Well-defined podophyllotoxin polyprodrug brushes: preparation via RAFT polymerization and evaluation as drug carriers

Abstract

Novel poly(triethylene glycol methacrylate)-b-poly(podophyllotoxin methacrylate) copolymers (PTP) with a well-defined structure were designed and synthesized by direct RAFT polymerization with the hydrophobic monomer derivative from the anticancer drug podophyllotoxin. After optimizing the hydrophilic/hydrophobic ratio, the polyprodrug brush PT₄₅P₁₄ was utilized as a carrier to prepare polyprodrug nanoparticles (PT₄₅P₁₄ NPs) via the dialysis method. The polyprodrug nanoparticles presented a drug-loading content of approximately 40% and excellent storage and medium stabilities. The release of POD from PT₄₅P₁₄ NPs showed a sustained and pH-dependent release manner within 72 h; the release rate was increased under acidic conditions because ester bonds cleaved faster in a low pH environment. PT₄₅P₁₄ NPs presented higher cytotoxicity against Hela cells compared with free POD, the antitumor efficacy in vitro was enhanced 5-fold, and the cellular uptake mechanism was proven to be sucrose-blocking clathrin-mediated endocytosis. According to their great drug-loading content, moderate hydrophilicity, appropriate particle size, pH-sensitive release, and enhanced antitumor efficacy, PT₄₅P₁₄ NPs as efficient drug delivery systems could have potential application in pH-sensitive cancer therapy.