Dual-responsive click-crosslinked micelles designed for enhanced chemotherapy for solid tumors.,Biomaterials Science

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Dual-responsive click-crosslinked micelles designed for enhanced chemotherapy for solid tumors.
Biomaterials Science ( IF 5.8 ) Pub Date : 2020-05-06 , DOI: 10.1039/d0bm00078g
Rong Jin ₁ , Jing Sun ₁ , Liefu Zhou ₁ , Xuelian Guo ₁ , Aoneng Cao ₁

Affiliation

The design of multiple stimuli-responsive, stable polymeric drug carriers is key for efficient drug release against solid tumors. Herein, core-crosslinked micelles were readily prepared from a pair of redox/pH-sensitive clickable copolymers. The two copolymers comprised the same poly(ethylene glycol) (PEG)-poly(ε-benzyloxycarbonyl-l-lysine) (PZLL) block but with either disulfide-linked azadibenzocyclooctyne (DBCO) or azide (AZ) group-tagged branched polyethylenimine (BPEI, 1.8 kDa). The data showed that an equivalent of the two copolymers could self-assemble into nanosized micelles with the crosslinked core via the DBCO-AZ click chemistry. The click-crosslinked micelles showed excellent size stability under multiple dilutions but destabilization in an acidic or reductive environment. Besides, they could load doxorubicin (DOX), an anticancer drug, and mediate slow drug release in a neutral environment but sufficient drug unloading under acidic plus reductive conditions. In vitro, DOX-loaded crosslinked micelles led to higher DOX accumulation in the cellular nucleus in comparison with non-crosslinked micelles from the PEG-PZLL-BPEI copolymer (PP), thus causing more marked cytotoxicity in SKOV-3 cells. In vivo, DOX-loaded crosslinked micelles caused significant growth inhibition of SKOV-3 tumors xenografted in BALB/c nude mice, and showed superior anticancer efficacy to non-crosslinked PP micelles. Chemotherapy with core-crosslinked micelles had no adverse side effects on the health (serum levels and body weight) of the mice. This study highlights the design of clickable block copolymers to easily construct core-crosslinked and multiple stimuli-responsive micelles for enhanced anticancer therapy.

中文翻译：

设计用于增强实体瘤化学疗法的双反应单击交联胶束。

多种刺激响应，稳定的聚合物药物载体的设计是有效释放针对实体瘤的药物的关键。在此，容易从一对氧化还原/ pH敏感的可点击共聚物制备核交联的胶束。两种共聚物包含相同的聚（乙二醇）（PEG）-聚（ε-苄氧基羰基-1-赖氨酸）（PZLL）嵌段，但带有二硫键连接的azadibenzocyclooctyne（DBCO）或叠氮化物（AZ）基团标记的支链聚乙烯亚胺（ BPEI，1.8 kDa）。数据表明，两种共聚物的等价物可以通过DBCO-AZ点击化学反应自组装成具有交联核的纳米胶束。单击交联的胶束在多次稀释下显示出优异的尺寸稳定性，但在酸性或还原性环境中不稳定。此外，他们可以加载抗癌药阿霉素（DOX），并在中性环境中介导缓慢的药物释放，但在酸性和还原性条件下可充分释放药物。在体外，与来自PEG-PZLL-BPEI共聚物（PP）的非交联胶束相比，加载DOX的交联胶束导致细胞核中更高的DOX积累，从而在SKOV-3细胞中引起更明显的细胞毒性。在体内，负载DOX的交联胶束显着抑制了在BALB / c裸鼠中异种移植的SKOV-3肿瘤的生长，并显示出比非交联PP胶束更高的抗癌功效。用核心交联的胶束进行化学疗法对小鼠的健康（血清水平和体重）没有不利的副作用。

更新日期：2020-03-06

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