Stroma penetrating and immune modulating nanoparticles for image-guided therapy of pancreatic cancer

用于胰腺癌图像引导治疗的基质穿透和免疫调节纳米颗粒

• 批准号: 10437015
• 负责人: Hui Mao
• 金额: $ 46.28万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437015
• 关键词: Affinity; Basement membrane; Biodistribution; Biological; Biology; CD8B1 gene; Cancer Model; Catalytic Domain; Cells; Clinical; Coupled; Cytoskeleton; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Disease; Distant; Dose; Doxorubicin; Drug Delivery Systems; Drug Kinetics; Drug Monitoring; Drug Targeting; Drug resistance; Duct (organ) structure; Effector Cell; Engineering; Environment; Extracellular Matrix; Fibroblasts; Goals; Human; ITGAX gene; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; Infiltration; KRAS oncogenesis; Lead; Ligands; MMP14 gene; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Monitor; Mus; Myeloid-derived suppressor cells; Nano delivery; PDL1 inhibitors; PLAUR gene; Peptides; Pharmaceutical Preparations; Phenotype; Population; Prognosis; Property; Proteins; Recombinants; Regulatory T-Lymphocyte; Research; Research Project Grants; Resectable; Resistance; Signal Transduction; Spleen; Stromal Cells; Therapeutic Effect; Tissues; Transgenic Mice; Translational Research; Translations; Treatment Efficacy; Tumor-infiltrating immune cells; Urokinase Plasminogen Activator Receptor; advanced pancreatic cancer; cancer immunotherapy; cancer therapy; cancer type; cell killing; cell type; checkpoint therapy; chemotherapy; cytotoxic; cytotoxic CD8 T cells; design; draining lymph node; drug distribution; effector T cell; image guided; image guided therapy; image-guided drug delivery; imaging agent; immune checkpoint; immunoregulation; improved; innovation; irinotecan; iron oxide nanoparticle; macrophage; mouse model; nano; nanoparticle; nanoparticle delivery; nanoparticle drug; neoplastic cell; novel; novel therapeutics; outreach; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; patient derived xenograft model; peptidomimetics; programmed cell death ligand 1; programmed cell death protein 1; response; sialic acid binding Ig-like lectin; success; targeted cancer therapy; targeted delivery; targeted imaging; targeted treatment; theranostics; therapy resistant; treatment response; tumor; tumor growth; tumor-immune system interactions

Project Summary Resistance to therapy is the major challenge for the treatment of pancreatic cancer. Despite recent successes in immune checkpoint therapy of several human cancer types, pancreatic cancer showed a poor response to the immunotherapy. Increasing evidence reveals that a dense stromal barrier in pancreatic cancer blocks drug delivery and intratumoral distribution. The physical barrier of stromal and biological barrier from immunosuppressive responses further limit the number and function of infiltrating effector T cells. The objective of this project is to develop a new immunotherapy strategy by co-delivery of tumor penetrating and immunomodulating theranostic nanoparticles and PD-L1 inhibitors. Our innovative uPAR targeted and stroma breaking ligand consists of the amino terminal fragment (ATF) of uPA and the catalytic domain of matrix metalloproteinase-14 (ATFmmp14). It targets multiple cell types in tumors and promotes nanoparticle/drugs migrating through stromal and extracellular matrix barriers to reach tumor cells. ATFmmp14 conjugated magnetic iron oxide nanoparticle (IONP) carrying Doxorubicin or SN38 enabled magnetic resonance imaging (MRI) guided targeted delivery of nanoparticle/drug in tumors, and strong therapeutic effect in pancreatic cancer patient derived xenograft (PDX) and Kras-driven transgenic mouse tumor models. Notably, targeted delivery of the theranostic IONPs into tumors promoted infiltration of immune effector cells and decreased immunosuppressive cells, converting an immune “cold” pancreatic tumor into a “hot” tumor. We further developed an ultrasmall IONP PD-L1 inhibitor (Nano-iPD-L1) using an engineered PD-L1 blocking peptide. We showed that Nano-iPD-L1 selectively accumulated in pancreatic tumors following systemic delivery. Co-delivery of Nano-iPD-L1 with ATFmmp14-IONP/drug enhanced intratumroal delivery and significantly inhibited tumor growth in a mouse pancreatic cancer model. Therefore, we hypothesize that improved drug delivery in pancreatic tumors by co- administrations of stroma penetrating ATFmmp14-IONP/SN38 and Nano-iPD-L1 leads to a strong therapeutic efficacy through direct tumor cell killing, modulating immunosuppressive stroma, and blocking PD-L1 function to generate a strong response from cytotoxic T cells. In the proposed study, we will first investigate and optimize dose and therapeutic efficacy of co-delivery of ATFmmp14-IONP/SN38 and Nano-iPD-L1 in mouse pancreatic cancer models (Aim1). Followed by non-invasive MRI to assess theranostic IONP delivery and tumor response after the combined therapy using ATFmmp14-IONP/SN38 and Nano-iPD-L1 in transgenic mouse and pancreatic cancer PDX models (Aim 2). Finally, the effects of an enhanced intratumoral accumulation of ATFmmp14- IONP/SN38 and Nano-iPD-L1 on promoting infiltration of effector immune cells, modulating stromal immunosuppressive cells and factors, and activating cytotoxic T cells will be investigated in transgenic mouse pancreatic tumor models (Aim 3). Results of this study should provide us with new targeted theranostic IONPs and immunotherapy for translation of this novel therapy for advanced pancreatic cancer.

项目摘要 对治疗的抵抗力是治疗胰腺癌的主要挑战。尽管最近取得了成功 在几种人类癌症类型的免疫检查点疗法中，胰腺癌对此的反应较差 免疫疗法。越来越多的证据表明，胰腺癌的密集基质屏障阻止药物 递送和肿瘤内分布。基质和生物屏障的物理障碍 免疫抑制反应进一步限制了浸润效应T细胞的数量和功能。目标 这个项目的是通过肿瘤穿透和 免疫调节疗法纳米颗粒和PD-L1抑制剂。我们的创新UPAR针对性和基层 断裂配体由UPA的氨基末端片段（ATF）和矩阵的催化结构域组成 金属蛋白酶14（ATFMMP14）。它针对肿瘤中的多种细胞类型，并促进纳米颗粒/药物 通过基质和细胞外基质屏障迁移到达肿瘤细胞。 ATFMMP14共轭磁性 载有阿霉素或SN38的氧化铁纳米颗粒（IONP）引导了磁共振成像（MRI） 针对肿瘤中纳米颗粒/药物的靶向递送，以及胰腺癌患者的强理论效应 衍生的异种移植（PDX）和KRAS驱动的转基因小鼠肿瘤模型。值得注意的是，有针对性的交付 疗法离子肿瘤促进了免疫效应细胞的浸润，并改善了免疫抑制作用 细胞，将免疫“冷”胰腺肿瘤转化为“热”肿瘤。我们进一步开发了一个超质离子 PD-L1抑制剂（纳米IPD-L1）使用工程PD-L1阻断肽。我们证明了纳米IPD-L1 全身分娩后有选择地积聚在胰腺肿瘤中。纳米IPD-L1的共同传递 ATFMMP14-IONP/药物增强了肿瘤内递送，并显着抑制了小鼠的肿瘤生长 胰腺癌模型。因此，我们假设通过共同提高了胰腺肿瘤中药物的递送 基质的施用ATFMMP14-IONP/SN38和Nano-IPD-L1导致了强大的理论 通过直接肿瘤细胞杀死，调节免疫抑制基质的功效，并阻止PD-L1功能 从细胞毒性T细胞产生强烈的反应。在拟议的研究中，我们将首先调查并优化 小鼠胰腺中ATFMMP14-IOMP/SN38和纳米IPD-L1共递送的剂量和治疗效率 癌症模型（AIM1）。然后进行非侵入性MRI评估疗法IONP递送和肿瘤反应 使用ATFMMP14-IOMP/SN38和纳米IPD-L1进行联合治疗后，在转基因小鼠和胰腺中 癌症PDX模型（AIM 2）。最后，ATFMMP14-的肿瘤内积累增强的影响 IONP/SN38和纳米IPD-L1用于促进效应子免疫球的浸润，调节基质 免疫抑制细胞和因子以及激活的细胞毒性T细胞将在转基因小鼠中研究 胰腺肿瘤模型（AIM 3）。这项研究的结果应为我们提供新的靶向疗法IONP 和用于转化这种新型胰腺癌疗法的免疫疗法。