Camptothesome is a sphingomyelin-conjugated camptothecin (SM-CSS-CPT) nanovesicle that fortified the therapeutic delivery of CPT in diverse cancer types. To mitigate the Camptothesome-induced IDO1 negative feedback mechanism, we had co-encapsulated, indoximod (IND, IDO1 inhibitor) into Camptothesome using doxorubicin-derived IND (DOX-IND). To maximize the therapeutic potential of DOX-IND/Camptothesome, herein, we first dissected the synergistic drug ratio (DOX-IND/SM-CSS-CPT) via systematical in vitro screening. DOX-IND/Camptothesome with optimal drug ratio synchronized in vivo drug delivery with significantly higher tumor uptake compared to free drugs. This optimum DOX-IND/Camptothesome outperformed the combination of Camptothesome, Doxil and IND or other IDO1 inhibitors (BMS-986205 or epacadostat) in treating mice bearing late-stage MC38 tumors, and combination with immune checkpoint blockade (ICB) enabled it to eradicate 60 % of large tumors. Further, this optimized co-delivery Camptothesome beat Folfox and Folfiri, two first-line combination chemotherapies for colorectal cancer in antitumor efficacy and exhibited no side effects as compared to the severe systemic toxicities associated with Folfox and Folfiri. Finally, we demonstrated that the synergistic DOX-IND/Camptothesome was superior to the combined use of Onivyde + Doxil + IND in curbing the advanced orthotopic CT26-Luc tumors and eliminated 40 % tumors with complete metastasis remission when cooperated with ICB, eliciting stronger anti-CRC immune responses and greater reversal of immunosuppression. These results corroborated that with precise optimal synergistic drug ratio, the therapeutic potential of DOX-IND/Camptothesome can be fully unleased, which warrants further clinical investigation to benefit the cancer patients.

Camptothesome 是一种鞘磷脂结合的喜树碱 (SM-CSS-CPT) 纳米囊泡，可增强 CPT 在多种癌症类型中的治疗传递。为了减轻 Camptothesome 诱导的 IDO1 负反馈机制，我们使用阿霉素衍生的 IND (DOX-IND) 将吲哚莫德（IND，IDO1 抑制剂）共同封装到 Camptothesome 中。为了最大限度地发挥 DOX-IND/Camptothesome 的治疗潜力，我们首先通过系统的体外筛选来剖析协同药物比例 (DOX-IND/SM-CSS-CPT)。 DOX-IND/Camptothesome 具有最佳药物比例，同步体内药物递送，与游离药物相比，肿瘤摄取显着更高。在治疗患有晚期 MC38 肿瘤的小鼠中，这种最佳的 DOX-IND/Camptothesome 优于 Camptothesome、Doxil 和 IND 或其他 IDO1 抑制剂（BMS-986205 或 epacadostat）的组合，并且与免疫检查点阻断（ICB）的组合使其能够根除60%的大肿瘤。此外，这种优化的联合给药 Camptothesome 在抗肿瘤功效方面击败了 Folfox 和 Folfiri 这两种结直肠癌一线联合化疗药物，并且与 Folfox 和 Folfiri 相关的严重全身毒性相比，没有表现出任何副作用。最后，我们证明了协同DOX-IND/Camptothesome在抑制晚期原位CT26-Luc肿瘤方面优于联合使用Onivyde + Doxil + IND，与ICB配合时消除了40%的肿瘤并完全转移缓解，引发更强的抗肿瘤作用。 -CRC免疫反应和免疫抑制的更大逆转。这些结果证实，通过精确的最佳协同药物配比，DOX-IND/Camptothesome的治疗潜力可以得到充分释放，值得进一步的临床研究，造福癌症患者。