Precision Medicine Research Center & Sichuan Provincial Key Laboratory of Precision Medicine and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
National Chengdu Center for Safety Evaluation of Drugs, West China Hospital, Sichuan University, Chengdu, China.
Drug Deliv. 2021 Dec;28(1):2495-2509. doi: 10.1080/10717544.2021.2008052.
Stimuli-responsive nanotherapeutics hold great promise in precision oncology. In this study, a facile strategy was used to develop a new class of pH-responsive micelles, which contain methoxy polyethylene glycol (mPEG) and poly(carbobenzoxy-l-glutamic acid, BLG) as amphiphilic copolymer, and β-thiopropionate as acid-labile linkage. The mPEG-S-PBLG copolymer was synthesized through one-step ring-opening polymerization (ROP) and thiol-ene click reaction, and was able to efficiently encapsulate doxorubicin (DOX) to form micelles. The physicochemical characteristics, cellular uptake, tumor targeting, and anti-tumor efficacy of DOX-loaded micelles were investigated. DOX-loaded micelles were stable under physiological conditions and disintegrated under acidic conditions. DOX-loaded micelles can be internalized into cancer cells and release drugs in response to low pH in endosomes/lysosomes, resulting in cell death. Furthermore, the micellar formulation significantly prolonged the blood circulation, reduced the cardiac distribution, and selectively delivered more drugs to tumor tissue. Finally, compared with free DOX, DOX-loaded micelles significantly improved the anti-tumor efficacy and reduced systemic and cardiac toxicity in two different tumor xenograft models. These results suggest that mPEG-S-PBLG micelles have translational potential in the precise delivery of anti-cancer drugs.
刺激响应型纳米治疗在精准肿瘤学中具有巨大的应用前景。在本研究中，我们采用了一种简便的策略来开发一类新型的 pH 响应性胶束，其包含甲氧基聚乙二醇（mPEG）和聚（N-羧基-β-丙氨酸，BLG）作为两亲性共聚物，以及β-硫丙酸酯作为酸不稳定键。mPEG-S-PBLG 共聚物通过一步开环聚合（ROP）和硫醇-烯点击反应合成，能够高效包载阿霉素（DOX）形成胶束。我们考察了载 DOX 胶束的理化性质、细胞摄取、肿瘤靶向和抗肿瘤疗效。在生理条件下，载 DOX 胶束稳定，在酸性条件下崩解。载 DOX 胶束可以被内化进入癌细胞，并在内涵体/溶酶体的低 pH 环境下响应释放药物，导致细胞死亡。此外，胶束制剂显著延长了血液循环时间，减少了心脏分布，并选择性地将更多的药物递送到肿瘤组织。最后，与游离 DOX 相比，载 DOX 胶束在两种不同的肿瘤异种移植模型中显著提高了抗肿瘤疗效，同时降低了全身和心脏毒性。这些结果表明，mPEG-S-PBLG 胶束在抗癌药物的精准递送方面具有转化应用的潜力。
