Abstract

The fabrication of novel and intelligent delivery systems that can effectively deliver therapeutics to the targeted site and release payload in enhanced/controlled manner is highly desired to overcome the multiple challenges in chemotherapy. The present article demonstrates the potential application of dual stimuli responsive nanogels as tumor microenvironment targeted drug delivery carrier. Disulfide cross-linked pH and redox responsive PEG-PDMAEMA nanogels were synthesized by atom transfer radical polymerization (ATRP). The nanogels were characterized by nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The PEG-PDMAEMA nanogels exhibited dual stimuli-responsive release of the encapsulated model anticancer drug (doxorubicin, DOX) due to the acidic pH-response of dimethyl amine group in PDMAEMA and reductive cleavage of the disulfide linkages. A relatively higher release of DOX was observed from the nanogels at pH 5.0 than at pH 7.4. DOX release was further accelerated in tumor simulated environment of pH 5.0 and 10 mM glutathione (GSH). Confocal microscopy images revealed that DOX-loaded PEG-PDMAEMA nanogels can rapidly internalize and effectively deliver the drug into the cells. The nanogels exhibited higher cytotoxicity in GSH-OEt pretreated HeLa cells than untreated cells. The dual stimuli responsive nanogels synthesized in this study exhibited many favorable traits, such as pH and redox dependent controlled release of drug, biodegradability, biocompatibility, and enhanced cytotoxicity, which endow them as a promising candidate for anticancer drug delivery.

摘要

非常需要能够有效地将治疗药物输送到目标部位并以增强/受控方式释放有效载荷的新型智能输送系统的制造，以克服化疗中的多重挑战。本文展示了双刺激响应纳米凝胶作为肿瘤微环境靶向药物递送载体的潜在应用。通过原子转移自由基聚合（ATRP）合成二硫化物交联的 pH 值和氧化还原响应 PEG-PDMAEMA 纳米凝胶。通过核磁共振 (NMR) 光谱、傅里叶变换红外光谱 (FTIR) 和 X 射线衍射 (XRD) 对纳米凝胶进行表征。PEG-PDMAEMA 纳米凝胶表现出包封的模型抗癌药物（多柔比星、DOX) 由于 PDMAEMA 中二甲胺基团的酸性 pH 响应和二硫键的还原裂解。在 pH 5.0 下观察到纳米凝胶释放的 DOX 比在 pH 7.4 下更高。在 pH 5.0 和 10 mM 谷胱甘肽 (GSH) 的肿瘤模拟环境中，DOX 释放进一步加速。共聚焦显微镜图像显示，负载 DOX 的 PEG-PDMAEMA 纳米凝胶可以快速内化并有效地将药物输送到细胞中。与未处理的细胞相比，纳米凝胶在 GSH-OEt 预处理的 HeLa 细胞中表现出更高的细胞毒性。本研究合成的双刺激响应纳米凝胶具有许多有利的特性，如 pH 值和氧化还原依赖性药物控释、生物降解性、生物相容性和增强的细胞毒性，使其成为抗癌药物递送的有希望的候选者。