DataSheet2_A Co-delivery System Based on a Dimeric Prodrug and Star-Shaped Polymeric Prodrug Micelles for Drug Delivery.PDF

Chemotherapy is one of the commonly used therapies for the treatment of malignant tumors. Insufficient drug-loading capacity is the major challenge for polymeric micelle–based drug delivery systems of chemotherapy. Here, the redox-responsive star-shaped polymeric prodrug (PSSP) and the dimeric prodrug of paclitaxel (PTX) were prepared. Then the dimeric prodrug of PTX (diPTX, diP) was loaded into the core of the star-shaped polymeric prodrug micelles of PSSP by hydrophobic interaction forming the redox-responsive prodrug micelles of diPTX@PSSP for intracellular drug release in tumor cells. The hydrodynamic diameter of diPTX@PSSP nanoparticles was 114.3 nm ± 2.1 (PDI = 0.219 ± 0.016), and the micelles had long-term colloidal stability and the drug-loading content (DLC) of diPTX and PTX is 16.7 and 46.9%, respectively. The prepared micelles could broke under the reductive microenvironment within tumor cells, as a result, the dimeric prodrug of diP and polymeric prodrug micelles of PSSP were rapidly disassembled, leading to the rapid release of intracellular drugs. In vitro release studies showed that under the condition of reduced glutathione (GSH) (10 mM), the release of PTX was significantly accelerated with approximately 86.6% released within 21 h, and the released PTX in cytoplasm could promote the disintegration of microtubules and induce cell apoptosis. These results indicated that the new type of this reduction-sensitive nanodrug delivery system based on dimeric prodrug@polymeric prodrug micelles would be a promising technology in chemotherapy.

化疗是临床治疗恶性肿瘤的常用手段之一。基于聚合物胶束（polymeric micelle）的化疗药物递送系统，其载药量不足是当前面临的主要挑战。本研究成功制备了氧化还原响应型星形聚合物前药（redox-responsive star-shaped polymeric prodrug, PSSP）与紫杉醇（paclitaxel, PTX）二聚体前药。随后通过疏水作用将紫杉醇二聚体前药（diPTX，简称diP）载入PSSP星形聚合物前药胶束的疏水核心，构建得到diPTX@PSSP氧化还原响应型前药胶束，以实现肿瘤细胞内的药物释放。diPTX@PSSP纳米粒的流体动力学直径为114.3 nm ± 2.1，多分散性指数（PDI）为0.219 ± 0.016；该胶束具备良好的长期胶体稳定性，且diPTX与PTX的载药量（DLC）分别为16.7%与46.9%。所制备的胶束可在肿瘤细胞内的还原微环境中发生解离，diP二聚体前药与PSSP星形聚合物前药胶束会快速解聚，进而实现细胞内药物的快速释放。体外释放实验结果表明，在10 mM还原型谷胱甘肽（GSH）的还原环境下，PTX的释放速率显著提升，21小时内累积释放量约达86.6%；释放入细胞质的PTX可促进微管解聚，并诱导细胞凋亡。上述结果证实，这款基于二聚体前药@聚合物前药胶束的新型还原响应型纳米药物递送系统，在化疗领域具备良好的应用前景。