Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China.
Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China.
J Control Release. 2022 Jan;341:498-510. doi: 10.1016/j.jconrel.2021.12.002. Epub 2021 Dec 7.
Triple negative breast cancer (TNBC) with easy metastasis, "cold" tumor immune microenvironment, and lack of targeted therapy remains poorly prognosed. Chemo-immunotherapy deemed as a potential treatment for TNBC is however confronted by low TNBC selectivity, pronounced systemic toxicity, and limited immunogenic cell death (ICD) induction. Here, employing clinically validated ATN peptide as a ligand and reduction-sensitive biodegradable micelles as a vehicle we constructed αβ integrin-targeted micellar paclitaxel (ATN-MPTX) to elicit strong and selective ICD and chemo-immunotherapy of TNBC. ATN-MPTX exhibited evident targetability and prominent uptake in αβ integrin-positive 4 T1 cells and induced significantly stronger ICD than free PTX and non-targeted MPTX. The therapeutic studies in 4 T1 TNBC model demonstrated that ATN-MPTX caused superior tumor accumulation and treatment efficacy to all controls. Of note, ATN-MPTX plus nano-STING agonist further augmented the immunotherapeutic effects by increasing secretion of proinflammatory cytokines and CD4 and CD8 T cells in the tumor and spleen while reducing T, leading to significantly improved inhibition of 4 T1 primary tumor and more interestingly mitigated lung metastases. This strong and selective ICD induction of ATN-MPTX renders it an interesting tool to enhance chemo-immunotherapy of TNBC.
三阴性乳腺癌（TNBC）易转移，“冷”肿瘤免疫微环境，缺乏靶向治疗，预后较差。化疗免疫治疗被认为是一种潜在的 TNBC 治疗方法，但存在 TNBC 选择性低、全身毒性明显和免疫原性细胞死亡（ICD）诱导有限等问题。在这里，我们使用临床验证的 ATN 肽作为配体和还原敏感的可生物降解胶束作为载体，构建了 αβ 整合素靶向胶束紫杉醇（ATN-MPTX），以引发强烈和选择性的 ICD 以及 TNBC 的化疗免疫治疗。ATN-MPTX 在 αβ 整合素阳性 4T1 细胞中表现出明显的靶向性和摄取作用，并诱导明显强于游离 PTX 和非靶向 MPTX 的 ICD。在 4T1 TNBC 模型中的治疗研究表明，ATN-MPTX 引起的肿瘤蓄积和治疗效果均优于所有对照组。值得注意的是，ATN-MPTX 加纳米 STING 激动剂通过增加肿瘤和脾脏中促炎细胞因子和 CD4 和 CD8 T 细胞的分泌，同时减少 T 细胞，进一步增强了免疫治疗效果，从而显著抑制了 4T1 原发性肿瘤，更有趣的是减轻了肺转移。ATN-MPTX 的这种强烈和选择性 ICD 诱导使其成为增强 TNBC 化疗免疫治疗的一种有趣工具。
