Several studies have demonstrated that CSCs are responsible for replenishing bulk tumor cells, generating new tumors and causing metastasis and relapse. Although combination therapy with multiple chemotherapeutics is considered to be a promising approach for simultaneously eliminating non-CSCs and CSCs, it is difficult to deliver drugs into the inner region of a solid tumor where the CSCs are located due to a lack of capillaries. Here, we synthesized a pH-sensitive polymer, poly(ethylene glycol)-benzoic imine-poly(γ-benzyl-l-aspartate)-b-poly(1-vinylimidazole) block copolymer (PPBV), to develop a pH multistage responsive micellar system for co-delivering paclitaxel and curcumin and synergistically eliminating breast cancer stem cells (bCSCs) and non-bCSCs. This pH multistage responsive micellar system could intelligently switch its surface charge from neutral to positive, de-shield its PEG layer and reduce its size after long-circulation and extravasation from leaky blood vessels at tumor sites, thus facilitating their cellular uptake and deep tumor penetration. These advantages were also beneficial for the combinational therapy efficacy of PTX and CUR to reach the maximum level and achieve superior tumor inhibition activity and effective bCSCs-killing capacity in vivo. Consequently, this pH multistage responsive micellar system is a powerful platform for collaborative therapy with PTX and CUR to simultaneously eliminate bCSCs and non-CSCs.

中文翻译：

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具有电荷开关和PEG层分离功能的pH多级响应胶束系统，用于共同递送紫杉醇和姜黄素，可协同消除乳腺癌干细胞

多项研究表明，CSC负责补充大量肿瘤细胞，产生新肿瘤并引起转移和复发。尽管与多种化学疗法相结合的治疗被认为是同时消除非CSC和CSC的一种有前途的方法，但是由于缺乏毛细血管，很难将药物输送到CSC所位于的实体瘤的内部区域。在这里，我们合成了一种对pH敏感的聚合物，聚乙二醇-苯甲亚胺-聚（γ-苄基-1-天冬氨酸）-b-聚（1-乙烯基咪唑）嵌段共聚物（PPBV），以开发一种pH多级响应胶束体系，用于共递送紫杉醇和姜黄素，并协同消除乳腺癌干细胞（bCSCs）和非bCSCs。这种pH多阶段响应性胶束系统可以智能地将其表面电荷从中性转换为正电荷，对PEG层进行屏蔽，并在长循环和从肿瘤部位渗漏血管中渗出后减小其尺寸，从而促进其细胞摄取和深层肿瘤渗透。这些优势也有利于PTX和CUR的联合治疗功效达到最高水平，并在体内获得优异的肿瘤抑制活性和有效的bCSCs杀伤能力。。因此，此pH多阶段反应性胶束系统是使用PTX和CUR进行联合治疗以同时消除bCSC和非CSC的强大平台。