Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, South Carolina 29208, United States.
Mol Pharm. 2012 Sep 4;9(9):2719-29. doi: 10.1021/mp300274g. Epub 2012 Aug 22.
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 IC(50) 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.
为了模拟临床给药模式，即先给予高负荷剂量，然后给予低维持剂量，我们设计了一种新型的基于聚（2-(吡啶-2-基二硫基)乙基丙烯酰胺）（PDS）的纳米粒子给药系统。通过自由基聚合合成了带有侧链功能的 PDS。聚乙二醇和环（精氨酸-甘氨酸-天冬氨酸-苯丙氨酸-半胱氨酸）（cRGD）肽通过巯基-二硫键交换反应被连接到 PDS 上，得到 RPDSG 聚合物。通过共溶剂透析法制备了载有多柔比星的 RPDSG/DOX，即载有多柔比星的 RPDSG 纳米粒子。纳米粒子在 PBS 中的粒径为 50.13 ± 0.5nm。RPDSG/DOX 纳米粒子在生理条件下稳定，而在酸性 pH 值和氧化还原电势的触发下，能够快速释放多柔比星。此外，它表现出两相释放动力学，为癌症治疗提供了负荷剂量和维持剂量。RGD 肽的连接增强了 RPDSG/DOX 纳米粒子的细胞摄取和核定位。RPDSG/DOX 对 HCT-116 结肠癌细胞的 IC（50）接近游离多柔比星。由于 RGD 靶向作用和两相释放动力学的协同作用，RPDSG/DOX 纳米粒子在浓度高于 5 μM 时，显示出比游离 DOX 更高的抗癌疗效。这些结果表明，RPDSG/DOX 可能是一种有前途的肿瘤靶向化疗纳米药物。
