Gil Moon Soo, Thambi Thavasyappan, Phan V H Giang, Kim Seong Han, Lee Doo Sung
School of Chemical Engineering, Theranostic Macromolecules Research Center, Sungkyunkwan University, Suwon, Republic of Korea.
J Mater Chem B. 2017 Sep 14;5(34):7140-7152. doi: 10.1039/c7tb00873b. Epub 2017 Aug 18.
Cisplatin (CDDP) is a well-known anticancer agent, and it has been widely used to treat various solid tumors during clinical cancer therapy. Nevertheless, therapeutic applications of CDDP are hampered by its severe side effects. Although CDDP can be encapsulated into nano-scale drug delivery formulations to improve its physicochemical properties, the lack of stability in the formulation and cancer cell-specific targetability have prompted the exploration of novel vectors for the targeted delivery of CDDP. Here, we introduce CDDP-bearing chondroitin sulfate nanogels (CS-nanogels) that are synthesized through a chelating ligand-metal coordination cross-linking reaction, and then incorporated into pH- and temperature-responsive bioresorbable poly(ethylene glycol)-poly(β-aminoester urethane) (PEG-PAEU) hydrogels for cancer cell-specific delivery of CDDP. The CS-nanogels released from the hydrogels exhibit a pH-dependent release of CDDP. CDDP was released slowly under physiological conditions (pH 7.4), whereas the release of CDDP was triggered under acidic conditions (pH 5.0). Confocal microscopy images demonstrated that fluorescein-5-thiosemicarbazide-labeled CS-nanogels released from the hydrogels selectively bound to the A549 lung carcinoma cell line through the overexpressing CD44 receptor but not to NIH 3T3 cells. An in vitro cytotoxicity test indicated that CS-nanogels released from the hydrogels effectively inhibited the growth of A549 lung carcinoma cells. Subcutaneous injection of CS-nanogel-loaded PEG-PAEU copolymer sols into the dorsal region of Sprague-Dawley rats spontaneously formed a viscoelastic gel without causing noticeable inflammation at the injection site and was found to be bioresorbable in eight weeks. Overall, the injectable hydrogel-incorporated CS-nanogels were demonstrated to be a useful formulation for the targeted delivery of CDDP.
顺铂（CDDP）是一种著名的抗癌药物，在临床癌症治疗中已被广泛用于治疗各种实体瘤。然而，CDDP的治疗应用受到其严重副作用的阻碍。尽管CDDP可以被封装到纳米级药物递送制剂中以改善其物理化学性质，但制剂中缺乏稳定性以及癌细胞特异性靶向性促使人们探索用于CDDP靶向递送的新型载体。在此，我们介绍了负载CDDP的硫酸软骨素纳米凝胶（CS-纳米凝胶），其通过螯合配体-金属配位交联反应合成，然后掺入pH和温度响应性可生物降解的聚（乙二醇）-聚（β-氨基酯聚氨酯）（PEG-PAEU）水凝胶中，用于CDDP的癌细胞特异性递送。从水凝胶中释放的CS-纳米凝胶表现出CDDP的pH依赖性释放。CDDP在生理条件（pH 7.4）下缓慢释放，而在酸性条件（pH 5.0）下触发CDDP的释放。共聚焦显微镜图像表明，从水凝胶中释放的荧光素-5-硫代半卡巴腙标记的CS-纳米凝胶通过过表达的CD44受体选择性地与A549肺癌细胞系结合，而不与NIH 3T3细胞结合。体外细胞毒性试验表明，从水凝胶中释放的CS-纳米凝胶有效地抑制了A549肺癌细胞的生长。将负载CS-纳米凝胶的PEG-PAEU共聚物溶胶皮下注射到Sprague-Dawley大鼠的背部区域，自发形成了一种粘弹性凝胶，在注射部位未引起明显炎症，并且发现在八周内可生物吸收。总体而言，可注射水凝胶掺入的CS-纳米凝胶被证明是一种用于CDDP靶向递送的有用制剂。
