A Phospholipid-Derived Nanotherapeutic Platform for Improved Colorectal Cancer Immunochemotherapy

用于改进结直肠癌免疫化疗的磷脂衍生纳米治疗平台

• 批准号: 10658146
• 负责人: Jianqin Lu
• 金额: $ 34.51万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658146
• 关键词: Antineoplastic Agents; Blood Circulation; Blood Circulation Time; Camptothecin; Cancer Etiology; Cancer Model; Cancer Patient; Cells; Cessation of life; Charge; Clinic; Clinical; Clinical Trials; Colorectal Cancer; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Development; Disulfides; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Kinetics; Drug Modelings; Encapsulated; Goals; Hydrophobicity; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immuno-Chemotherapy; Immunocompetent; Immunosuppression; In Vitro; Interferon Type II; Kinetics; Lactones; Length; Lipid Bilayers; Liposomes; Maximum Tolerated Dose; Measures; Mediating; Memory; Microsatellite Instability; Mismatch Repair Deficiency; Monoclonal Antibodies; Mus; PD-1 blockade; PD-1 inhibitors; PD-1/PD-L1; Pathway interactions; Patients; Pharmaceutical Preparations; Phospholipids; Regimen; Regulatory T-Lymphocyte; Safety; Secure; Series; Solubility; Structure-Activity Relationship; System; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Translating; Transportation; Treatment Efficacy; Tryptophan; Tryptophan 2,3 Dioxygenase; Tumor Immunity; Up-Regulation; Vertebral column; amphiphilicity; anti-cancer; antitumor effect; cancer cell; cancer therapy; cancer type; chemotherapy; clinical application; colon cancer patients; effector T cell; fortification; hydroxyl group; immune checkpoint; immune checkpoint blockade; immunogenic; immunogenic cell death; improved; in vivo; inhibitor; innovation; liposomal delivery; nanotechnology platform; nanotherapeutic; novel; pi bond; response; screening; self assembly; side effect; standard of care; success; systemic toxicity; tumor; tumor eradication; uptake

Project Summary/Abstract While immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer treatment paradigm, the response rate is limited to a small subset of cancer patients (~20%). For colorectal cancer (CRC), the second leading cause of cancer-related deaths in US, only patients (~4%) with mismatch-repair-deficient or microsatellite instability-high tumors can respond to ICIs, leaving the vast majority of CRC patients with limited to no clinical benefit. Chemotherapy has been increasingly manifested to contribute significantly to the overall antitumor efficacy when combined with ICIs via switching the tumors from “immune-cold” to ‘immune-hot’. However, owing to the poor solubility and pharmacokinetics, limited tumor accumulation, and non-specific toxicities to healthy tissues, the utility of chemotherapeutics in enhancing the efficacy of ICIs has been considerably hindered. To render a safer and more efficacious chemotherapy-enabled immune response to cooperate with ICIs, our long- term goal is to develop an innovative and multifunctional liposomal nanotherapeutic platform via conjugating anticancer agents to the backbone phospholipid of liposome. We have developed a phospholipid-derived camptothecin (CPT) liposome (Camptothesome) nanoplatform, which significantly prolonged blood circulation time, enhanced tumor uptake and therapeutic efficacy and minimized systemic toxicities compared to free CPT. Moreover, Camptothesome potentiated the anti-CRC efficacy of PD-L1/PD-1 inhibitors, resulting in partial eradication of tumors in immunocompetent mice. To improve the efficacy of this combined therapy, we used Camptothesome to co-deliver an inhibitor targeting another independent immune checkpoint, Indoleamine 2,3- dioxygenase (IDO1), which markedly enhanced anti-CRC efficacy and immunity. To further strengthen the delivery efficiency and explore the potential of this nanoplatform in enhancing PD-L1/PD-1 blockade therapy, in this proposal we will: Aim 1: Improve the Camptothesome system for enhanced therapeutic delivery. Aim 2: Determine the tumor delivery efficiency and pharmacokinetics of the improved co-delivery system in murine CRC models. Aim 3: Define antitumor effects of the improved co-delivery system with or without PD-L1/PD-1 blockade in murine CRC models. The mechanistic action for the in vivo antitumor efficacy and immune responses of the combined therapy will also be elucidated. Successful completion of this proposal will result in an innovative and multifunctional nanotherapeutic platform for improved and safe CRC immunochemotherapy. Moreover, given that IDO1 is expressed in diverse cancer cells, and the broad applicability of this nanoplatform to other anticancer drugs, our combination nanotherapeutic system has the potential to revolutionize cancer treatment paradigms.

项目总结/摘要 虽然免疫检查点抑制剂（ICI）已经改变了癌症治疗范式的面貌， 缓解率仅限于一小部分癌症患者（约20%）。对于结肠直肠癌（CRC）， 美国癌症相关死亡的主要原因，仅错配修复缺陷或微卫星 不稳定性高的肿瘤可以对ICI作出反应，使绝大多数CRC患者的临床表现有限或没有。 效益化疗已经越来越多地被证明对整体抗肿瘤治疗有显著贡献。 通过将肿瘤从“免疫冷”转换为“免疫热”，与ICI组合时的疗效。但由于 溶解性和药代动力学差，肿瘤蓄积有限，对健康人的非特异性毒性 在组织中，化学治疗剂在增强ICI功效方面的效用已经受到相当大的阻碍。到 提供一个更安全，更有效的化疗使免疫反应，以配合ICI，我们的长期- 长期目标是通过缀合， 脂质体的骨架磷脂。我们开发了一种磷脂衍生的 喜树碱（CPT）脂质体（Camptothesome）纳米平台，显著延长血液循环 与游离CPT相比，其具有更短的时间、增强的肿瘤摄取和治疗功效以及最小化的全身毒性。 此外，Camptothesome增强了PD-L1/PD-1抑制剂的抗CRC功效，导致部分CRC 在免疫活性小鼠中根除肿瘤。为了提高这种联合治疗的疗效，我们使用了 Camptothesome共同递送靶向另一个独立免疫检查点的抑制剂，吲哚胺2，3- 双加氧酶（IDO 1），其显著增强抗CRC功效和免疫力。进一步加强 递送效率，并探索这种纳米平台在增强PD-L1/PD-1阻断治疗， 我们将在本建议中： 目的1：改进Camptothesome系统以增强治疗递送。 目的2：测定改良的共给药系统的肿瘤给药效率和药代动力学 在鼠CRC模型中。 目的3：确定有或没有PD-L1/PD-1阻断的改进的共递送系统的抗肿瘤作用 在鼠CRC模型中。本文还探讨了抗肿瘤药物的体内抗肿瘤疗效和免疫应答的机制。 还将阐明联合治疗。成功完成这一提案将导致一个创新的和 用于改善和安全的CRC免疫化疗的多功能纳米平台。而且，鉴于 IDO1在不同的癌细胞中表达，并且这种纳米平台对其他抗癌药物的广泛适用性， 药物，我们的组合纳米系统有可能彻底改变癌症治疗模式。