Cai Liqiong, Xu Gaofei, Shi Changying, Guo Dandan, Wang Xu, Luo Juntao
Department of Pharmacology, SUNY Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY 13210, United States.
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei 430022, China.
Biomaterials. 2015 Jan;37:456-468. doi: 10.1016/j.biomaterials.2014.10.044. Epub 2014 Oct 31.
Cisplatin (CDDP) and paclitaxel (PTX) are two established chemotherapeutic drugs used in combination for the treatment of many cancers, including ovarian cancer. We have recently developed a three-layered linear-dendritic telodendrimer micelles (TM) by introducing carboxylic acid groups in the adjacent layer via "thio-ene" click chemistry for CDDP complexation and conjugating cholic acids via peptide chemistry in the interior layer of telodendrimer for PTX encapsulation. We hypothesize that the co-delivery of low dosage PTX with CDDP could act synergistically to increase the treatment efficacy and reduce their toxic side effects. This design allowed us to co-deliver PTX and CDDP at various drug ratios to ovarian cancer cells. The in vitro cellular assays revealed strongest synergism in anti-tumor effects when delivered at a 1:2 PTX/CDDP loading ratio. Using the SKOV-3 ovarian cancer xenograft mouse model, we demonstrate that our co-encapsulation approach resulted in an efficient tumor-targeted drug delivery, decreased cytotoxic effects and stronger anti-tumor effect, when compared with free drug combination or the single loading TM formulations.
顺铂（CDDP）和紫杉醇（PTX）是两种已确立的化疗药物，常联合用于治疗包括卵巢癌在内的多种癌症。我们最近通过“硫醇-烯”点击化学在相邻层引入羧酸基团以络合CDDP，并通过肽化学在端odendrimer的内层共轭胆酸以封装PTX，从而开发出一种三层线性-树枝状端odendrimer胶束（TM）。我们假设低剂量PTX与CDDP的共同递送可以协同作用，提高治疗效果并降低其毒副作用。这种设计使我们能够以各种药物比例将PTX和CDDP共同递送至卵巢癌细胞。体外细胞试验显示，当以1:2的PTX/CDDP负载比例递送时，抗肿瘤作用的协同性最强。使用SKOV-3卵巢癌异种移植小鼠模型，我们证明与游离药物组合或单一负载TM制剂相比，我们的共封装方法实现了高效的肿瘤靶向药物递送，降低了细胞毒性作用并具有更强的抗肿瘤作用。
