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Ismail M, Liu J, Wang N, Zhang D, Qin C, Shi B, Zheng M. Advanced nanoparticle engineering for precision therapeutics of brain diseases. Biomaterials 2025; 318:123138. [PMID: 39914193 DOI: 10.1016/j.biomaterials.2025.123138] [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: 09/18/2024] [Revised: 12/31/2024] [Accepted: 01/23/2025] [Indexed: 03/05/2025]
Abstract
Despite the increasing global prevalence of neurological disorders, the development of nanoparticle (NP) technologies for brain-targeted therapies confronts considerable challenges. One of the key obstacles in treating brain diseases is the blood-brain barrier (BBB), which restricts the penetration of NP-based therapies into the brain. To address this issue, NPs can be installed with specific ligands or bioengineered to boost their precision and efficacy in targeting brain-diseased cells by navigating across the BBB, ultimately improving patient treatment outcomes. At the outset of this review, we highlighted the critical role of ligand-functionalized or bioengineered NPs in treating brain diseases from a clinical perspective. We then identified the key obstacles and challenges NPs encounter during brain delivery, including immune clearance, capture by the reticuloendothelial system (RES), the BBB, and the complex post-BBB microenvironment. Following this, we overviewed the recent progress in NPs engineering, focusing on ligand-functionalization or bionic designs to enable active BBB transcytosis and targeted delivery to brain-diseased cells. Lastly, we summarized the critical challenges hindering clinical translation, including scalability issues and off-target effects, while outlining future opportunities for designing cutting-edge brain delivery technologies.
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Affiliation(s)
- Muhammad Ismail
- Huaihe Hospital of Henan University, Henan University, Kaifeng, Henan 475000, China; Henan-Macquarie University Joint Centre for Biomedical Innovation, Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Jiayi Liu
- Henan-Macquarie University Joint Centre for Biomedical Innovation, Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Ningyang Wang
- Henan-Macquarie University Joint Centre for Biomedical Innovation, Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Dongya Zhang
- Huaihe Hospital of Henan University, Henan University, Kaifeng, Henan 475000, China; Henan-Macquarie University Joint Centre for Biomedical Innovation, Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Changjiang Qin
- Huaihe Hospital of Henan University, Henan University, Kaifeng, Henan 475000, China.
| | - Bingyang Shi
- Henan-Macquarie University Joint Centre for Biomedical Innovation, Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China; Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, 2109, Australia.
| | - Meng Zheng
- Huaihe Hospital of Henan University, Henan University, Kaifeng, Henan 475000, China; Henan-Macquarie University Joint Centre for Biomedical Innovation, Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China.
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2
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Pardridge WM. Brain gene therapy with Trojan horse lipid nanoparticles. Trends Mol Med 2023; 29:343-353. [PMID: 36907687 PMCID: PMC10005896 DOI: 10.1016/j.molmed.2023.02.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 02/16/2023] [Accepted: 02/20/2023] [Indexed: 03/13/2023]
Abstract
The COVID-19 mRNA vaccine was developed by the scalable manufacture of lipid nanoparticles (LNPs) that encapsulate mRNA within the lipid. There are many potential applications for this large nucleic acid delivery technology, including the delivery of plasmid DNA for gene therapy. However, gene therapy for the brain requires LNP delivery across the blood-brain barrier (BBB). It is proposed that LNPs could be reformulated for brain delivery by conjugation of receptor-specific monoclonal antibodies (MAbs) to the LNP surface. The MAb acts as a molecular Trojan horse to trigger receptor-mediated transcytosis (RMT) of the LNP across the BBB and subsequent localization to the nucleus for transcription of the therapeutic gene. Trojan horse LNPs could enable new approaches to gene therapy of the brain.
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Li J, Zhang Z, Zhang B, Yan X, Fan K. Transferrin receptor 1 targeted nanomedicine for brain tumor therapy. Biomater Sci 2023; 11:3394-3413. [PMID: 36847174 DOI: 10.1039/d2bm02152h] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Achieving effective drug delivery to traverse the blood-brain barrier (BBB) and target tumor cells remains the greatest challenge for brain tumor therapy. Importantly, the overexpressed membrane receptors on the brain endothelial cells, especially transferrin receptor 1 (TfR1), which mediate their ligands/antibodies to overcome the BBB by transcytosis, have been emerging as promising targets for brain tumor therapy. By employing ligands (e.g., transferrin, H-ferritin), antibodies or targeting peptides of TfR1 or aptamers, various functional nano-formulations have been developed in the last decade. These agents showed great potential for the treatment of brain diseases due to their ideal size, high loading capacity, controlled drug release and suitable pharmacokinetics. Herein, we summarize the latest advances on TfR1-targeted nanomedicine for brain tumor therapy. Moreover, we also discuss the strategies of improving stability, targeting ability and accumulation of nano-formulations in brain tumors for better outcomes. In this review, we hope to provide inspiration for the rational design of TfR1-targeted nanomedicine against brain tumors.
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Affiliation(s)
- Jianru Li
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P. R. China.
| | - Zixia Zhang
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P. R. China.
| | - Baoli Zhang
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P. R. China.
| | - Xiyun Yan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P. R. China. .,Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, China.,University of Chinese Academy of Sciences, Beijing 101408, China
| | - Kelong Fan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P. R. China. .,Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, China.,University of Chinese Academy of Sciences, Beijing 101408, China
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Abstract
This Review examines the state-of-the-art in the delivery of nucleic acid therapies that are directed to the vascular endothelium. First, we review the most important homeostatic functions and properties of the vascular endothelium and summarize the nucleic acid tools that are currently available for gene therapy and nucleic acid delivery. Second, we consider the opportunities available with the endothelium as a therapeutic target and the experimental models that exist to evaluate the potential of those opportunities. Finally, we review the progress to date from investigations that are directly targeting the vascular endothelium: for vascular disease, for peri-transplant therapy, for angiogenic therapies, for pulmonary endothelial disease, and for the blood-brain barrier, ending with a summary of the future outlook in this field.
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Affiliation(s)
| | | | | | - W. Mark Saltzman
- Department of Biomedical Engineering
- Department of Chemical & Environmental Engineering
- Department of Cellular & Molecular Physiology
- Department of Dermatology, Yale School of Medicine, New Haven, CT 06510
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5
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Kaur T, Upadhyay J, Pukale S, Mathur A, Ansari MN. Investigation of Trends in the Research on Transferrin Receptor-Mediated Drug Delivery via a Bibliometric and Thematic Analysis. Pharmaceutics 2022; 14:pharmaceutics14122574. [PMID: 36559067 PMCID: PMC9788388 DOI: 10.3390/pharmaceutics14122574] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/18/2022] [Accepted: 11/20/2022] [Indexed: 11/25/2022] Open
Abstract
This study systematically reviews and characterizes the existing literature on transferrin/transferrin receptor-mediated drug delivery. Transferrin is an iron-binding protein. It can be used as a ligand to deliver various proteins, genes, ions, and drugs to the target site via transferrin receptors for therapeutic or diagnostic purposes via transferrin receptors. This study is based on a cross-sectional bibliometric analysis of 583 papers limited to the subject areas of pharmacology, toxicology, and pharmaceutics as extracted from the Scopus database in mid-September 2022. The data were analyzed, and we carried out a performance analysis and science mapping. There was a significant increase in research from 2018 onward. The countries that contributed the most were the USA and China, and most of the existing research was found to be from single-country publications. Research studies on transferrin/transferrin receptor-mediated drug delivery focus on drug delivery across the blood-brain barrier in the form of nanoparticles. The thematic analysis revealed four themes: transferrin/transferrin receptor-mediated drug delivery to the brain, cancer cells, gene therapy, nanoparticles, and liposomes as drug delivery systems. This study is relevant to academics, practitioners, and decision makers interested in targeted and site-specific drug delivery.
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Affiliation(s)
- Tarnjot Kaur
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, University of Petroleum and Energy Studies, Energy Acre Campus Bidholi, Dehradun 248007, India
| | - Jyoti Upadhyay
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, University of Petroleum and Energy Studies, Energy Acre Campus Bidholi, Dehradun 248007, India
- Correspondence: (J.U.); (M.N.A.)
| | | | - Ashish Mathur
- Centre for Interdisciplinary Research and Innovation (CIDRI), University of Petroleum and Energy Studies, Dehradun 248007, India
- Department of Physics, University of Petroleum and Energy Studies, Dehradun 248007, India
| | - Mohd Nazam Ansari
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
- Correspondence: (J.U.); (M.N.A.)
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Pardridge WM. A Historical Review of Brain Drug Delivery. Pharmaceutics 2022; 14:1283. [PMID: 35745855 PMCID: PMC9229021 DOI: 10.3390/pharmaceutics14061283] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/01/2022] [Accepted: 06/07/2022] [Indexed: 12/13/2022] Open
Abstract
The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood-brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Drugs that do not cross the BBB can be re-engineered for transport on endogenous BBB carrier-mediated transport and receptor-mediated transport systems, which were identified during the 1970s-1980s. By the 1990s, a multitude of brain drug delivery technologies emerged, including trans-cranial delivery, CSF delivery, BBB disruption, lipid carriers, prodrugs, stem cells, exosomes, nanoparticles, gene therapy, and biologics. The advantages and limitations of each of these brain drug delivery technologies are critically reviewed.
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Affiliation(s)
- William M Pardridge
- Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
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Rawal SU, Patel BM, Patel MM. New Drug Delivery Systems Developed for Brain Targeting. Drugs 2022; 82:749-792. [PMID: 35596879 DOI: 10.1007/s40265-022-01717-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2022] [Indexed: 11/26/2022]
Abstract
The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSF) are two of the most complex and sophisticated concierges that defend the central nervous system (CNS) by numerous mechanisms. While they maintain the neuro-ecological homeostasis through the regulated entry of essential biomolecules, their conservative nature challenges the entry of most of the drugs intended for CNS delivery. Targeted delivery challenges for a diverse spectrum of therapeutic agents/drugs (non-small molecules, small molecules, gene-based therapeutics, protein and peptides, antibodies) are diverse and demand specialized delivery and disease-targeting strategies. This review aims to capture the trends that have shaped the current brain targeting research scenario. This review discusses the physiological, neuropharmacological, and etiological factors that participate in the transportation of various drug delivery cargoes across the BBB/BCSF and influence their therapeutic intracranial concentrations. Recent research works spanning various invasive, minimally invasive, and non-invasive brain- targeting approaches are discussed. While the pre-clinical outcomes from many of these approaches seem promising, further research is warranted to overcome the translational glitches that prevent their clinical use. Non-invasive approaches like intranasal administration, P-glycoprotein (P-gp) inhibition, pro-drugs, and carrier/targeted nanocarrier-aided delivery systems (alone or often in combination) hold positive clinical prospects for brain targeting if explored further in the right direction.
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Affiliation(s)
- Shruti U Rawal
- Department of Pharmaceutics, Institute of Pharmacy, Nirma University, SG Highway, Chharodi, Ahmedabad, Gujarat, 382481, India
- Department of Pharmaceutical Technology, L.J. Institute of Pharmacy, L J University, Sarkhej-Sanand Circle Off. S.G. Road, Ahmedabad, Gujarat, 382210, India
| | - Bhoomika M Patel
- Department of Pharmacology, Institute of Pharmacy, Nirma University, SG Highway, Chharodi, Ahmedabad, Gujarat, 382481, India
| | - Mayur M Patel
- Department of Pharmaceutics, Institute of Pharmacy, Nirma University, SG Highway, Chharodi, Ahmedabad, Gujarat, 382481, India.
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Vetter VC, Wagner E. Targeting nucleic acid-based therapeutics to tumors: Challenges and strategies for polyplexes. J Control Release 2022; 346:110-135. [PMID: 35436520 DOI: 10.1016/j.jconrel.2022.04.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/07/2022] [Accepted: 04/10/2022] [Indexed: 12/18/2022]
Abstract
The current medical reality of cancer gene therapy is reflected by more than ten approved products on the global market, including oncolytic and other viral vectors and CAR T-cells as ex vivo gene-modified cell therapeutics. The development of synthetic antitumoral nucleic acid therapeutics has been proceeding at a lower but steady pace, fueled by a plethora of alternative nucleic acid platforms (from various antisense oligonucleotides, siRNA, microRNA, lncRNA, sgRNA, to larger mRNA and DNA) and several classes of physical and chemical delivery technologies. This review summarizes the challenges and strategies for tumor-targeted nucleic acid delivery. Focusing primarily on polyplexes (polycation complexes) as nanocarriers, delivery options across multiple barriers into tumor cells are illustrated.
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Affiliation(s)
- Victoria C Vetter
- Pharmaceutical Biotechnology, Center for System-based Drug Research, Ludwig-Maximilians-Universität, Munich 81377, Germany
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Center for System-based Drug Research, Ludwig-Maximilians-Universität, Munich 81377, Germany; Center for NanoScience (CeNS), Ludwig-Maximilians-Universität, Munich 81377, Germany.
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9
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Zheng T, Wang W, Mohammadniaei M, Ashley J, Zhang M, Zhou N, Shen J, Sun Y. Anti-MicroRNA-21 Oligonucleotide Loaded Spermine-Modified Acetalated Dextran Nanoparticles for B1 Receptor-Targeted Gene Therapy and Antiangiogenesis Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103812. [PMID: 34936240 PMCID: PMC8844571 DOI: 10.1002/advs.202103812] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/22/2021] [Indexed: 05/10/2023]
Abstract
The use of nanoparticles (NPs) to deliver small inhibiting microRNAs (miRNAs) has shown great promise for treating cancer. However, constructing a miRNA delivery system that targets brain cancers, such as glioblastoma multiforme (GBM), remains technically challenging due to the existence of the blood-tumor barrier (BTB). In this work, a novel targeted antisense miRNA-21 oligonucleotide (ATMO-21) delivery system is developed for GBM treatment. Bradykinin ligand agonist-decorated spermine-modified acetalated dextran NPs (SpAcDex NPs) could temporarily open the BTB by activating G-protein-coupled receptors that are expressed in tumor blood vessels and tumor cells, which increase transportation to and accumulation in tumor sites. ATMO-21 achieves high loading in the SpAcDex NPs (over 90%) and undergoes gradual controlled release with the degradation of the NPs in acidic lysosomal compartments. This allows for cell apoptosis and inhibition of the expression of vascular endothelial growth factor by downregulating hypoxia-inducible factor (HIF-1α) protein. An in vivo orthotopic U87MG glioma model confirms that the released ATMO-21 shows significant therapeutic efficacy in inhibiting tumor growth and angiogenesis, demonstrating that agonist-modified SpAcDex NPs represent a promising strategy for GBM treatment combining targeted gene therapy and antiangiogenic therapy.
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Affiliation(s)
- Tao Zheng
- Department of Health TechnologyTechnical University of DenmarkKongens LyngbyDK‐2800Denmark
| | - Wentao Wang
- Department of Health TechnologyTechnical University of DenmarkKongens LyngbyDK‐2800Denmark
| | - Mohsen Mohammadniaei
- Department of Health TechnologyTechnical University of DenmarkKongens LyngbyDK‐2800Denmark
| | - Jon Ashley
- Department of Health TechnologyTechnical University of DenmarkKongens LyngbyDK‐2800Denmark
| | - Ming Zhang
- Department of Health TechnologyTechnical University of DenmarkKongens LyngbyDK‐2800Denmark
- Jiangsu Collaborative Innovation Center for Biomedical Functional MaterialsSchool of Chemistry and Materials ScienceNanjing Normal UniversityNanjing210023P. R. China
| | - Ninglin Zhou
- Jiangsu Collaborative Innovation Center for Biomedical Functional MaterialsSchool of Chemistry and Materials ScienceNanjing Normal UniversityNanjing210023P. R. China
| | - Jian Shen
- Jiangsu Collaborative Innovation Center for Biomedical Functional MaterialsSchool of Chemistry and Materials ScienceNanjing Normal UniversityNanjing210023P. R. China
| | - Yi Sun
- Department of Health TechnologyTechnical University of DenmarkKongens LyngbyDK‐2800Denmark
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Griffith JI, Rathi S, Zhang W, Zhang W, Drewes LR, Sarkaria JN, Elmquist WF. Addressing BBB Heterogeneity: A New Paradigm for Drug Delivery to Brain Tumors. Pharmaceutics 2020; 12:E1205. [PMID: 33322488 PMCID: PMC7763839 DOI: 10.3390/pharmaceutics12121205] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/08/2020] [Accepted: 12/10/2020] [Indexed: 12/11/2022] Open
Abstract
Effective treatments for brain tumors remain one of the most urgent and unmet needs in modern oncology. This is due not only to the presence of the neurovascular unit/blood-brain barrier (NVU/BBB) but also to the heterogeneity of barrier alteration in the case of brain tumors, which results in what is referred to as the blood-tumor barrier (BTB). Herein, we discuss this heterogeneity, how it contributes to the failure of novel pharmaceutical treatment strategies, and why a "whole brain" approach to the treatment of brain tumors might be beneficial. We discuss various methods by which these obstacles might be overcome and assess how these strategies are progressing in the clinic. We believe that by approaching brain tumor treatment from this perspective, a new paradigm for drug delivery to brain tumors might be established.
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Affiliation(s)
- Jessica I. Griffith
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; (S.R.); (W.Z.); (W.Z.)
| | - Sneha Rathi
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; (S.R.); (W.Z.); (W.Z.)
| | - Wenqiu Zhang
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; (S.R.); (W.Z.); (W.Z.)
| | - Wenjuan Zhang
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; (S.R.); (W.Z.); (W.Z.)
| | - Lester R. Drewes
- Department of Biomedical Sciences, University of Minnesota Medical School—Duluth, Duluth, MN 55812, USA;
| | - Jann N. Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55902, USA;
| | - William F. Elmquist
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; (S.R.); (W.Z.); (W.Z.)
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11
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Pardridge WM. Brain Delivery of Nanomedicines: Trojan Horse Liposomes for Plasmid DNA Gene Therapy of the Brain. FRONTIERS IN MEDICAL TECHNOLOGY 2020; 2:602236. [PMID: 35047884 PMCID: PMC8757841 DOI: 10.3389/fmedt.2020.602236] [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: 09/02/2020] [Accepted: 10/06/2020] [Indexed: 12/14/2022] Open
Abstract
Non-viral gene therapy of the brain is enabled by the development of plasmid DNA brain delivery technology, which requires the engineering and manufacturing of nanomedicines that cross the blood-brain barrier (BBB). The development of such nanomedicines is a multi-faceted problem that requires progress at multiple levels. First, the type of nanocontainer, e.g., nanoparticle or liposome, which encapsulates the plasmid DNA, must be developed. Second, the type of molecular Trojan horse, e.g., peptide or receptor-specific monoclonal antibody (MAb), must be selected for incorporation on the surface of the nanomedicine, as this Trojan horse engages specific receptors expressed on the BBB, and the brain cell membrane, to trigger transport of the nanomedicine from blood into brain cells beyond the BBB. Third, the plasmid DNA must be engineered without bacterial elements, such as antibiotic resistance genes, to enable administration to humans; the plasmid DNA must also be engineered with tissue-specific gene promoters upstream of the therapeutic gene, to insure gene expression in the target organ with minimal off-target expression. Fourth, upstream manufacturing of the nanomedicine must be developed and scalable so as to meet market demand for the target disease, e.g., annual long-term treatment of 1,000 patients with an orphan disease, short term treatment of 10,000 patients with malignant glioma, or 100,000 patients with new onset Parkinson's disease. Fifth, downstream manufacturing problems, such as nanomedicine lyophilization, must be solved to ensure the nanomedicine has a commercially viable shelf-life for treatment of CNS disease in humans.
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Affiliation(s)
- William M Pardridge
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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12
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Abstract
Background:
Drug delivery to cancerous brain is a challenging task as it is
surrounded by an efficient protective barrier. The main hurdles for delivery of bioactive
molecules to cancerous brain are blood brain barrier (BBB), the invasive nature of gliomas,
drug resistance, and difficult brain interstitium transportation. Therefore, treatment
of brain cancer with the available drug regimen is difficult and has shown little improvement
in recent years.
Methods:
We searched about recent advancements in the use of nanomedicine for effective
treatment of the brain cancer. We focused on the use of liposomes, nanoparticles,
polymeric micelles, and dendrimers to improve brain cancer therapy.
Results:
Nanomedicines are well suited for the treatment of brain cancer owing to their
highly acceptable biological, chemical, and physical properties. Smaller size of nanomedicines
also enhances their anticancer potential and penetration into blood brain barrier
(BBB).
Conclusion:
Recently, nanomedicine based approaches have been developed and investigated
for effective treatment of brain cancer. Some of these have been translated into
clinical practice, in order to attain therapeutic needs of gliomas. Future advancements in
nanomedicines will likely produce significant changes in methods and practice of brain
cancer therapy.
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Affiliation(s)
- Shivani Verma
- I. K. Gujral Punjab Technical University, Jalandhar-Punjab 144601, India
| | - Puneet Utreja
- I. K. Gujral Punjab Technical University, Jalandhar-Punjab 144601, India
| | - Lalit Kumar
- I. K. Gujral Punjab Technical University, Jalandhar-Punjab 144601, India
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13
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Pardridge WM. Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain. Front Aging Neurosci 2020; 11:373. [PMID: 31998120 PMCID: PMC6966240 DOI: 10.3389/fnagi.2019.00373] [Citation(s) in RCA: 235] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 12/19/2019] [Indexed: 01/02/2023] Open
Abstract
Alzheimer’s disease (AD) and treatment of the brain in aging require the development of new biologic drugs, such as recombinant proteins or gene therapies. Biologics are large molecule therapeutics that do not cross the blood-brain barrier (BBB). BBB drug delivery is the limiting factor in the future development of new therapeutics for the brain. The delivery of recombinant protein or gene medicines to the brain is a binary process: either the brain drug developer re-engineers the biologic with BBB drug delivery technology, or goes forward with brain drug development in the absence of a BBB delivery platform. The presence of BBB delivery technology allows for engineering the therapeutic to enable entry into the brain across the BBB from blood. Brain drug development may still take place in the absence of BBB delivery technology, but with a reliance on approaches that have rarely led to FDA approval, e.g., CSF injection, stem cells, small molecules, and others. CSF injection of drug is the most widely practiced approach to brain delivery that bypasses the BBB. However, drug injection into the CSF results in limited drug penetration to the brain parenchyma, owing to the rapid export of CSF from the brain to blood. A CSF injection of a drug is equivalent to a slow intravenous (IV) infusion of the pharmaceutical. Given the profound effect the existence of the BBB has on brain drug development, future drug or gene development for the brain will be accelerated by future advances in BBB delivery technology in parallel with new drug discovery.
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Affiliation(s)
- William M Pardridge
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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Johnsen KB, Burkhart A, Thomsen LB, Andresen TL, Moos T. Targeting the transferrin receptor for brain drug delivery. Prog Neurobiol 2019; 181:101665. [DOI: 10.1016/j.pneurobio.2019.101665] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/10/2019] [Accepted: 07/18/2019] [Indexed: 02/07/2023]
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Abstract
Delivery of imaging agents and pharmaceutical payloads to the central nervous system (CNS) is essential for efficient diagnosis and treatment of brain diseases. However, therapeutic delivery is often restricted by the blood-brain barrier (BBB), which prevents transport of clinical compounds to their region of interest. This review discusses the methods that have been used to avoid or overcome this barrier, presenting the use of biologically-derived nanomaterial systems as an efficient strategy for the diagnosis and treatment of CNS diseases. Biological nanomaterials have many advantages over synthetic systems, including being biodegradable, biocompatible, easily surface functionalised for conjugation of targeting moieties, and are often able to self-assemble. These abilities are discussed in relation to various systems, including liposomes, dendrimers, and viral nanoparticles.
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Abstract
Polyglutamine diseases are hereditary degenerative disorders of the nervous system that have remained, to this date, untreatable. Promisingly, investigation into their molecular etiology and the development of increasingly perfected tools have contributed to the design of novel strategies with therapeutic potential. Encouraging studies have explored gene therapy as a means to counteract cell demise and loss in this context. The current chapter addresses the two main focuses of research in the area: the characteristics of the systems used to deliver nucleic acids to cells and the molecular and cellular actions of the therapeutic agents. Vectors used in gene therapy have to satisfyingly reach the tissues and cell types of interest, while eliciting the lowest toxicity possible. Both viral and non-viral systems have been developed for the delivery of nucleic acids to the central nervous system, each with its respective advantages and shortcomings. Since each polyglutamine disease is caused by mutation of a single gene, many gene therapy strategies have tried to halt degeneration by silencing the corresponding protein products, usually recurring to RNA interference. The potential of small interfering RNAs, short hairpin RNAs and microRNAs has been investigated. Overexpression of protective genes has also been evaluated as a means of decreasing mutant protein toxicity and operate beneficial alterations. Recent gene editing tools promise yet other ways of interfering with the disease-causing genes, at the most upstream points possible. Results obtained in both cell and animal models encourage further delving into this type of therapeutic strategies and support the future use of gene therapy in the treatment of polyglutamine diseases.
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Yang R, Wei T, Goldberg H, Wang W, Cullion K, Kohane DS. Getting Drugs Across Biological Barriers. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2017; 29:10.1002/adma.201606596. [PMID: 28752600 PMCID: PMC5683089 DOI: 10.1002/adma.201606596] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 05/30/2017] [Indexed: 05/13/2023]
Abstract
The delivery of drugs to a target site frequently involves crossing biological barriers. The degree and nature of the impediment to flux, as well as the potential approaches to overcoming it, depend on the tissue, the drug, and numerous other factors. Here an overview of approaches that have been taken to crossing biological barriers is presented, with special attention to transdermal drug delivery. Technology and knowledge pertaining to addressing these issues in a variety of organs could have a significant clinical impact.
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Affiliation(s)
- Rong Yang
- Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Tuo Wei
- Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Hannah Goldberg
- Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Weiping Wang
- Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Kathleen Cullion
- Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Daniel S Kohane
- Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
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Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease. J Control Release 2017; 260:61-77. [PMID: 28549949 DOI: 10.1016/j.jconrel.2017.05.019] [Citation(s) in RCA: 225] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Revised: 05/12/2017] [Accepted: 05/13/2017] [Indexed: 12/20/2022]
Abstract
In this modern era, with the help of various advanced technologies, medical science has overcome most of the health-related issues successfully. Though, some diseases still remain unresolved due to various physiological barriers. One such condition is Alzheimer; a neurodegenerative disorder characterized by progressive memory impairment, behavioral abnormalities, mood swing and disturbed routine activities of the person suffering from. It is well known to all that the brain is entirely covered by a protective layer commonly known as blood brain barrier (BBB) which is responsible to maintain the homeostasis of brain by restricting the entry of toxic substances, drug molecules, various proteins and peptides, small hydrophilic molecules, large lipophilic substances and so many other peripheral components to protect the brain from any harmful stimuli. This functionally essential structure creates a major hurdle for delivery of any drug into the brain. Still, there are some provisions on BBB which facilitate the entry of useful substances in the brain via specific mechanisms like passive diffusion, receptor-mediated transcytosis, carrier-mediated transcytosis etc. Another important factor for drug transport is the selection of a suitable drug delivery systems like, liposome, which is a novel drug carrier system offering a potential approach to resolving this problem. Its unique phospholipid bilayer structure (similar to physiological membrane) had made it more compatible with the lipoidal layer of BBB and helps the drug to enter the brain. The present review work focused on various surface modifications with functional ligand (like lactoferrin, transferrin etc.) and carrier molecules (such as glutathione, glucose etc.) on the liposomal structure to enhance its brain targeting ability towards the successful treatment of Alzheimer disease.
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20
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Wang D, Wu LP. Nanomaterials for delivery of nucleic acid to the central nervous system (CNS). MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2017; 70:1039-1046. [PMID: 27772703 DOI: 10.1016/j.msec.2016.04.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 03/11/2016] [Accepted: 04/04/2016] [Indexed: 11/08/2022]
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The “fate” of polymeric and lipid nanoparticles for brain delivery and targeting: Strategies and mechanism of blood–brain barrier crossing and trafficking into the central nervous system. J Drug Deliv Sci Technol 2016. [DOI: 10.1016/j.jddst.2015.07.007] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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22
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Johnsen KB, Moos T. Revisiting nanoparticle technology for blood–brain barrier transport: Unfolding at the endothelial gate improves the fate of transferrin receptor-targeted liposomes. J Control Release 2016; 222:32-46. [DOI: 10.1016/j.jconrel.2015.11.032] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/28/2015] [Accepted: 11/30/2015] [Indexed: 12/25/2022]
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23
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Cornford EM, Hyman S, Cornford ME, Chytrova G, Rhee J, Suzuki T, Yamagata T, Yamakawa K, Penichet ML, Pardridge WM. Non-invasive gene targeting to the fetal brain after intravenous administration and transplacental transfer of plasmid DNA using PEGylated immunoliposomes. J Drug Target 2015; 24:58-67. [PMID: 26133964 DOI: 10.3109/1061186x.2015.1055569] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Research was undertaken to establish transplacental delivery of active genes to fetal brain by a non-viral vector, antibody-specific targeted therapeutic procedure. PEGylated immunoliposomes (PILs) containing firefly luciferase DNA under the influence of the SV40 promoter injected intravenously into near-term pregnant mice produced luminometric evidence of CNS tissue luciferase activity at 48-h post-injection in all newborn pups. In utero delivery of this pGL3 DNA was shown after a single i.v. injection in maternal and neonatal brains, spleen and lesser amounts in lungs, with only negligible background levels in negative controls exposed to unencapsulated pDNA. In addition to studies of normal wild-type mice, we similarly injected pregnant Lafora Knockout (EPM2a null-mutant) and demonstrated luciferase activity days later in the maternal and newborn pup brains of both types. Delivery of PILs containing a second reporter gene (the pSV40 beta-galactosidase transgene) transplacentally by the same procedure was also successful. Histochemical and biochemical demonstration of beta-galactosidase was documented for all mutant and non-mutant neonates. Brain areas of highest Lafora body development (such as the hippocampus and pontine nuclei) showed intraneuronal beta-glucosidase activity. We conclude that receptor-mediated transport of PIL-borne gene therapeutics across both the placental barrier as well as the fetal BBB in utero is feasible.
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Affiliation(s)
- Eain M Cornford
- a Neurology and Research Services, VA Greater Los Angeles Healthcare System, West Los Angeles Medical Center , Los Angeles , CA , USA .,b Department of Neurology , David Geffen School of Medicine at UCLA , Los Angeles , CA , USA
| | - Shigeyo Hyman
- a Neurology and Research Services, VA Greater Los Angeles Healthcare System, West Los Angeles Medical Center , Los Angeles , CA , USA .,b Department of Neurology , David Geffen School of Medicine at UCLA , Los Angeles , CA , USA
| | - Marcia E Cornford
- c Department of Pathology , Harbor-UCLA Medical Center , Torrance , CA , USA .,d Department of Pathology , David Geffen School of Medicine at UCLA , Los Angeles , CA , USA
| | - Gabriela Chytrova
- a Neurology and Research Services, VA Greater Los Angeles Healthcare System, West Los Angeles Medical Center , Los Angeles , CA , USA .,b Department of Neurology , David Geffen School of Medicine at UCLA , Los Angeles , CA , USA
| | - Jennifer Rhee
- a Neurology and Research Services, VA Greater Los Angeles Healthcare System, West Los Angeles Medical Center , Los Angeles , CA , USA
| | | | | | | | - Manuel L Penichet
- f Division of Surgical Oncology , Department of Surgery, David Geffen School of Medicine at UCLA , Los Angeles , CA , USA .,g Department of Microbiology , Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA , Los Angeles , CA , USA .,h Jonsson Comprehensive Cancer Center , UCLA, Los Angeles , CA , USA .,i The Molecular Biology Institute , UCLA, Los Angeles , CA , USA , and
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Bishayee K, Khuda-Bukhsh AR, Huh SO. PLGA-Loaded Gold-Nanoparticles Precipitated with Quercetin Downregulate HDAC-Akt Activities Controlling Proliferation and Activate p53-ROS Crosstalk to Induce Apoptosis in Hepatocarcinoma Cells. Mol Cells 2015; 38:518-27. [PMID: 25947292 PMCID: PMC4469909 DOI: 10.14348/molcells.2015.2339] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 02/26/2015] [Accepted: 03/04/2015] [Indexed: 01/24/2023] Open
Abstract
Controlled release of medications remains the most convenient way to deliver drugs. In this study, we precipitated gold nanoparticles with quercetin. We loaded gold-quercetin into poly(DL-lactide-co-glycolide) nanoparticles (NQ) and tested the biological activity of NQ on HepG2 hepatocarcinoma cells to acquire the sustained release property. We determined by circular dichroism spectroscopy that NQ effectively caused conformational changes in DNA and modulated different proteins related to epigenetic modifications and cell cycle control. The mitochondrial membrane potential (MMP), reactive oxygen species (ROS), cell cycle, apoptosis, DNA damage, and caspase 3 activity were analyzed by flow cytometry, and the expression profiles of different anti- and pro-apoptotic as well as epigenetic signals were studied by immunoblotting. A cytotoxicity assay indicated that NQ preferentially killed cancer cells, compared to normal cells. NQ interacted with HepG2 cell DNA and reduced histone deacetylases to control cell proliferation and arrest the cell cycle at the sub-G stage. Activities of cell cycle-related proteins, such as p21(WAF), cdk1, and pAkt, were modulated. NQ induced apoptosis in HepG2 cells by activating p53-ROS crosstalk and induces epigenetic modifications leading to inhibited proliferation and cell cycle arrest.
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Affiliation(s)
- Kausik Bishayee
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon 200-702,
Korea
- Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani 741235,
India
| | - Anisur Rahman Khuda-Bukhsh
- Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani 741235,
India
| | - Sung-Oh Huh
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon 200-702,
Korea
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25
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Garg T, Bhandari S, Rath G, Goyal AK. Current strategies for targeted delivery of bio-active drug molecules in the treatment of brain tumor. J Drug Target 2015; 23:865-87. [PMID: 25835469 DOI: 10.3109/1061186x.2015.1029930] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Brain tumor is one of the most challenging diseases to treat. The major obstacle in the specific drug delivery to brain is blood-brain barrier (BBB). Mostly available anti-cancer drugs are large hydrophobic molecules which have limited permeability via BBB. Therefore, it is clear that the protective barriers confining the passage of the foreign particles into the brain are the main impediment for the brain drug delivery. Hence, the major challenge in drug development and delivery for the neurological diseases is to design non-invasive nanocarrier systems that can assist controlled and targeted drug delivery to the specific regions of the brain. In this review article, our major focus to treat brain tumor by study numerous strategies includes intracerebral implants, BBB disruption, intraventricular infusion, convection-enhanced delivery, intra-arterial drug delivery, intrathecal drug delivery, injection, catheters, pumps, microdialysis, RNA interference, antisense therapy, gene therapy, monoclonal/cationic antibodies conjugate, endogenous transporters, lipophilic analogues, prodrugs, efflux transporters, direct conjugation of antitumor drugs, direct targeting of liposomes, nanoparticles, solid-lipid nanoparticles, polymeric micelles, dendrimers and albumin-based drug carriers.
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Affiliation(s)
| | - Saurav Bhandari
- b Department of Quality Assurance , ISF College of Pharmacy , Moga , Punjab , India
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26
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Chiarelli PA, Kievit FM, Zhang M, Ellenbogen RG. Bionanotechnology and the future of glioma. Surg Neurol Int 2015; 6:S45-58. [PMID: 25722933 PMCID: PMC4338483 DOI: 10.4103/2152-7806.151334] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 10/15/2014] [Indexed: 01/01/2023] Open
Abstract
Designer nanoscaled materials have the potential to revolutionize diagnosis and treatment for glioma. This review summarizes current progress in nanoparticle-based therapies for glioma treatment including targeting, drug delivery, gene delivery, and direct tumor ablation. Preclinical and current human clinical trials are discussed. Although progress in the field has been significant over the past decade, many successful strategies demonstrated in the laboratory have yet to be implemented in human clinical trials. Looking forward, we provide examples of combined treatment strategies, which harness the potential for nanoparticles to interact with their biochemical environment, and simultaneously with externally applied photons or magnetic fields. We present our notion of the "ideal" nanoparticle for glioma, a concept that may soon be realized.
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Affiliation(s)
- Peter A Chiarelli
- Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, USA
| | - Forrest M Kievit
- Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, USA
| | - Miqin Zhang
- Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, USA ; Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, USA
| | - Richard G Ellenbogen
- Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, USA
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27
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Pardridge WM. Targeted delivery of protein and gene medicines through the blood-brain barrier. Clin Pharmacol Ther 2014; 97:347-61. [PMID: 25669455 DOI: 10.1002/cpt.18] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 09/25/2014] [Indexed: 11/05/2022]
Abstract
The development of biologic drugs (recombinant proteins, therapeutic antibodies, peptides, nucleic acid therapeutics) as new treatments of brain disorders has been difficult, and a major reason is the lack of transport through the blood-brain barrier (BBB) of these large molecule pharmaceuticals. Biologic drugs can be re-engineered as brain-penetrating neuropharmaceuticals using BBB molecular Trojan horse technology. Certain peptidomimetic monoclonal antibodies that target endogenous receptors on the BBB, such as the insulin or transferrin receptor, enable the re-engineering of biologic drugs that cross the BBB.
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Affiliation(s)
- W M Pardridge
- ArmaGen Technologies, Inc., Calabasas, California, USA
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28
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Tajes M, Ramos-Fernández E, Weng-Jiang X, Bosch-Morató M, Guivernau B, Eraso-Pichot A, Salvador B, Fernàndez-Busquets X, Roquer J, Muñoz FJ. The blood-brain barrier: structure, function and therapeutic approaches to cross it. Mol Membr Biol 2014; 31:152-67. [PMID: 25046533 DOI: 10.3109/09687688.2014.937468] [Citation(s) in RCA: 185] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The blood-brain barrier (BBB) is constituted by a specialized vascular endothelium that interacts directly with astrocytes, neurons and pericytes. It protects the brain from the molecules of the systemic circulation but it has to be overcome for the proper treatment of brain cancer, psychiatric disorders or neurodegenerative diseases, which are dramatically increasing as the population ages. In the present work we have revised the current knowledge on the cellular structure of the BBB and the different procedures utilized currently and those proposed to cross it. Chemical modifications of the drugs, such as increasing their lipophilicity, turn them more prone to be internalized in the brain. Other mechanisms are the use of molecular tools to bind the drugs such as small immunoglobulins, liposomes or nanoparticles that will act as Trojan Horses favoring the drug delivery in brain. This fusion of the classical pharmacology with nanotechnology has opened a wide field to many different approaches with promising results to hypothesize that BBB will not be a major problem for the new generation of neuroactive drugs. The present review provides an overview of all state-of-the-art of the BBB structure and function, as well as of the classic strategies and these appeared in recent years to deliver drugs into the brain for the treatment of Central Nervous System (CNS) diseases.
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Affiliation(s)
- Marta Tajes
- Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF) , Barcelona, Spain
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Combination-targeting to multiple endothelial cell adhesion molecules modulates binding, endocytosis, and in vivo biodistribution of drug nanocarriers and their therapeutic cargoes. J Control Release 2014; 188:87-98. [PMID: 24933603 DOI: 10.1016/j.jconrel.2014.06.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Revised: 05/24/2014] [Accepted: 06/07/2014] [Indexed: 01/11/2023]
Abstract
Designing of drug nanocarriers to aid delivery of therapeutics is an expanding field that can improve medical treatments. Nanocarriers are often functionalized with elements that recognize cell-surface molecules involved in subcellular transport to improve targeting and endocytosis of therapeutics. Combination-targeting using several affinity elements further modulates this outcome. The most studied example is endothelial targeting via multiple cell adhesion molecules (CAMs), which mimics the strategy of leukocytes to adhere and traverse the vascular endothelium. Yet, the implications of this strategy on intracellular transport and in vivo biodistribution remain uncharacterized. We examined this using nanocarriers functionalized for dual- or triple-targeting to intercellular, platelet-endothelial, and/or vascular CAMs (ICAM-1, PECAM-1, VCAM-1). These molecules differ in expression level, location, pathological stimulation, and/or endocytic pathway. In endothelial cells, binding of PECAM-1/VCAM-1-targeted nanocarriers was intermediate to single-targeted counterparts and enhanced in disease-like conditions. ICAM-1/PECAM-1-targeted nanocarriers surpassed PECAM-1/VCAM-1 in control, but showed lower selectivity toward disease-like conditions. Triple-targeting resulted in binding similar to ICAM-1/PECAM-1 combination and displayed the highest selectivity in disease-like conditions. All combinations were effectively internalized by the cells, with slightly better performance when targeting receptors of different endocytic pathways. In vivo, ICAM-1/PECAM-1-targeted nanocarriers outperformed PECAM-1/VCAM-1 in control and disease-like conditions, and triple-targeted counterparts slightly enhanced this outcome in some organs. As a result, delivery of a model therapeutic cargo (acid sphingomyelinase, deficient in Niemann-Pick disease A-B) was enhanced to all affected organs by triple-targeted nanocarriers, particularly in disease-like conditions. Therefore, multi-CAM targeting may aid the optimization of some therapeutic nanocarriers, where the combination and multiplicity of the affinity moieties utilized allow modulation of targeting performance.
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Abstract
Brain tumors remain a significant health problem. Advances in the biology of the blood-brain barrier are improving the ability of researchers to target therapeutic peptides, small molecules and other drugs to brain tumors. Simple methods to improve blood-brain barrier penetration include chemical modification, glycosylation and pegylation. Drug-delivery vehicles, such as nanoparticles and liposomes, are also under study. Targeting vectors include natural ligands (e.g., epidermal growth factor) or monoclonal antibodies to receptors (e.g., transferrin or insulin). Other vector-mediated delivery approaches involve the conjugation of a therapeutic peptide or protein with a targeting molecule that can induce transcytosis across blood-brain barrier endothelial cells. The most commonly used vectors are peptidomimetic antibodies to endothelial receptors, such as the transferrin and insulin receptors.
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Affiliation(s)
- Herbert B Newton
- Dardinger Neuro-oncology Center, Division of Neuro-oncology, 465 Means Hall, 1654 Upham Drive, Columbus, OH 43210, USA.
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31
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Markoutsa E, Papadia K, Giannou AD, Spella M, Cagnotto A, Salmona M, Stathopoulos GT, Antimisiaris SG. Mono and dually decorated nanoliposomes for brain targeting, in vitro and in vivo studies. Pharm Res 2013; 31:1275-89. [PMID: 24338512 DOI: 10.1007/s11095-013-1249-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 11/10/2013] [Indexed: 12/12/2022]
Abstract
PURPOSE Mono- and dual-decorated (DUAL) liposomes (LIP) were prepared, by immobilization of MAb against transferrin (TfR[OX26 or RI7217]) and/or a peptide analogue of ApoΕ3 (APOe) -to target low-density lipoprotein receptor(LPR)-, characterized physicochemically and investigated for BBB-targeting, in-vitro and in-vivo. METHODS Human microvascular endothelial cells (hCMEC/D3) were used as BBB model, and brain targeting was studied by in-vivo imaging of DiR-labelled formulations (at two doses and surface ligand densities), followed by ex-vivo organ imaging. RESULTS LIP diameter was between 100 nm and 150 nm, their stability was good and they were non-cytotoxic. LIP uptake and transport across the hCMEC/D3 cell monolayer was significantly affected by decoration with APOe or MAb, the DUAL exerting an additive effect. Intact vesicle-transcytosis was confirmed by equal transport of hydrophilic and lipophilic labels. In-vivo and ex-vivo results confirmed MAb and DUAL-LIP increased brain targeting compared to non-targeted PEG-LIPs, but not for APOe (also targeting ability of DUAL-LIP was not higher than MAb-LIP). The contradiction between in-vitro and in-vivo results was overruled when in-vitro studies (uptake and monolayer transport) were carried out in presence of serum proteins, revealing their important role in targeted-nanoformulation performance. CONCLUSIONS A peptide analogue of ApoΕ3 was found to target BBB and increase the targeting potential of TfR-MAb decorated LIP, in-vitro, but not in-vivo, indicating that different types of ligands (small peptides and antibodies) are affected differently by in-vivo applying conditions. In-vitro tests, carried out in presence of serum proteins, may be a helpful predictive "targetability" tool.
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Affiliation(s)
- E Markoutsa
- Laboratory of Pharmaceutical Technology, Department of Pharmacy, University of Patras, Rio, Patras, 26510, Greece
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Ko YT. Nanoparticle-mediated delivery of oligonucleotides to the blood-brain barrier: in vitro and in situ brain perfusion studies on the uptake mechanisms. J Drug Target 2013; 21:866-73. [PMID: 23952765 DOI: 10.3109/1061186x.2013.829077] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Except for the few exceptions where topical administration is feasible, progress towards broad clinical application of nucleic acid therapeutics requires development of effective systemic delivery strategies. The central nervous system represents a particularly difficult organ for systemic delivery due to the blood-brain barrier. We previously reported a nanoparticulate delivery system for targeted brain delivery of oligonucleotides upon systemic administration, i.e. liposome-encapsulated polyethylenimine/oligonucleotides polyplexes. In this study, cellular uptake and intracellular trafficking of the nanoparticles were further investigated using in situ brain perfusion technique followed by colocalization and fluorescence resonance energy transfer techniques. The brain endothelial uptake and possibly parenchymal accumulation were readily visualized upon administration via internal carotid artery perfusion. The nanoparticles were colocalized with early-endosome antigen, which confirms the brain endothelial uptake through transferrin receptor-mediated endocytosis. Fluorescence resonance energy transfer analysis also suggested the nanoparticles entered the brain endothelial cells while maintaining their integrity. Together, the enhanced brain uptake, as claimed previously, of the antibody-targeted nanoparticles was clearly confirmed with more convincing evidences. In addition, the experimental techniques described here should be applicable to the studies involving nanoparticle-mediated brain delivery of nucleic acid therapeutics.
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Affiliation(s)
- Young Tag Ko
- College of Pharmacy, Gachon University , Incheon , South Korea
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33
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Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells. Ther Deliv 2013; 4:629-40. [PMID: 23647279 DOI: 10.4155/tde.13.21] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The potential use of many promising novel drugs is limited by their inability to specifically reach their site of action after intravenous administration, without secondary effects on healthy tissues. In order to remediate this problem, the protein transferrin (Tf) has been extensively studied as a targeting molecule for the transport of drug and gene delivery systems to the brain and cancer cells. A wide range of delivery approaches have been developed to target the Tf receptor and they have already improved the specific delivery of Tf-bearing therapeutic agents to their site of action. This review provides a summary of the numerous delivery strategies used to target the Tf receptor and focuses on recent therapeutic advances.
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Papademetriou IT, Garnacho C, Schuchman EH, Muro S. In vivo performance of polymer nanocarriers dually-targeted to epitopes of the same or different receptors. Biomaterials 2013; 34:3459-66. [PMID: 23398883 DOI: 10.1016/j.biomaterials.2013.01.069] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2012] [Accepted: 01/16/2013] [Indexed: 12/31/2022]
Abstract
Modification of drug delivery nanomaterials with affinity molecules that facilitate targeting, has rendered a new class of ligands for cell receptors, which often possess valency and dimensions different from natural counterparts. Designing strategies to target multiple receptors or, never explored, multiple epitopes on the same receptor may modulate the biodistribution properties of these nanomaterials. We examined this using antibody-directed targeting of polymer nanocarriers to transferrin receptor (TfR) and intercellular adhesion molecule 1 (ICAM-1). Regarding epitopes on one receptor, nanocarriers addressed with anti-TfR-R17 maintained brain and lung targeting in mice, compared with "free" antibody, while anti-TfR-8D3 nanocarriers lost specificity. Coating nanocarriers with both antibodies decreased targeting in brain and liver, not lungs, modulating biodistribution. Regarding different receptors, nanocarriers coated with both anti-ICAM and anti-TfR displayed intermediate specific accumulation in lungs and higher in liver, compared to single-targeted nanocarriers, while brain targeting was comparable to TfR- and lower than ICAM-1-targeted nanocarriers. Tracing a model therapeutic cargo, acid sphingomyelinase (enzyme replacement for Niemann-Pick Disease A-B), showed that combined-targeted anti-ICAM/TfR nanocarriers enhanced enzyme delivery versus "free" enzyme, with biodistribution patterns different from single-targeted nanocarriers. Hence, targeting nanocarriers to multiple epitopes or receptors holds promise to control distribution of drug delivery nanomaterials in the body.
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Affiliation(s)
- Iason T Papademetriou
- Fischell Department of Bioengineering, School of Engineering, University of Maryland, College Park, MD 20742, USA
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Abstract
INTRODUCTION Development of drug delivery systems for brain delivery is one of the most challenging research topics in pharmaceutical areas, mainly due to the presence of the blood-brain barrier (BBB), which separates the blood from the cerebral parenchyma thus limiting the brain uptake of the majority of therapeutic agents. Among the several carriers, which have been studied to overcome this problem, liposomes have gained increasing attention as promising strategies for brain-targeted drug delivery. The most advantageous features of liposomes are their ability to incorporate and deliver large amounts of drug and the possibility to decorate their surface with different ligands. AREAS COVERED The purpose of this review is to explore the different approaches studied to transport and deliver therapeutics and imaging agents to the brain by using liposomes. In the first part of the review, particular attention is paid to describe the anatomy of the BBB and different physiological transport mechanisms available for drug permeation. In the second part, the different strategies for the delivery of a drug to the brain using liposomes are reviewed for each transport mechanism. EXPERT OPINION Over the last decade, there have been significant developments concerning liposomal brain delivery systems conjugated with selected ligands with high specificity and low immunogenicity. An universally useful liposomal formulation for brain targeting does not exist but liposome design must be modulated by the appropriate choice of the specific homing device and transport mechanism.
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Affiliation(s)
- Francesco Lai
- University of Cagliari, Dipartimento di Scienze della Vita e dell'Ambiente, Via Ospedale 72, 09124 Cagliari, Italy
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Orthmann A, Fichtner I, Zeisig R. Improving the transport of chemotherapeutic drugs across the blood-brain barrier. Expert Rev Clin Pharmacol 2012; 4:477-90. [PMID: 22114857 DOI: 10.1586/ecp.11.26] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The successful treatment of brain tumors or metastases in the brain is still hampered by the very efficient blood-brain barrier, which prevents the cerebral accumulation of a pharmacologically sufficient amount of a drug. Beside the possibility of disintegrating the functionality of this effective working barrier, a nanocarrier-mediated transport is presently an interesting and promising method to increase the drug concentration in the brain. Nanocarriers are small vesicles (<200 nm) and can be prepared by polymerization, resulting in nanoparticles, or by producing superficial lipid structures to incorporate the drug. In this context, liposomes are of importance owing to their ability to adapt their properties to the pharmacological requirements. In this article, we will give an overview of current possibilities of enhancing anticancer drug transport across the blood-brain barrier, based on its structure and functionality. Special consideration will be given to recent liposomal approaches that use active targeting for receptor-mediated transport across this physiological barrier.
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Affiliation(s)
- Andrea Orthmann
- Max Delbrück Center for Molecular Medicine, Experimental Pharmacology, Robert-Rössle-Str. 10, 13122 Berlin, German
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Abstract
Research into treatments for diseases of the CNS has made impressive strides in the past few decades, but therapeutic options are limited for many patients with CNS disorders. Nanotechnology has emerged as an exciting and promising new means of treating neurological disease, with the potential to fundamentally change the way we approach CNS-targeted therapeutics. Molecules can be nanoengineered to cross the blood-brain barrier, target specific cell or signalling systems, respond to endogenous stimuli, or act as vehicles for gene delivery, or as a matrix to promote axon elongation and support cell survival. The wide variety of available nanotechnologies allows the selection of a nanoscale material with the characteristics best suited to the therapeutic challenges posed by an individual CNS disorder. In this Review, we describe recent advances in the development of nanotechnology for the treatment of neurological disorders-in particular, neurodegenerative disease and malignant brain tumours-and for the promotion of neuroregeneration.
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Affiliation(s)
- Maya Srikanth
- Department of Neurology, Northwestern University Feinberg School of Medicine, Ward 10-233, 303 E. Chicago Avenue, Chicago, IL 60611, USA. maya@ fsm.northwestern.edu
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Vlieghe P, Khrestchatisky M. Medicinal chemistry based approaches and nanotechnology-based systems to improve CNS drug targeting and delivery. Med Res Rev 2012; 33:457-516. [PMID: 22434495 DOI: 10.1002/med.21252] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The central nervous system (CNS) is protected by various barriers, which regulate nervous tissue homeostasis and control the selective and specific uptake, efflux, and metabolism of endogenous and exogenous molecules. Among these barriers is the blood-brain barrier (BBB), a physical and physiological barrier that filters very efficiently and selectively the entry of compounds from the blood to the brain and protects nervous tissue from harmful substances and infectious agents present in the bloodstream. The BBB also prevents the entry of potential drugs. As a result, various drug targeting and delivery strategies are currently being developed to enhance the transport of drugs from the blood to the brain. Following a general introduction, we briefly overview in this review article the fundamental physiological properties of the BBB. Then, we describe current strategies to bypass the BBB (i.e., invasive methods, alternative approaches, and temporary opening) and to cross it (i.e., noninvasive approaches). This section is followed by a chapter addressing the chemical and technological solutions developed to cross the BBB. A special emphasis is given to prodrug-targeting approaches and targeted nanotechnology-based systems, two promising strategies for BBB targeting and delivery of drugs to the brain.
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Affiliation(s)
- Patrick Vlieghe
- VECT-HORUS S.A.S., Faculté de Médecine Secteur Nord, CS80011, Boulevard Pierre Dramard, 13344 Marseille Cedex 15, France.
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Affiliation(s)
- Joshua I. Cutler
- Department of Chemistry and International
Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
| | - Evelyn Auyeung
- Department of Chemistry and International
Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
| | - Chad A. Mirkin
- Department of Chemistry and International
Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
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Hu K, Shi Y, Jiang W, Han J, Huang S, Jiang X. Lactoferrin conjugated PEG-PLGA nanoparticles for brain delivery: preparation, characterization and efficacy in Parkinson's disease. Int J Pharm 2011; 415:273-83. [PMID: 21651967 DOI: 10.1016/j.ijpharm.2011.05.062] [Citation(s) in RCA: 165] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Revised: 05/04/2011] [Accepted: 05/24/2011] [Indexed: 11/25/2022]
Abstract
A novel biodegradable brain drug delivery system, the lactoferrin (Lf) conjugated polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticle (Lf-NP) was constructed in this paper with its in vitro and in vivo delivery properties evaluated by a fluorescent probe coumarin-6. Lf was thiolated and conjugated to the distal maleimide function surrounding on the pegylated nanoparticle to form Lf-NP. TEM observation and ELISA analysis confirmed the existence of active Lf on the surface of Lf-NP. The results of qualitative and quantitative uptake studies of coumarin-6 incorporated Lf-NP showed a more pronounced accumulation of Lf-NP in bEnd.3 cells than that of unconjugated nanoparticle (NP). Further uptake inhibition study indicated that the increased uptake of Lf-NP was via an additional clathrin mediated endocytosis processes. Following intravenous administration, a near 3 fold of coumarin-6 was found in the mice brain carried by Lf-NP compared to that carried by NP. Intravenous injection of urocortin loaded Lf-NP effectively attenuated the striatum lesion caused by 6-hydroxydopamine in rats as indicated by the behavioral test, the immunohistochemistry test and striatal transmitter content detection results. The cell viability test and CD68 immunohistochemistry demonstrated the acceptable toxicity of the system. All these results demonstrated that Lf-NP was a promising brain drug delivery system with reasonable toxicity.
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Affiliation(s)
- Kaili Hu
- Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
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Uptake and permeability studies of BBB-targeting immunoliposomes using the hCMEC/D3 cell line. Eur J Pharm Biopharm 2010; 77:265-74. [PMID: 21118722 DOI: 10.1016/j.ejpb.2010.11.015] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2010] [Revised: 11/19/2010] [Accepted: 11/23/2010] [Indexed: 02/03/2023]
Abstract
The targeting potential of OX-26-decorated immunoliposomes was investigated, using the human brain endothelial cell line hCMEC/D3 as a model of the blood-brain barrier (BBB). Immuno-nanoliposomes were prepared by the biotin/streptavidin ligation strategy, and their uptake by hCMEC/D3 cells and permeability through cell monolayers was studied. In order to elucidate the mechanisms of uptake, pH-sensitive fluorescence signal of HPTS was used, while transport was measured using double labeled immunoliposomes (with aqueous and lipid membrane fluorescent tags). PEGylated and non-specific-IgG-decorated liposomes were studied under identical conditions, as controls. CHO-K1 cells (which do not overexpress the transferrin receptor) were studied in some cases for comparative purposes. Experimental results reveal that hCMEC/D3 cells are good models for in vitro screening of BBB-targeting nanoparticulate drug delivery systems. Uptake and transcytosis of immunoliposome-associated dyes by cell monolayers was substantially higher compared to those of control liposomes. HPTS-entrapping OX-26-immunoliposome uptake indicated lysosomal localization and receptor-mediated mechanism. The ratio of aqueous/lipid label transport is affected by pre-incubation with antibody, or use of high lipid doses, suggesting that vesicles are transported intact after lysosome saturation. Co-decoration with a second ligand slightly decreases OX-26-decorated vesicle uptake, but not transcytosis, proving that the biotin-streptavidin technique can be applied for the generation of dual-targeting nanoliposomes.
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Liu X, Abbott NL. Characterization of the nanostructure of complexes formed by single- or double-stranded oligonucleotides with a cationic surfactant. J Phys Chem B 2010; 114:15554-64. [PMID: 21062067 DOI: 10.1021/jp107936b] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
We report the use of dynamic light scattering (DLS), small-angle neutron scattering (SANS), and small-angle X-ray scattering (SAXS) to characterize the nanostructure of complexes formed by either single- or double-stranded oligonucleotides with a cationic surfactant (cetyltrimethylammonium bromide, CTAB) in aqueous solution (1 mM Li(2)SO(4)). For single-stranded oligonucleotides 5'-A(20)-3' and 5'-CCCCATTCTAGCAGCCCGGG-3', both the appearance of two Bragg peaks (at 0.14 and 0.28 Å(-1)) in SAXS spectra with a spacing of 1:2 and form factor fits to SANS spectra are consistent with the presence of multilamellar vesicles (with, on average, 6-9 layers with a periodicity of 45-48 Å). Some samples showed evidence of an additional Bragg peak (at 0.20 Å(-1)) associated with periodic packing (with a periodicity of 31 Å) of the oligonucleotides within the lamellae of the nanostructure. The nucleotide composition of the single-stranded oligonucleotides was also found to impact the number and size of the complexes formed with CTAB. In contrast to 5'-A(20)-3' and 5'-CCCCATTCTAGCAGCCCGGG-3', 5'-T(20)-3' did not change the state of aggregation of CTAB (globular micelles) over a wide range of oligonucleotide:CTAB charge ratios. These results support the proposition that hydrophobic interactions, as well as electrostatics, play a central role in the formation of complexes between cationic amphiphiles and single-stranded oligonucleotides and thus give rise to nanostructures that depend on nucleotide composition. In contrast to the single-stranded oligonucleotides, for double-stranded oligonucleotides mixed with CTAB, three Bragg peaks (0.13, 0.23, and 0.25 Å(-1)) in SAXS spectra with a spacing ratio of 1:√3:√4 and characteristic changes in SANS spectra indicate formation of a hexagonal nanostructure. Also, the composition of the double-stranded oligonucleotides did not measurably impact the nanostructure of complexes formed with CTAB, suggesting that electrostatic interactions dominate the formation of these complexes. Overall, these results provide insights into the intermolecular interactions that occur between cationic amphiphiles and oligonucleotides and establish that single and double-stranded oligonucleotides form complexes with cationic surfactants that differ in nanostructure. The results also provide guidance for the design of oligonucleotide complexes with cationic amphiphiles.
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Affiliation(s)
- Xiaoyang Liu
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, 1415 Engineering Drive, Madison, Wisconsin 53705-1691, United States
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Chen H, Tang L, Qin Y, Yin Y, Tang J, Tang W, Sun X, Zhang Z, Liu J, He Q. Lactoferrin-modified procationic liposomes as a novel drug carrier for brain delivery. Eur J Pharm Sci 2010; 40:94-102. [DOI: 10.1016/j.ejps.2010.03.007] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2009] [Revised: 01/02/2010] [Accepted: 03/09/2010] [Indexed: 11/24/2022]
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Pardridge WM. Preparation of Trojan horse liposomes (THLs) for gene transfer across the blood-brain barrier. Cold Spring Harb Protoc 2010; 2010:pdb.prot5407. [PMID: 20360361 DOI: 10.1101/pdb.prot5407] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Nonviral plasmid DNA is delivered to the brain via a transvascular route across the blood-brain barrier (BBB) following intravenous administration of DNA encapsulated within Trojan horse liposomes (THLs), also called PEGylated immunoliposomes (PILs). The liposome surface is covered with several thousand strands of polymer (e.g., polyethylene glycol [PEG]), and the tips of 1%-2% of the polymer strands are conjugated with a targeting monoclonal antibody that acts as a molecular Trojan horse (MTH). The MTH binds to a receptor (e.g., for transferrin or insulin) on the BBB and brain cell membrane, triggering receptor-mediated transcytosis of the THL across the BBB in vivo, and receptor-mediated endocytosis into brain cells beyond the BBB. The persistence of transgene expression in the brain is inversely related to the rate of degradation of the episomal plasmid DNA. THL technology enables an exogenous gene to be widely expressed in the majority of cells in adult brain (or other organs) within 1 d of a single intravenous administration. Applications of the THLs include tissue-specific gene expression with tissue-specific promoters, complete normalization of striatal tyrosine hydroxylase in experimental Parkinson's disease following intravenous tyrosine hydroxylase gene therapy, a 100% increase in survival time of mice with brain tumors following weekly intravenous antisense gene therapy using THLs, and a 90% increase in survival time with weekly intravenous RNA interference (RNAi) gene therapy in mice with intracranial brain tumors. This protocol describes the preparation of THLs for use in gene transfer in vitro or in vivo.
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Ye F, Gao Q, Cai MJ. Therapeutic targeting of EGFR in malignant gliomas. Expert Opin Ther Targets 2010; 14:303-16. [DOI: 10.1517/14728221003598948] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Gadji M, Crous AMT, Fortin D, Krcek J, Torchia M, Mai S, Drouin R, Klonisch T. EGF receptor inhibitors in the treatment of glioblastoma multiform: Old clinical allies and newly emerging therapeutic concepts. Eur J Pharmacol 2009; 625:23-30. [DOI: 10.1016/j.ejphar.2009.10.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Revised: 09/27/2009] [Accepted: 10/08/2009] [Indexed: 12/26/2022]
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Dhanikula RS, Hammady T, Hildgen P. On the Mechanism and Dynamics of Uptake and Permeation of Polyether-Copolyester Dendrimers Across an In Vitro Blood–Brain Barrier Model. J Pharm Sci 2009; 98:3748-60. [DOI: 10.1002/jps.21669] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Huang R, Han L, Li J, Ren F, Ke W, Jiang C, Pei Y. Neuroprotection in a 6-hydroxydopamine-lesioned Parkinson model using lactoferrin-modified nanoparticles. J Gene Med 2009; 11:754-63. [DOI: 10.1002/jgm.1361] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
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Karpel-Massler G, Schmidt U, Unterberg A, Halatsch ME. Therapeutic inhibition of the epidermal growth factor receptor in high-grade gliomas: where do we stand? Mol Cancer Res 2009; 7:1000-12. [PMID: 19584260 DOI: 10.1158/1541-7786.mcr-08-0479] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
High-grade gliomas account for the majority of intra-axial brain tumors. Despite abundant therapeutic efforts, clinical outcome is still poor. Thus, new therapeutic approaches are intensely being investigated. Overexpression of the epidermal growth factor receptor (HER1/EGFR) is found in various epithelial tumors and represents one of the most common molecular abnormalities seen in high-grade gliomas. Dysregulated HER1/EGFR is found in 40% to 50% of glioblastoma, the most malignant subtype of glioma. Several agents such as tyrosine kinase (TK) inhibitors, antibodies, radio-immuno conjugates, ligand-toxin conjugates, or RNA-based agents have been developed to target HER1/EGFR or its mutant form, EGFRvIII. To date, most agents are in various stages of clinical development. Clinical data are sparse but most advanced for TK inhibitors. Although data from experimental studies seem promising, proof of a significant clinical benefit is still missing. Among the problems that have to be further addressed is the prediction of the individual patient's response to HER1/EGFR-targeted therapeutics based on molecular determinants. It is quite possible that blocking HER1/EGFR alone will not sufficiently translate into a clinical benefit. Therefore, a multiple target approach concomitantly aimed at different molecular sites might be a favorable concept. This review focuses on current HER1/EGFR-targeted therapeutics and their development for high-grade gliomas.
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Barchet TM, Amiji MM. Challenges and opportunities in CNS delivery of therapeutics for neurodegenerative diseases. Expert Opin Drug Deliv 2009; 6:211-25. [PMID: 19290842 DOI: 10.1517/17425240902758188] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
With an increase in lifespan and changing population demographics, the incidence of central nervous system (CNS) diseases is expected to increase significantly in the 21st century. The most challenging of the CNS diseases are neurodegenerative diseases, characterized by age-related gradual decline in neurological function, often accompanied by neuronal death. Alzheimer's disease, Parkinson's disease and Huntington's disease are some examples of neurodegenerative diseases and have been well described in terms of disease mechanisms and pathology. However, successful treatment strategies for neurodegenerative diseases have so far been limited. Delivery of drugs into the CNS is one of the most challenging problems faced in the treatment of neurodegeneration. In this review, we describe the difficulties with CNS therapy, especially with the use of biological macromolecules, such as proteins and nucleic acid constructs. CNS therapeutics also represents a huge opportunity and examples of strategies that can enhance therapeutic delivery for the treatment of neurodegenerative diseases are emphasized. It is anticipated that with an increase in biological understanding of neurodegenerative diseases, there will be even more therapeutic opportunities. As such, these delivery strategies have a very important role to play in the future in the translation of CNS therapeutics from bench to bedside.
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Affiliation(s)
- Thomas M Barchet
- Department of Pharmaceutical Sciences, Northeastern University, School of Pharmacy, 110 Mugar Life Sciences Building, Boston, Massachussets, MA 02115, USA
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