Limited effectiveness of Raf and MEK inhibitors has impelled the interest to use the inhibitors of Extra-cellular Receptor Kinase (ERK) pathway in combination with Gemcitabine (GEM) in pancreatic cancer. However, off-target abundance of ERK receptors, challenging physico-chemical properties, and dose-limiting toxicity of the inhibitor has presented critical challenges towards fabricating this combination amenable for clinical translation. Herein we report a pharmaceutical nanoformulation of GEM and an ERK inhibitor (SCH 772984) co-stabilized within a pH-sensing nanocarrier (NC, with a hydrodynamic diameter of 161 ± 5.0 nm). The NCs were modularly derived from a triblock, self-assembling copolymer, and were chemically conjugated with GEM and encapsulated with SCH772984 at a loading content of 20.2% and 18.3%, respectively. Through pH-mediated unfolding of the individual blocks of the copolymer, the NCs were able to control the release of encapsulated drugs, traffic through cellular membranes, engage target receptors, suppress proliferation of pancreatic cancer cells, and accumulate at disease sites. Collectively our studies showed the feasibility of co-delivery of a combination chemotherapy consisting of GEM and an ERK inhibitor from a NC platform, which can sense and respond to tumor microenvironment of pancreatic cancer setting.

中文翻译：

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微环境传感，纳米载体介导的联合化疗治疗胰腺癌。

Raf和MEK抑制剂的疗效有限，促使人们有兴趣将胞外受体激酶（ERK）抑制剂与吉西他滨（GEM）联合用于胰腺癌。然而，ERK受体的脱靶丰度，具有挑战性的理化性质和抑制剂的剂量限制性毒性为制造适合临床翻译的组合提出了严峻挑战。本文中，我们报道了在pH敏感纳米载体（NC，流体动力学直径为161±5.0 nm）内共同稳定的GEM和ERK抑制剂（SCH 772984）的药物纳米制剂。NCs是从三嵌段，自组装共聚物中模块化衍生而来的，并与GEM化学共轭，并分别以20.2％和18.3％的负载量用SCH772984封装。通过pH介导的共聚物各个嵌段的解折叠，NC能够控制封装药物的释放，通过细胞膜的运输，与靶受体结合，抑制胰腺癌细胞的增殖以及在疾病部位蓄积。我们的研究共同表明，从NC平台共同交付由GEM和ERK抑制剂组成的联合化疗的可行性，该联合化疗可以感测和响应胰腺癌的肿瘤微环境。