与传统方法相比，纳米药物递送系统（NDDS）的最大优势是通过细胞防御机制的饱和，将大量药物有效靶向和递送到癌细胞中，从而提高其治疗效果。在此，我们设计了双pH/氧化还原响应的DTX负载聚(β-氨基酯)(PBAS)胶束，其装饰有嵌合肽和TA1适体。体外和体内结果表明，设计的纳米平台在血液循环中具有不可检测的性质，但在暴露于4T1乳腺癌的肿瘤微环境（TME）后，它突然变成了双靶向纳米颗粒（NPs）（含有两个配体， SRL-2 和 TA1 适体）。在癌细胞的高 GSH 和低 pH 条件下，双重靶向 NP 被破坏，导致 DTX 释放放大（24 小时约为 70%）。负载 DTX 的 MMP-9 敏感七肽/TA1 适体修饰的聚（β-氨基酯）（MST@PBAS）胶束和游离 DTX 暴露 48 小时后测定的 IC50 值分别为 1.5 µg/ml 和 7.5 µg/毫升，分别。纳米配方 DTX 的细胞毒性比游离 DTX 强 5 倍（P 值 0.001）。细胞周期测定测试结果表明，暴露于 MST@PBAS 胶束后，亚 G1 群体 (48%) 显着增加，表明细胞周期停滞引起的细胞凋亡已经发生。负载 DTX 的 MST@PBAS 胶束显示早期凋亡水平 (59.8%) 显着高于游离 DTX (44.7%)（P 值 ˂ 0.001）。有趣的是，体外摄取研究表明，与单靶向 NP 相比，双靶向 NP 的 TME 积累显着更高（6 倍）（P 值 < 0.001），体内生物分布和荧光 TUNEL 测定实验进一步证实了这一点。 NPs 治疗组在 4T1 荷瘤 Balb/c 小鼠中表现出显着的肿瘤生长抑制作用，其抑制效果仅为药物模型 DTX 治疗剂量 (TD) 的 1/10。总之，巧妙设计的纳米结构通过增强肿瘤靶向性、更准确地输送化疗药物、促进药物释放、减少治疗剂量和降低抗癌药物的副作用，证明了改善的抗癌效果。© 2024。作者。

Effective targeting and delivery of large amounts of medications into the cancer cells enhance their therapeutic efficacy through saturation of cellular defensive mechanisms, which is the most privilege of nano drug delivery systems (NDDS) compared to traditional approaches. Herein, we designed dual-pH/redox responsive DTX-loaded poly (β-amino ester) (PBAS) micelles decorated with a chimeric peptide and TA1 aptamer. In vitro and in vivo results demonstrated that the designed nanoplatform possessed an undetectable nature in the blood circulation, but after exposure to the tumor microenvironment (TME) of 4T1 breast cancer, it suddenly changed into dual targeting nanoparticles (NPs) (containing two ligands, SRL-2 and TA1 aptamer). The dual targeting NPs destruction in the high GSH and low pH conditions of the cancer cells led to amplified DTX release (around 70% at 24 h). The IC50 value of DTX-loaded MMP-9 sensitive heptapeptide/TA1 aptamer-modified poly (β-amino ester) (MST@PBAS) micelles and free DTX after 48 h of exposure was determined to be 1.5 µg/ml and 7.5 µg/ml, respectively. The nano-formulated DTX exhibited cytotoxicity that was 5-fold stronger than free DTX (Pvalue˂0.001). Cell cycle assay test results showed that following exposure to MST@PBAS micelles, a considerable rise in the sub G1 population (48%) suggested that apoptosis by cell cycle arrest had occurred. DTX-loaded MST@PBAS micelles revealed significantly higher (Pvalue ˂ 0.001) levels of early apoptosis (59.8%) than free DTX (44.7%). Interestingly, in vitro uptake studies showed a significantly higher TME accumulation of dual targeted NPs (6-fold) compared to single targeted NPs (Pvalue < 0.001) which further confirmed by in vivo biodistribution and fluorescent TUNEL assay experiments. NPs treated groups demonstrated notable tumor growth inhibition in 4T1 tumor bearing Balb/c mice by only 1/10th of the DTX therapeutic dose (TD) as a drug model. In conclusion, cleverly designed nanostructures here demonstrated improved anticancer effects by enhancing tumor targeting, delivering chemotherapeutic agents more accurately, promoting drug release, reducing the therapeutic dosage, and lowering side effects of anticancer drugs.© 2024. The Author(s).