具有多种药理学成果的创新化疗纳米药物递送系统（NDDS）已成为癌症治疗中充满希望的治疗策略之一。本研究重点关注低 pH 值和高水平谷胱甘肽 (GSH) 作为肿瘤微环境 (TME) 的两个突出特征，设计了一种新型 TME 靶向 pH/氧化还原双响应 P (AMA-co-DMAEMA)-b- PCL-SS-PCL-b-P (AMA-co-DMAEMA) 纳米颗粒 (NP) 用于深度肿瘤渗透和靶向抗肿瘤治疗。带正电的纳米粒子与带负电的细胞膜表现出强烈的静电相互作用，显着增强细胞的摄取。此外，这些纳米粒子具有独特的尺寸收缩特性，在TME内从98.24±27.78纳米转变到45.56±20.62纳米。这种显着的尺寸变化使得 MDA-MB-231 细胞在短短 30 分钟内即可实现约 100% 的吸收，从而大大提高了药物递送效率。这种尺寸可切换性通过增强渗透性和保留（EPR）效应实现被动靶向，促进对肿瘤的深度渗透。 NP 还表现出在 TME 中改善了 pH/氧化还原触发的药物释放（24 小时时约 70%），并且在细胞活力测试中没有表现出毒性。用负载多西他赛 (DTX) 的 NP 处理的细胞的细胞周期结果显示 G2/M (84.6±1.16%) 停滞。在处理的细胞中，负载 DTX 的 NPs 显示出比游离 DTX (51.8±3.2%) 更多的细胞凋亡 (62.6±3.7%)。蛋白质印迹和 RT-PCR 检测显示，与游离 DTX 相比，负载 DTX 的 NP 处理细胞的凋亡基因和蛋白质表达显着上调（P 值<.001）。总之，这些研究结果表明，这种新型设计的 NP 有希望作为 TME 靶向 NDDS。

Innovation chemotherapeutic nano drug delivery systems (NDDSs) with various pharmacological achievement have become one of the hopeful therapeutic strategies in cancer therapy. This study focused on low pH, and high levels of glutathione (GSH) as two prominent characteristics of the tumor microenvironment (TME) to design a novel TME-targeted pH/redox dual-responsive P (AMA-co-DMAEMA)-b-PCL-SS-PCL-b-P (AMA-co-DMAEMA) nanoparticles (NPs) for deep tumor penetration and targeted anti-tumor therapy. The positively charged NPs exhibit strong electrostatic interactions with negatively charged cell membranes, significantly enhancing cellular uptake. Moreover, these NPs possess the unique size-shrinkable property, transitioning from 98.24 ± 27.78 to 45.56 ± 20.62 nm within the TME. This remarkable size change fosters an impressive uptake of approximately 100% by MDA-MB-231 cells within just 30 min, thereby greatly improving drug delivery efficiency. This size switchability enables passive targeting through the enhanced permeability and retention (EPR) effect, facilitating deep penetration into tumors. The NPs also demonstrate improved pH/redox-triggered drug release (∼70% at 24 h) within the TME and exhibit no toxicity in cell viability test. The cell cycle results of treated cells with docetaxel (DTX)-loaded NPs revealed G2/M (84.6 ± 1.16%) arrest. The DTX-loaded NPs showed more apoptosis (62.6 ± 3.7%) than the free DTX (51.8 ± 3.2%) in treated cells. The western blot and RT-PCR assays revealed that apoptotic genes and proteins expression of treated cells were significantly upregulated with the DTX-loaded NPs vs. the free DTX (Pvalue<.001). In conclusion, these findings suggest that this novel-engineered NPs holds promise as a TME-targeted NDDS.