≥ 5 PV-CTC per 7.5 ml blood) and BCLC stage (P = 0.055). The result of CTC-NGS was consistent with that of tissue-NGS in 60% cases, revealing that KMT2C was a common highly-frequent mutated gene. Conclusion The combination of immunomagnetic separation of CTCs and anti-tumor marker identification technology can be regarded as a new technology of CTCs detection in peripheral blood of patients with HCC. Trial registration EHBHKY2020-k-024. Registered 17 August 2020—Retrospectively registered![]()
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Affiliation(s)
- Bin Yi
- Department of Organ Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Tian Wu
- Jukang (Shanghai) Biotechnology Co. Ltd., 28, Xiangle Rd., Shanghai, 201800, China
| | - Nan Zhu
- Department of Organ Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yao Huang
- Department of Organ Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xiaoyu Yang
- Department of Organ Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lei Yuan
- Department I of Biliary Tract, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, No. 225, Changhai Rd., Shanghai, 200438, China
| | - Yingjun Wu
- Department I of Biliary Tract, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, No. 225, Changhai Rd., Shanghai, 200438, China
| | - Xiaofei Liang
- Jukang (Shanghai) Biotechnology Co. Ltd., 28, Xiangle Rd., Shanghai, 201800, China.
| | - Xiaoqing Jiang
- Department I of Biliary Tract, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, No. 225, Changhai Rd., Shanghai, 200438, China.
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19
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Wu H, Wang MD, Liang L, Xing H, Zhang CW, Shen F, Huang DS, Yang T. Nanotechnology for Hepatocellular Carcinoma: From Surveillance, Diagnosis to Management. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2005236. [PMID: 33448111 DOI: 10.1002/smll.202005236] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/08/2020] [Indexed: 06/12/2023]
Abstract
Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer-related death worldwide. However, the clinical diagnosis and treatment modalities are still relatively limited, which urgently require the development of new effective technologies. Recently, nanotechnology has gained extensive attention in HCC surveillance, imaging and pathological diagnosis, and therapeutic strategies. Typically, nanomedicines have been focused on early HCC diagnosis and precise treatment of advanced HCC, which has developed and improved a variety of new technologies and agents for future clinical practice. Furthermore, strategies of facilitating drug release and delivery in current treatment processes such as ablation, systematic therapy, transcatheter arterial chemoembolization, molecular targeted therapy, and immune-modulating therapy have also been studied widely. This review summarizes the recent advances in this area according to current clinical HCC guidelines: 1) Nanoparticle-based HCC surveillance; 2) Nanotechnology for HCC diagnosis; 3) Therapeutic advances for HCC Management; 4) Limitations of applications in nanotechnology for HCC; 5) Conclusions and perspectives. Although there are still many limitations and difficulties to overcome, the investigations of nanomedicines are believed to show potential applications in clinical practice.
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Affiliation(s)
- Han Wu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, 310014, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200438, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200438, China
| | - Lei Liang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, 310014, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China
| | - Hao Xing
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200438, China
| | - Cheng-Wu Zhang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200438, China
| | - Dong-Sheng Huang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, 310014, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Tian Yang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, 310014, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200438, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China
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Kukkar D, Kukkar P, Kumar V, Hong J, Kim KH, Deep A. Recent advances in nanoscale materials for antibody-based cancer theranostics. Biosens Bioelectron 2020; 173:112787. [PMID: 33190049 DOI: 10.1016/j.bios.2020.112787] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 10/08/2020] [Accepted: 10/30/2020] [Indexed: 02/07/2023]
Abstract
The quest for advanced management tools or options of various cancers has been on the rise to efficiently reduce their risks of mortality without the demerits of conventional treatments (e.g., undesirable side effects of the medications on non-target tissues, non-targeted distribution, slow clearance of the administered drugs, and the development of drug resistance over the duration of therapy). In this context, nanomaterials-antibody conjugates can offer numerous advantages in the development of cancer theranostics over conventional delivery systems (e.g., highly specific and enhanced biodistribution of the drug in targeted tissues, prolonged systemic circulation, low toxicity, and minimally invasive molecular imaging). This review comprehensively discusses and evaluates recent advances in the application of nanomaterial-antibody bioconjugates for cancer theranostics for the further advancement in the control of diverse cancerous diseases. Further, discussion is expanded to cover the various challenges and limitations associated with the design and development of nanomaterial-antibody conjugates applicable towards better management of cancer.
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Affiliation(s)
- Deepak Kukkar
- Department of Nanotechnology, Sri Guru Granth Sahib World University, Fatehgarh Sahib, Punjab, 140406, India
| | - Preeti Kukkar
- Department of Chemistry, Mata Gujri College, Fatehgarh Sahib, Punjab, 140406, India
| | - Vanish Kumar
- National Agri-Food Biotechnology Institute (NABI), S.A.S. Nagar, Punjab, 140306, India
| | - Jongki Hong
- College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea
| | - Ki-Hyun Kim
- Department of Civil and Environmental Engineering, Hanyang University, Seoul, 04763 Republic of Korea.
| | - Akash Deep
- Central Scientific Instruments Organization (CSIR-CSIO), Sector 30 C, Chandigarh, 160030, India.
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Zongyi Y, Xiaowu L. Immunotherapy for hepatocellular carcinoma. Cancer Lett 2020; 470:8-17. [DOI: 10.1016/j.canlet.2019.12.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/25/2019] [Accepted: 12/01/2019] [Indexed: 02/08/2023]
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22
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Wang W, Wei C. Advances in the early diagnosis of hepatocellular carcinoma. Genes Dis 2020; 7:308-319. [PMID: 32884985 PMCID: PMC7452544 DOI: 10.1016/j.gendis.2020.01.014] [Citation(s) in RCA: 249] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/10/2020] [Accepted: 01/20/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers globally. In contrast to the declining death rates observed for all other common cancers such as breast, lung, and prostate cancers, the death rates for HCC continue to increase by ~2–3% per year because HCC is frequently diagnosed late and there is no curative therapy for an advanced HCC. The early diagnosis of HCC is truly a big challenge. Over the past years, the early diagnosis of HCC has relied on surveillance with ultrasonography (US) and serological assessments of alpha-fetoprotein (AFP). However, the specificity and sensitivity of US/AFP is not satisfactory enough to detect early onset HCC. Recent technological advancements offer hope for early HCC diagnosis. Herein, we review the progress made in HCC diagnostics, with a focus on emerging imaging techniques and biomarkers for early disease diagnosis.
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Affiliation(s)
- Weiyi Wang
- Xiamen Amplly Bio-engineering Co., Ltd, Xiamen, PR China
| | - Chao Wei
- Xiamen Amplly Bio-engineering Co., Ltd, Xiamen, PR China
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