Department of Organic Chemistry, Faculty of Chemistry, Urmia University, Urmia, Iran.
Drug Applied Research Center and Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
Sci Rep. 2023 Dec 18;13(1):22475. doi: 10.1038/s41598-023-49446-x.
Tumor microenvironment (TME) targeted strategy could control the drug release in tumor cells more accurately and creates a new opportunity for enhanced site-specific targeted delivery. In this study, (PAA-b-PCL-S-S-PCL-b-PAA) copolymeric nanoparticles (NPs) with size-switchable ability and dual pH/redox-triggered drug release behavior were designed to significantly promote cancer uptake (cell internalization of around 100% at 30 min) and site-specific targeted doxorubicin (DOX) delivery in MDA-MB-231 tumor cells. NPs surface charge was shifted from - 17.8 to - 2.4 and their size shrunk from 170.3 to 93 nm in TME. The cell cycle results showed that DOX-loaded NPs showed G2/M (68%) arrest, while free DOX showed sub-G1 arrest (22%). Apoptosis tests confirmed that the cells treated with DOX-loaded NPs showed a higher amount of apoptosis (71.6%) than the free DOX (49.8%). Western blot and RT-PCR assays revealed that the apoptotic genes and protein levels were significantly upregulated using the DOX-loaded NPs vs. the free DOX (P < 0.001). In conclusion, dual pH/redox-responsive and size-switchable DOX-loaded NPs developed here showed outstanding anti-tumoral features compared with free DOX that might present a prospective platform for tumor site-specific accumulation and drug release that suggest further in vivo research.
肿瘤微环境（TME）靶向策略可以更准确地控制肿瘤细胞中的药物释放，并为增强的靶向递药提供新的机会。在这项研究中，设计了具有尺寸可切换能力和双重 pH/还原响应性药物释放行为的（PAA-b-PCL-S-S-PCL-b-PAA）两亲性嵌段共聚物纳米粒子（NPs），以显著促进癌症摄取（在 30 分钟内达到约 100%的细胞内化）和 MDA-MB-231 肿瘤细胞中特异性靶向阿霉素（DOX）的递送。NPs 的表面电荷从-17.8 变为-2.4，其尺寸从 170.3nm 缩小到 TME 中的 93nm。细胞周期结果表明，载 DOX 的 NPs 使 DOX 显示 G2/M（68%）停滞，而游离 DOX 显示亚 G1 停滞（22%）。凋亡试验证实，用载 DOX 的 NPs 处理的细胞显示出比游离 DOX（49.8%）更高的凋亡量（71.6%）。Western blot 和 RT-PCR 分析表明，与游离 DOX 相比，载 DOX 的 NPs 显著上调了凋亡基因和蛋白水平（P < 0.001）。总之，与游离 DOX 相比，本文开发的双重 pH/还原响应性和尺寸可切换的载 DOX NPs 表现出优异的抗肿瘤特性，这可能为肿瘤特异性积累和药物释放提供有前景的平台，提示进一步的体内研究。
