Abstract
Owing to the naturally high toxicity, poor water solubility, and other side effects of podophyllotoxin (PPT), its applications are limited. To address these issues, we developed a new PPT delivery system, in which the hydrophilic drug methotrexate (MTX) and the hydrophobic drug PPT were linked by a reduction-responsive disulfide bond to form an amphiphilic drug-drug conjugate prodrug (MTX-SS-PPT). The conjugate could self-assemble into spherical nanoaggregates in aqueous solution and self-deliver to tumor tissues. In addition, MTX could target to folate-receptor-positive cells. Over-expression of glutathione in tumor cells broke the disulfide bonds and released the free drug. In vitro and in vivo experiments indicated that the nanodrug could effectively improve the biocompatibility and reduce the toxicity of PPT.
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