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.

为了提高化疗药物的抗肿瘤效率并减少副作用，根据肿瘤组织的生理特性和肿瘤细胞内微环境，建立了具有长循环，主动靶向，氧化还原和pH触发药物释放特性的多功能药物递送系统。 4.聚酰胺型胺树枝状大分子（PAMAM）。首先，引入氧化还原可裂解的二硫键（SS），以将聚乙二醇（PEG）与PAMAM连接以形成PAMAM-SS-PEG（PSSP）。然后将cRGD肽应用于PSSP的PEG末端以构建RGD-PSSP偶联物。最后，将抗肿瘤化学治疗药物阿霉素（DOX）封装到RGD-PSSP偶联物的疏水腔中，构建了RGD-PSSP / DOX药物递送系统。在体外实验表明，RGD-PSSP / DOX NPs具有明显的氧化还原和pH双重敏感药物释放曲线。MTT和细胞摄取观察表明，cRGD修饰可以增加细胞毒性，并促进B16细胞和HUVEC细胞的摄取，二者均在细胞膜上过表达整联蛋白ανβ3。细胞摄取机制研究进一步揭示，RGD-PSSP / DOX通过整合素ανβ3对cRGD肽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而被内化。值得注意的是，RGD-PSSP / DOX在体内具有优异的抗癌活性和较低的心脏和肾脏毒性，可被视为有效抗肿瘤化疗药物的潜在候选药物。