Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
Colloids Surf B Biointerfaces. 2020 Oct;194:111195. doi: 10.1016/j.colsurfb.2020.111195. Epub 2020 Jun 12.
To improve antitumor efficiency of chemotherapy and reduce side effect, according to the physiological characteristics of tumor tissues and tumor intracellular microenvironment, a multifunctional drug delivery system with properties of long circulation, active targeting, redox and pH triggered drug release was established based on the Generation 4 polyamidoamine dendrimer (PAMAM). First, the redox cleavable disulfide bonds (SS) were introduced for linking polyethylene glycol (PEG) with PAMAM to form PAMAM-S-S-PEG (PSSP). Then cRGD peptide was applied to the PEG end of PSSP to construct RGD-PSSP conjugates. Finally, encapsulating the antitumor chemotherapy drug doxorubicin (DOX) into the hydrophobic cavity of RGD-PSSP conjugates constructed the RGD-PSSP/DOX drug delivery system. The in vitro experiments displayed that RGD-PSSP/DOX NPs showed obviously redox and pH dual sensitive drug release profile. MTT and cell uptake observation elucidated cRGD modification could increase the cytotoxicity, and promote the uptake of B16 cells and HUVEC cells both overexpressing integrin ανβ3on cell membrane. Cell uptake mechanism investigation further revealed that RGD-PSSP/DOX interacted with plasma membrane via specific recognition of cRGD peptide with integrin ανβ3, and was subsequently internalized mainly through clathrin- and caveolin-mediated endocytosis. Remarkably, RGD-PSSP/DOX presented superior anticancer activity and lower heart and kidney toxicity in vivo, which could be regarded as a potential candidate for efficient antitumor chemotherapy drug delivery.
为了提高化疗的抗肿瘤效率，降低其副作用，根据肿瘤组织的生理特性和肿瘤细胞内微环境，以第四代聚酰胺-胺树枝状大分子（PAMAM）为载体，构建了一种具有长循环、主动靶向、氧化还原和 pH 触发药物释放功能的多功能药物传递系统。首先，引入可还原的二硫键（SS）将聚乙二醇（PEG）与 PAMAM 连接，形成 PAMAM-S-S-PEG（PSSP）。然后将 cRGD 肽连接到 PSSP 的 PEG 端，构建 RGD-PSSP 缀合物。最后，将抗肿瘤化疗药物阿霉素（DOX）包载入 RGD-PSSP 缀合物的疏水腔中，构建了 RGD-PSSP/DOX 药物传递系统。体外实验表明，RGD-PSSP/DOX NPs 表现出明显的氧化还原和 pH 双重敏感的药物释放特性。MTT 和细胞摄取观察表明，cRGD 修饰可以提高细胞毒性，并促进细胞膜上过度表达整合素 ανβ3 的 B16 细胞和 HUVEC 细胞的摄取。细胞摄取机制研究进一步表明，RGD-PSSP/DOX 通过 cRGD 肽与整合素 ανβ3 的特异性识别与质膜相互作用，随后主要通过网格蛋白和小窝蛋白介导的内吞作用内化。值得注意的是，RGD-PSSP/DOX 在体内表现出优异的抗肿瘤活性和较低的心肾毒性，可作为一种有效的抗肿瘤化疗药物传递的潜在候选药物。
