Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6486106 | Biomaterials | 2015 | 12 Pages |
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 (20-120Â 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 20Â nm and released PPT at â¼5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30Â nm and 120Â nm respectively) that displayed slower drug release (â¼2.5%/day and â¼1%/day respectively). The 20Â 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 20Â 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 120Â nm) exhibited increased liver uptake. Within the tumor, >90% of the 20Â nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20Â 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.
Related Topics
Physical Sciences and Engineering
Chemical Engineering
Bioengineering
Authors
Aniruddha Roy, Mark J. Ernsting, Elijus Undzys, Shyh-Dar Li,