伊立替康（IRT）是治疗结直肠癌的经典临床化疗药物，已被发现可诱导免疫原性细胞死亡（ICD），同时对肿瘤细胞发挥细胞毒性。与免疫调节剂联合使用时，这种效应可能会被放大。不幸的是，没有靶向能力的免费药物会产生不良的结果和强烈的副作用。为了解决这些问题，在这项工作中，构建了一种基于两亲性聚（β-氨基酯）衍生物的酸敏感胶束，以共同传递IRT和免疫佐剂咪喹莫特（IMQ）（称为PII）。 PII在正常生理条件下保持稳定。被肿瘤细胞内化后，PII 在酸性溶酶体中解离并迅速释放 IRT 和 IMQ。在CT26肿瘤小鼠模型中，与游离药物溶液相比，PII使瘤内SN38（IRT的活性代谢物）和IMQ浓度增加高达9.39和3.44倍。 PII的抑瘤率达到87.29%。这可能受益于 IRT 诱导的 ICD，促进树突状细胞 (DC) 成熟和 CD8 T 细胞的瘤内浸润。此外，IMQ增强DC的抗原呈递能力并刺激肿瘤相关巨噬细胞分泌肿瘤杀伤细胞因子。 PII 提供了一种通过化疗和免疫调节协同作用来对抗结直肠癌的有效策略。版权所有 © 2023。由 Elsevier B.V. 出版。

Irinotecan (IRT), a classic clinical chemotherapeutic agent for treating colorectal cancer, has been found to induce immunogenic cell death (ICD) while exerting cytotoxicity in tumor cells. This effect is likely to be amplified in combination with immune modulators. Unfortunately, free drugs without targeting capacity would receive poor outcomes and strong side effects. To address these issues, in this work, an acid-sensitive micelle based on an amphiphilic poly(β-amino ester) derivative was constructed to co-deliver IRT and the immune adjuvant imiquimod (IMQ), termed PII. PII kept stable under normal physiological conditions. After internalization by tumor cells, PII dissociated in acidic lysosomes and released IRT and IMQ rapidly. In the CT26 tumor mouse model, PII increased the intra-tumoral SN38 (the active metabolite of IRT) and IMQ concentrations by up to 9.39 and 3.44 times compared with the free drug solution. The tumor inhibition rate of PII achieved 87.29%. This might profit from that IRT induced ICD, which promoted dendritic cells (DCs) maturation and intra-tumoral infiltration of CD8+ T cells. In addition, IMQ enhanced the antigen presenting ability of DCs and stimulated tumor associated macrophages to secrete tumor-killing cytokines. PII provided an effective strategy to combat colorectal cancer by synergy of chemotherapy and immunoregulation.Copyright © 2023. Published by Elsevier B.V.