Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA; School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA; National Demonstration Center for Experimental Light Chemistry Engineering Education (Shaanxi University of Science & Technology), Shaanxi Provincial Key Laboratory of Papermaking Technology and Specialty Paper Development, College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science & Technology, Xi'an 710021, China.
J Control Release. 2023 May;357:274-286. doi: 10.1016/j.jconrel.2023.03.031. Epub 2023 Apr 5.
The application of numerous chemotherapeutic drugs has been limited due to poor solubility, adverse side effects, and even multidrug resistance in patients. Polymeric micelles with reversibly cross-linked structures provide a promising solution to these issues. Herein, we optimized and synthesized programable-released disulfide cross-linked micelle (PDCM) based on our previous well-defined dendrimers to deliver the antitumor drug betulinic acid (BA) and paclitaxel (PDCM@PTX) and evaluated the therapeutic efficacy of multidrug-resistant (MDR) simulative orthotopic intraperitoneal ovarian cancer mice models. Comprehensive results demonstrated that PDCM@PTX formed stable nanoparticles able to improve the pharmacokinetic profile and circulation time of PTX, allowing for increased tumor penetration. Furthermore, in the tumor microenvironment, the programable-switches (ester bonds and disulfide cross-linking) of PDCM@PTX were cleaved by the high concentration of glutathione (tumor microenvironment) and esterase (intracellular) present in the tumor, allowing for in situ release of PTX and BA, resulting in intensive therapeutic efficacy in MDR ovarian cancer.
由于溶解度差、不良反应大，甚至患者出现多药耐药性，许多化疗药物的应用受到限制。具有可逆交联结构的聚合物胶束为这些问题提供了一个有前景的解决方案。在此，我们基于之前的明确树状大分子优化并合成了可编程释放的二硫键交联胶束（PDCM），以递送抗肿瘤药物白桦脂酸（BA）和紫杉醇（PDCM@PTX），并评估了多药耐药（MDR）模拟原位腹腔卵巢癌小鼠模型的治疗效果。综合结果表明，PDCM@PTX 形成了稳定的纳米颗粒，能够改善 PTX 的药代动力学特征和循环时间，增加肿瘤穿透性。此外，在肿瘤微环境中，PDCM@PTX 的可编程开关（酯键和二硫键交联）被肿瘤中存在的高浓度谷胱甘肽（肿瘤微环境）和酯酶（细胞内）切割，导致 PTX 和 BA 的原位释放，从而对 MDR 卵巢癌产生强烈的治疗效果。
