Wang Siying, Xie Lanlan, Liu Yanjie, Yang Qilei, Jia Wenqiang, Zhao Dongmei, Zhao Xiuhua
47820Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin, People's Republic of China.
47820College of Chemistry, Chemical Engineering and Resource Utilization, Northeast Forestry University, Harbin, People's Republic of China.
J Biomater Appl. 2022 Aug;37(2):259-274. doi: 10.1177/08853282221088182. Epub 2022 May 9.
Amphiphilic polymer micellar carriers are the most commonly used nanocarriers for oral delivery of hydrophobic drugs because their hydrophilic shell can avoid the recognition of the reticuloendothelial system (RES), has excellent drug-carrying capacity, and protect the drug from inactivation in the gastrointestinal fluid. The polymer micelle shell can enter cancer cells by endocytosis, and autophagy in cells, degradation by lysosomal pathway, so as to release drugs, prolong the circulation time of drugs in vivo, and then achieve the effect of drug sustained release. In this study, the glutathione-responsive PLGA-ss-PEG loaded paclitaxel (PTX) micelles (PLGA-ss-PEG-PTX) were developed for anticancer therapy. With its long-term circulation and EPR (enhanced permeability and retention) effect, and the micelle had disulfide bond, which could be used as the recognition group of tumor microenvironment, so that the PLGA-ss-PEG-PTX could specifically accumulate at the tumor site, so as to produce better anti-tumor effect. The PLGA-ss-PEG-PTX was formulated by the emulsification method in this study. The drug loading was about 21.54%, the entrapment efficiency was about 94.2%, and the particle size range was about 90 nm with narrow particle size distribution. Cytotoxicity and embryonic toxicity experiments were carried out using mouse lung cancer cells (LLC) and zebrafish fertilized eggs. It was proved that the low concentration of blank micelles had little cytotoxicity, but high concentration of blank micelles had adverse effects on zebrafish embryonic development, resulting in embryonic malformation. The uptake of drugs by cancer cells was studied by a high connotation cell imaging analysis system. The experiments showed that the drug molecules encapsulated in micelles could achieve higher uptake by cells compared with free drug molecules. In addition, in the in vivo evaluation experiment of drugs, the PLGA-ss-PEG-PTX could significantly enhance the therapeutic effect of the PTX, improve its water solubility, and improve its oral bioavailability.
两亲性聚合物胶束载体是口服递送疏水性药物最常用的纳米载体，因为其亲水性外壳可避免被网状内皮系统（RES）识别，具有出色的载药能力，并能保护药物在胃肠液中不被灭活。聚合物胶束外壳可通过内吞作用进入癌细胞，并在细胞内通过自噬、经溶酶体途径降解，从而释放药物，延长药物在体内的循环时间，进而实现药物缓释效果。在本研究中，开发了用于抗癌治疗的谷胱甘肽响应型聚乳酸-羟基乙酸共聚物-二硫键-聚乙二醇（PLGA-ss-PEG）负载紫杉醇（PTX）胶束（PLGA-ss-PEG-PTX）。凭借其长期循环和增强的渗透滞留（EPR）效应，且该胶束含有二硫键，可作为肿瘤微环境的识别基团，使PLGA-ss-PEG-PTX能够特异性地在肿瘤部位蓄积，从而产生更好的抗肿瘤效果。本研究采用乳化法制备PLGA-ss-PEG-PTX。载药量约为21.54%，包封率约为94.2%，粒径范围约为90nm，粒径分布窄。使用小鼠肺癌细胞（LLC）和斑马鱼受精卵进行细胞毒性和胚胎毒性实验。结果表明，低浓度的空白胶束细胞毒性较小，但高浓度的空白胶束对斑马鱼胚胎发育有不良影响，导致胚胎畸形。通过高内涵细胞成像分析系统研究癌细胞对药物的摄取。实验表明，与游离药物分子相比，胶束包裹的药物分子能够实现更高的细胞摄取。此外，在药物的体内评价实验中，PLGA-ss-PEG-PTX可显著增强PTX的治疗效果，提高其水溶性，并改善其口服生物利用度。
