Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, P. R. China.
ACS Nano. 2024 Oct 1;18(39):26690-26703. doi: 10.1021/acsnano.4c06399. Epub 2024 Sep 20.
Herein, we constructed a paclitaxel (PTX) prodrug (PA) by conjugating PTX with acrylic acid as a cysteine-depleting agent. The as-synthesized PA can assemble with diacylphosphatidylethanolamine-PEG to form stable nanoparticles (PA NPs). After endocytosis into cells, PA NPs can specifically react with cysteine and trigger release of PTX for chemotherapy. On the other hand, the depletion of cysteine can greatly downregulate the intracellular content of glutathione and lead to oxidative stress outburst-provoking ferroptosis. The released PTX can elicit antitumor immune response by inducing immunogenic cell death, thus promoting dendritic cells maturation and cascaded cytotoxic T lymphocytes activation, which not only produces a robust immunotherapy effect but also synergizes the ferroptosis therapy by inhibiting cysteine transport via the release of interferon-γ in the activated immune system. As a result, PA NPs exhibit favorable in vitro and in vivo antitumor performance with reduced systemic toxicity. Our work highlights the potential of simple molecular design of prodrugs for enhancing the therapeutic efficacy toward malignant cancer.
在这里，我们通过将紫杉醇（PTX）与丙烯酸连接，构建了一种作为半胱氨酸耗竭剂的紫杉醇前药（PA）。合成的 PA 可以与二酰基磷脂酰乙醇胺-PEG 组装形成稳定的纳米颗粒（PA NPs）。PA NPs 被细胞内吞后，可以特异性地与半胱氨酸反应，并触发 PTX 的释放以进行化疗。另一方面，半胱氨酸的耗竭会大大降低细胞内谷胱甘肽的含量，导致氧化应激爆发引发铁死亡。释放的 PTX 通过诱导免疫原性细胞死亡引发抗肿瘤免疫反应，从而促进树突状细胞成熟和级联细胞毒性 T 淋巴细胞激活，不仅产生强大的免疫治疗效果，还通过在激活的免疫系统中释放干扰素-γ来抑制半胱氨酸转运，与铁死亡治疗协同增效。结果，PA NPs 表现出良好的体外和体内抗肿瘤性能，同时降低了全身毒性。我们的工作强调了通过简单的前药分子设计来提高恶性癌症治疗效果的潜力。
