释放奥沙利铂、阿霉素和吉西他滨的多目标前药是抑制肿瘤生长和诱导免疫原性细胞死亡的有效药物。
Multitargeting prodrugs that release oxaliplatin, doxorubicin and gemcitabine are potent inhibitors of tumor growth and effective inducers of immunogenic cell death.
发表日期：2023 Aug 30
作者：
Amrita Sarkar, Vojtech Novohradsky, Moumita Maji, Tomer Babu, Lenka Markova, Hana Kostrhunova, Jana Kasparkova, Valentina Gandin, Viktor Brabec, Dan Gibson
来源：
Cellular & Molecular Immunology
摘要：
一种多靶向前药（2），在癌细胞中以活性形式释放吉西他滨、奥沙利铂和柔红霉素，是一种具有nM IC50值的有效细胞毒剂；对人类（136）和小鼠（320）癌细胞具有很高的选择性指数。在CT26细胞中，它有效地诱导DAMPs（CALR、ATP和HMGB1）的释放，促进J774巨噬细胞对其比FDA药物或其联合给药更高效的吞噬作用。与未经处理的细胞相比，与J774巨噬细胞共培养并使用2处理的CT26细胞的存活率降低了32%，表明化学反应和免疫反应之间存在协同的抗增殖作用。2在两个小鼠模型（LLC和CT26）中明显抑制了体内肿瘤生长，比FDA药物或其联合给药造成的体重下降更显著。接种了使用2处理过的CT26细胞的小鼠在重复挑战研究中显示出80%的肿瘤缩小，而柔红霉素仅诱导了73%的肿瘤缩小。© 2023 Wiley-VCH GmbH.
A multitargeting prodrug (2) that releases in cancer cells gemcitabine, oxaliplatin, and doxorubicin in their active form is a potent cytotoxic agent with nM IC50s; is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 cells facilitating more efficient phagocytosis by J774 macrophages than the FDA drugs or their co-administration. The viability of CT26 cells co-cultured with J774 macrophages and treated with 2 was reduced by 32% compared to the non-treated, suggesting a synergistic antiproliferative effect between the chemical and immune reactions. 2 inhibited in vivo tumor growth in two murine models (LLC and CT26) better than the FDA drugs or their co-administration with significantly lower body weight loss. Mice inoculated with CT26 cells treated with 2 showed 80% tumor reduction in a re-challenge study compared to 73% induced by doxorubicin.© 2023 Wiley-VCH GmbH.