A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors

• Published in: Biomaterials 2015-06, Vol.52, p.335-346
• Main Authors: Roy, Aniruddha, Ernsting, Mark J, Undzys, Elijus, Li, Shyh-Dar
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Antineoplastic Agents - chemistry; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biocompatible Materials - chemistry; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemotherapy; Conjugates; Dentistry; Drug delivery; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Maximum Tolerated Dose; Mice; Multidrug resistance; Nanoparticles; Nanoparticles - chemistry; Nanostructure; Neoplasm Transplantation; Neoplasms - drug therapy; Neoplasms - pathology; Particle Size; Podophyllotoxin; Podophyllotoxin - chemistry; Polyethylene glycol; Polyethylene Glycols - chemistry; Toxicity; Tumors
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2015.02.041

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.