To mimic the clinic dosing pattern, initially administering high loading dose and then low maintenance dose, we designed a novel poly(2-(pyridin-2-yldisulfanyl)ethyl acrylate) (PDS) based nanoparticle delivery system. Side chain functional PDS was synthesized by free radical polymerization. Polyethylene glycol and cyclo(Arg-Gly-Asp-d-Phe-Cys) (cRGD) peptide was conjugated to PDS through thiol–disulfide exchange reaction to achieve RPDSG polymer. RPDSG/DOX, RPDSG nanoparticle loaded with doxorubicin, was fabricated by cosolvent dialysis method. The size of the nanoparticles was 50.13 ± 0.5 nm in PBS. The RPDSG/DOX nanoparticle is stable in physiological condition while quickly releasing doxorubicin with the trigger of acidic pH and redox potential. Furthermore, it shows a two-phase release kinetics, providing both loading dose and maintenance dose for cancer therapy. The conjugation of RGD peptide enhanced the cellular uptake and nuclear localization of the RPDSG/DOX nanoparticles. RPDSG/DOX exhibits IC₅₀ close to that of free doxorubicin for HCT-116 colon cancer cells. Due to the synergetic effect of RGD targeting effect and its two-phase release kinetics, RPDSG/DOX nanoparticles display significantly higher anticancer efficacy than that of free DOX at concentrations higher than 5 μM. These results suggest that RPDSG/DOX could be a promising nanotherapeutic for tumor-targeted chemotherapy.

中文翻译：

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pH和氧化还原双重响应纳米粒子的核靶向药物输送。

为了模拟临床给药模式，首先要给予高负荷剂量，然后再给予低维持剂量，我们设计了一种新型的基于聚（2-（吡啶-2-基二硫烷基）丙烯酸乙酯）（PDS）的纳米颗粒输送系统。通过自由基聚合合成侧链功能性PDS。聚乙二醇和环（Arg-Gly-Asp- d-Phe-Cys）（cRGD）肽通过硫醇-二硫键交换反应与PDS偶联，获得RPDSG聚合物。通过共溶剂渗析法制备了载有阿霉素的RPDSG纳米颗粒RPDSG / DOX。在PBS中，纳米颗粒的尺寸为50.13±0.5nm。RPDSG / DOX纳米颗粒在生理条件下稳定，同时在酸性pH和氧化还原电位的触发下快速释放阿霉素。此外，它显示了两相释放动力学，为癌症治疗提供了加载剂量和维持剂量。RGD肽的缀合增强了RPDSG / DOX纳米颗粒的细胞摄取和核定位。RPDSG / DOX展示IC ₅₀与HCT-116结肠癌细胞的游离阿霉素接近。由于RGD靶向作用及其两相释放动力学的协同作用，RPDSG / DOX纳米颗粒在高于5μM的浓度下显示出比游离DOX显着更高的抗癌功效。这些结果表明，RPDSG / DOX可能是针对肿瘤靶向化疗的有前途的纳米疗法。