School of Chemistry and Chemical Engineering, Chongqing University, 174 Shazheng Street, Chongqing, 400044, P. R. China.
Key Laboratory of Luminescent and Real-Time Analytical Chemistry, Ministry of Education, School of Materials and Energy, Southwest University, Chongqing, 400715, P. R. China.
Chem Asian J. 2019 Nov 4;14(21):3840-3844. doi: 10.1002/asia.201901070. Epub 2019 Oct 15.
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.
由于鬼臼毒素（PPT）毒性高、水溶性差和其他副作用，其应用受到限制。为了解决这些问题，我们开发了一种新的 PPT 给药系统，其中亲水性药物甲氨蝶呤（MTX）和疏水性药物 PPT 通过还原响应的二硫键连接形成两亲性药物-药物偶联前药（MTX-SS-PPT）。该偶联物可以在水溶液中自组装成球形纳米聚集体，并自行递送至肿瘤组织。此外，MTX 可以靶向叶酸受体阳性细胞。肿瘤细胞中谷胱甘肽的过表达会打破二硫键并释放游离药物。体外和体内实验表明，该纳米药物可以有效提高 PPT 的生物相容性并降低其毒性。
