title: A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors.
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.
authors.affiliation: Drug Delivery and Formulation, Drug Discovery Platform, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada; Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Roy
authors.affiliation: Drug Delivery and Formulation, Drug Discovery Platform, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada; Faculty of Engineering and Architectural Science, Ryerson University, Toronto, Ontario M5B 1Z2, Canada.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ernsting
authors.affiliation: Drug Delivery and Formulation, Drug Discovery Platform, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Elijus
authors.initials: E
authors.lastname: Undzys
authors.affiliation: Drug Delivery and Formulation, Drug Discovery Platform, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada; Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: shyh-dar.li@ubc.ca.
authors.forename: Shyh-Dar
authors.initials: SD
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001672:Biocompatible Materials / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D010316:Particle Size; D011034:Podophyllotoxin / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D011092:Polyethylene Glycols; D011034:Podophyllotoxin
keywords: Drug delivery; Multidrug resistance; Nanoparticles; Podophyllotoxin
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