Polypeptide micelles, though having been proved to be an appealing nanoplatform for cancer chemotherapy, are met with issues like inefficient drug encapsulation, gradual drug release, and low tumor cell selectivity and uptake. Here, we report on cRGD-decorated, small-sized, robust, and reduction-responsive polytyrosine micelles (cRGD-rPTM) based on poly(ethylene glycol)-b-poly(l-tyrosine)-lipoic acid (PEG-b-PTyr-LA) conjugate for high loading and targeted delivery of doxorubicin (Dox). Notably, cRGD-rPTM exhibited efficient loading of Dox, giving cRGD-rPTM-Dox with a drug loading content (DLC) of 18.5 wt % and a small size of 45 nm at a theoretical DLC of 20 wt %. cRGD-rPTM-Dox displayed reduction-triggered drug release, high selectivity and superior antiproliferative activity toward α_vβ₃ integrin positive MDA-MB-231 breast cancer cells (IC₅₀ = 1.5 μg/mL) to both nontargeted rPTM-Dox and clinical liposomal formulation (LP-Dox). cRGD-rPTM-Dox demonstrated a prolonged circulation time compared with the noncrosslinked cRGD-PTM-Dox control and significantly better accumulation in MDA-MB-231 breast tumor xenografts than nontargeted rPTM-Dox. Moreover, cRGD-rPTM-Dox at 6 mg Dox equiv/kg could remarkably suppress growth of MDA-MB-231 human breast tumor without inducing obvious side effects, outperforming both rPTM-Dox and LP-Dox. These reduction-responsive multifunctional polytyrosine micelles appear to be a viable and versatile nanoplatform for targeted chemotherapy.

中文翻译：

---

小型，耐用和还原反应性多肽胶束的建设，用于高负荷和靶向药物的化学治疗。

多肽胶束尽管已被证明是用于癌症化学疗法的引人注目的纳米平台，但仍遇到诸如药物封装效率低，药物逐渐释放以及肿瘤细胞选择性和摄取率低的问题。在这里，我们报道了基于聚（乙二醇）-b-聚（1-酪氨酸）-硫辛酸（PEG- b）的cRGD装饰，小巧，坚固且具有还原反应性的聚酪氨酸胶束（cRGD-rPTM）-PTyr-LA）偶联物可高负载并靶向递送阿霉素（Dox）。值得注意的是，cRGD-rPTM表现出有效的Dox负载量，在理论DLC为20 wt％的情况下，cRGD-rPTM-Dox的药物负载量（DLC）为18.5 wt％，小尺寸为45 nm。的cRGD-rPTM-DOX显示还原触发药物释放，高的选择性和优良的抗增殖活性的朝向α _v β ₃整联阳性MDA-MB-231乳腺癌细胞（IC ₅₀= 1.5μg/ mL）到非靶向rPTM-Dox和临床脂质体制剂（LP-Dox）。与非交联的cRGD-PTM-Dox对照相比，cRGD-rPTM-Dox的循环时间延长，与非靶向rPTM-Dox相比，MDA-MB-231乳腺异种移植物中的cRGD-rPTM-Dox明显更长。此外，cRGD-rPTM-Dox的剂量为6 mg Dox当量/千克时，可以显着抑制MDA-MB-231人乳腺肿瘤的生长，而不会引起明显的副作用，优于rPTM-Dox和LP-Dox。这些对还原反应敏感的多功能聚酪氨酸胶束似乎是靶向化疗的可行且多功能的纳米平台。