Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ 85721, United States.
NCI-designated University of Arizona Comprehensive Cancer Center, Tucson, AZ 85721, United States; Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Arizona, Tucson, AZ 85721, United States.
J Control Release. 2022 Sep;349:929-939. doi: 10.1016/j.jconrel.2022.07.042. Epub 2022 Aug 9.
Camptothesome is an innovative nanovesicle therapeutic comprising the sphingomyelin-derived camptothecin (CPT) lipid bilayer. In this work, we deciphered that Camptothesome was taken up by colorectal cancer (CRC) cells through primarily the clathrin-mediated endocytotic pathway and displayed the potential of eliciting robust immunogenic cancer cell death (ICD) via upregulating calreticulin, high mobility group box 1 protein (HMGB-1), and adenosine triphosphate (ATP), three hallmarks involved in the induction of ICD. In addition, use of dying MC38 tumor cells treated with Camptothesome as vaccine prevented tumor growth in 60% mice that received subsequent injection of live MC38 cells on the contralateral flank, validating Camptothesome was a legitimate ICD inducer in vivo. Camptothesome markedly reduced the acute bone marrow toxicity and gastrointestinal mucositis associated with free CPT and beat free CPT and Onivyde on anti-CRC efficacy and immune responses in a partially interferon gamma (IFN-γ)-dependent manner. Furthermore, Camptothesome enhanced the efficacy of immune checkpoint inhibitors to shrink late-stage orthotopic MC38 CRC tumors with diminished tumor metastasis and markedly prolonged mice survival.
喜树碱纳米囊泡是一种创新性的纳米载体治疗药物，由神经鞘磷脂衍生的喜树碱（CPT）脂质双分子层组成。在这项工作中，我们揭示了喜树碱纳米囊泡主要通过网格蛋白介导的内吞作用被结直肠癌细胞摄取，并通过上调钙网织蛋白、高迁移率族蛋白 1 蛋白（HMGB-1）和三磷酸腺苷（ATP），显示出诱发强烈免疫原性癌细胞死亡（ICD）的潜力，这三种标志物参与 ICD 的诱导。此外，用喜树碱纳米囊泡处理后的死亡 MC38 肿瘤细胞作为疫苗使用，可防止接受对侧注射活 MC38 细胞的 60%小鼠的肿瘤生长，验证了喜树碱纳米囊泡是体内真正的 ICD 诱导剂。喜树碱纳米囊泡显著降低了游离 CPT 相关的急性骨髓毒性和胃肠道黏膜炎，并在部分依赖干扰素γ（IFN-γ）的方式下，优于游离 CPT 和 Onivyde，提高了抗结直肠癌的疗效和免疫反应。此外，喜树碱纳米囊泡增强了免疫检查点抑制剂的疗效，缩小了晚期原位 MC38 结直肠肿瘤的体积，减少了肿瘤转移，并显著延长了小鼠的生存时间。
