A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors |
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| Institution: | 1. Drug Delivery and Formulation, Drug Discovery Platform, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada;2. Faculty of Engineering and Architectural Science, Ryerson University, Toronto, Ontario M5B 1Z2, Canada;3. Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada;1. Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States;2. Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, United States;3. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States;4. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205, United States;5. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States;6. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, United States;1. College of Chemistry and Chemical Engineering, Anhui University of Technology, Ma’anshan 243002, PR China;2. College of Life Sciences, Shanghai Normal University, Shanghai 201418, PR China;3. Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China;4. University of Chinese Academy of Sciences, Beijing 100049, PR China;1. State Key Laboratory of Bioreactor Engineering, Biomedical Nanotechnology Center, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, People’s Republic of China;2. Department of Bioproducts and Biosystems Engineering, University of Minnesota, St. Paul, MN 55108, USA;1. Jining First People’s Hospital, Jining Medical University, Jining 272000, PR China;2. Department of Pharmacy, Qingdao Municipal Hospital, Qingdao 266000, PR China;3. Department of Clinical & Translational Medicine, Jining Life Science Center, Jining 272000, PR China;4. Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining 272000, PR China;1. Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada;2. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada;3. Faculty of Engineering and Architectural Science, Ryerson University, Toronto, ON, Canada |
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| Abstract: | Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20–120 nm) depending on the PPT-to-PEG molar ratio (2–20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ～5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (～2.5%/day and ～1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT-NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity. |
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| Keywords: | Podophyllotoxin Multidrug resistance Nanoparticles Drug delivery |
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