Department of Nuclear Medicine, Peking University People's Hospital, Beijing 100044, China.
Faculty of Chemistry and Biochemistry, Ruhr-University Bochum, Universitätsstrasse 150, 44780 Bochum, Germany.
J Control Release. 2024 Sep;373:493-506. doi: 10.1016/j.jconrel.2024.07.042. Epub 2024 Jul 25.
Despite impressive advances in immune checkpoint blockade therapy, its efficacy as a standalone treatment remains limited. The influence of chemotherapeutic agents on tumor immunotherapy has progressively come to light in recent years, positioning them as promising contenders in the realm of combination therapy options for tumor immunotherapy. Herein, we present the rational design, synthesis, and biological evaluation of the first example of a Co(III) prodrug (Co2) capable of eliciting a localized cytotoxic effect while simultaneously inducing a systemic immune response via type II immunogenic cell death (ICD). To enhance its pharmacological properties, a glutathione-sensitive polymer was synthesized, and Co2 was encapsulated into polymeric nanoparticles (NP-Co2) to improve efficacy. Furthermore, NP-Co2 activates the GRP78/p-PERK/p-eIF2α/CHOP pathway, thereby inducing ICD in cancer cells. This facilitates the transformation of "cold tumors" into "hot tumors" and augments the effectiveness of the PD-1 monoclonal antibody (αPD-1). In essence, this nanomedicine, utilizing Co(III) prodrugs to induce ICD, provides a promising strategy to enhance chemotherapy and αPD-1 antibody-mediated cancer immunotherapy.
尽管免疫检查点阻断疗法取得了令人瞩目的进展，但作为单一治疗方法的疗效仍然有限。近年来，化疗药物对肿瘤免疫治疗的影响逐渐显现，使它们成为肿瘤免疫治疗联合治疗方案中颇具前景的候选药物。在此，我们提出了首例 Co(III)前药（Co2）的合理设计、合成和生物学评价，该前药能够通过 II 型免疫原性细胞死亡（ICD）引发局部细胞毒性效应，同时诱导全身性免疫反应。为了增强其药理学特性，合成了一种谷胱甘肽敏感的聚合物，并将 Co2 封装到聚合物纳米粒子（NP-Co2）中以提高疗效。此外，NP-Co2 激活 GRP78/p-PERK/p-eIF2α/CHOP 通路，从而诱导癌细胞发生 ICD。这有助于将“冷肿瘤”转化为“热肿瘤”，并增强 PD-1 单克隆抗体（αPD-1）的疗效。实际上，这种利用 Co(III)前药诱导 ICD 的纳米药物为增强化疗和αPD-1 抗体介导的癌症免疫治疗提供了一种有前途的策略。
