School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, People's Republic of China.
Int J Nanomedicine. 2020 Apr 24;15:2885-2902. doi: 10.2147/IJN.S249205. eCollection 2020.
Poor site-specific delivery and insufficient intracellular drug release in tumors are inherent disadvantages to successful chemotherapy. In this study, an extraordinary polymeric micelle nanoplatform was designed for the efficient delivery of paclitaxel (PTX) by combining dual receptor-mediated active targeting and stimuli response to intracellular reduction potential.
The dual-targeted redox-sensitive polymer, folic acid-hyaluronic acid-SS-vitamin E succinate (FHSV), was synthesized via an amidation reaction and characterized by H-NMR. Then, PTX-loaded FHSV micelles (PTX/FHSV) were prepared by a dialysis method. The physiochemical properties of the micelles were explored. Moreover, in vitro cytological experiments and in vivo animal studies were carried out to evaluate the antitumor efficacy of polymeric micelles.
The PTX/FHSV micelles exhibited a uniform, near-spherical morphology (148.8 ± 1.4 nm) and a high drug loading capacity (11.28% ± 0.25). Triggered by the high concentration of glutathione, PTX/FHSV micelles could quickly release their loaded drug into the release medium. The in vitro cytological evaluations showed that, compared with Taxol or single receptor-targeted micelles, FHSV micelles yielded higher cellular uptake by the dual receptor-mediated endocytosis pathway, thus leading to significantly superior cytotoxicity and apoptosis in tumor cells but less cytotoxicity in normal cells. More importantly, in the in vivo antitumor experiments, PTX/FHSV micelles exhibited enhanced tumor accumulation and produced remarkable tumor growth inhibition with minimal systemic toxicity.
Our results suggest that this well-designed FHSV polymer has promising potential for use as a vehicle of chemotherapeutic drugs for precise cancer therapy.
肿瘤内药物递送的局部靶向性差和细胞内药物释放不足是化疗成功的固有缺陷。在这项研究中，通过结合双重受体介导的主动靶向和对细胞内还原电位的刺激响应，设计了一种特殊的聚合物胶束纳米平台，用于高效递送紫杉醇（PTX）。
通过酰胺反应合成了双重靶向还原敏感聚合物，叶酸-透明质酸-SS-维生素 E 琥珀酸（FHSV），并通过 H-NMR 进行了表征。然后，通过透析法制备了载紫杉醇的 FHSV 胶束（PTX/FHSV）。研究了胶束的物理化学性质。此外，进行了体外细胞实验和体内动物研究，以评估聚合物胶束的抗肿瘤功效。
PTX/FHSV 胶束呈现均匀的近球形形态（148.8 ± 1.4 nm）和高载药能力（11.28% ± 0.25）。在高浓度谷胱甘肽的触发下，PTX/FHSV 胶束能够迅速将其载药释放到释放介质中。体外细胞实验评估表明，与 Taxol 或单受体靶向胶束相比，FHSV 胶束通过双重受体介导的内吞途径实现了更高的细胞摄取，从而导致肿瘤细胞的细胞毒性和凋亡显著增强，而对正常细胞的细胞毒性较小。更重要的是，在体内抗肿瘤实验中，PTX/FHSV 胶束表现出增强的肿瘤积累，并产生显著的肿瘤生长抑制作用，同时具有最小的全身毒性。
我们的结果表明，这种精心设计的 FHSV 聚合物具有作为化疗药物载体用于精确癌症治疗的巨大潜力。
