Masking and triggered unmasking of targeting ligands on nanocarriers to improve drug delivery to brain tumors |
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| Authors: | Kathleen M McNeeley Efstathios Karathanasis Ananth V Annapragada Ravi V Bellamkonda |
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| Institution: | 1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA;2. School of Health Information Sciences, University of Texas Health Science Center, Houston, TX 77030, USA;1. Department of Biomedical Engineering and Wisconsin Institutes for Discovery, University of Wisconsin–Madison, Madison, WI 53715, USA;2. Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA;1. Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan;2. Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan;3. Divison of Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan;4. Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan;5. Division of Medical Engineering Research, National Health Research Institutes, Miaoli, Taiwan;1. Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China;2. School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China;1. Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College Dublin, Dublin, Ireland;2. School of Medicine, Trinity College Dublin, Dublin, Ireland;3. School of Chemistry, Trinity College Dublin, Dublin, Ireland;4. Advanced Microscopy Laboratory, Trinity College Dublin, Dublin, Ireland;5. School of Physics, Trinity College Dublin, Dublin, Ireland;6. UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, D4 Dublin, Ireland;1. Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA;2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA;3. University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA;1. Department of Chemical, Metallurgical and Materials Engineering, Tshwane University of Technology, Pretoria, South Africa;2. Department of Chemistry, University of Fort Hare, Alice Campus, Eastern Cape, South Africa;3. Polymers and Composites, Council for Scientific and Industrial Research, Pretoria, South Africa;4. DST/CSIR National Centre for Nanostructured Materials, Council for Scientific and Industrial Research, Pretoria 0001, South Africa;5. Department of Chemistry, University of Johannesburg, Auckland Park, Johannesburg, South Africa |
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| Abstract: | Long-circulating nanocarriers have been extensively studied to deliver chemotherapeutics; however, the inclusion of targeting agents compromises circulation times thereby offsetting the benefits of active targeting. Here, we formulated cysteine-cleavable phospholipid–polyethylene glycol (PEG) to ‘mask’ nanocarrier bound targeting ligands from RES clearance and prolong circulation times of liposomes to allow passive targeting to tumors. This detachable polymer coating can be removed after nanocarrier extravasation to tumor is achieved to expose targeting ligands and promote active targeting to tumor cells. In vivo studies on folate receptor-targeted liposomes demonstrated our ability to prolong circulation in the bloodstream using this system thereby verifying the ‘masking’ capacity of cleavable phospholipid–PEG5000. Controlled modulation of uptake and cytotoxicity of targeted nanocarriers using cleavable phospholipid–PEG was demonstrated through in vitro studies. Finally, studies analyzing uptake by tumor cells in vivo confirmed enhanced intracellular delivery when tumor-inoculated animals received targeted liposomes containing cleavable phospholipid–PEG5000 followed by a cysteine infusion to expose folate after liposomes had extravasated to tumor. These results indicate that cleavable phospholipid–PEG can be used in nanocarrier formulations for controlled exposure of targeting ligands to ensure that circulation times remain uncompromised by the inclusion of targeting agents while enabling active targeting to tumors after removal of the polymer coating. |
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