Stimuli-responsive polymers have been of great interest in the fabrication of advanced drug delivery systems. In this study, a facile approach was developed to synthesize a dually temperature/pH-responsive drug delivery system with a core-shell structure to control the release of doxorubicin (DOX) at the target site. For this purpose, poly(acrylic acid) (PAA) nanospheres were first synthesized using the precipitation polymerization technique and were used as pH-responsive polymeric cores. Then, poly(N-isopropylacrylamide) (PNIPAM) with thermo-responsivity properties was coated on the outer surface of PAA cores via seed emulsion polymerization technique to render monodisperse PNIPAM-coated PAA (PNIPAM@PAA) nanospheres. The optimized PNIPAM@PAA nanospheres with an average particle size of 116.8 nm (PDI= 0.243), had a high negative surface charge (zeta potential= -47.6 mV). Then, DOX was loaded on PNIPAM@PAA nanospheres and the entrapment efficiency (EE) and drug loading (DL) capacity were measured to be 92.7% and 18.5%, respectively. The drug-loaded nanospheres exhibited a low leakage at neutral pH and physiological temperature, but drug release significantly enhanced at acidic pH (pH= 5.5), indicating the tumor-environment responsive drug release behavior of the prepared nanospheres. Also, kinetics studies showed that, the sustained release of DOX from PNIPAM@PAA nanospheres was consistent with the Fickian diffusion mechanism. Moreover, the anticancer efficacy of DOX-loaded nanospheres was evaluated in vitro against MCF-7 breast cancer cells. The obtained results revealed that, the incorporation of DOX into PNIPAM@PAA nanospheres increases its cytotoxicity against cancer cells compared to the free DOX. Our results suggest that, PNIPAM@PAA nanospheres can be considered as a promising vector to release anticancer drugs with dual-stimuli responsivity to pH and temperature.

刺激响应聚合物在先进药物输送系统的制造中引起了人们的极大兴趣。在这项研究中，开发了一种简便的方法来合成具有核壳结构的温度/pH 双重响应药物递送系统，以控制阿霉素 (DOX) 在靶位点的释放。为此，首先使用沉淀聚合技术合成聚丙烯酸（PAA）纳米球，并将其用作 pH 响应性聚合物核。然后，通过种子乳液聚合技术将具有热响应特性的聚（N-异丙基丙烯酰胺）（PNIPAM）涂覆在PAA核的外表面上，形成单分散PNIPAM涂覆的PAA（PNIPAM@PAA）纳米球。优化后的PNIPAM@PAA纳米球平均粒径为116.8 nm（PDI= 0.243），具有较高的负表面电荷（zeta电位= -47.6 mV）。然后，将DOX负载在PNIPAM@PAA纳米球上，测得包封率（EE）和载药量（DL）分别为92.7%和18.5%。载药纳米球在中性pH和生理温度下表现出低渗漏，但在酸性pH（pH = 5.5）下药物释放显着增强，表明所制备的纳米球具有肿瘤环境响应性药物释放行为。此外，动力学研究表明，PNIPAM@PAA纳米球中DOX的持续释放符合Fickian扩散机制。此外，在体外对 MCF-7 乳腺癌细胞的抗癌功效所得结果表明，与游离 DOX 相比，将 DOX 掺入 PNIPAM@PAA 纳米球中增加了其对癌细胞的细胞毒性。我们的结果表明，PNIPAM@PAA 纳米球可以被认为是一种有前途的载体，可以释放对 pH 和温度具有双重刺激响应的抗癌药物。