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

基本信息

批准号：
10249736
负责人：
Hui Mao
金额：
$ 48.61万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10249736
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 Myelogenous 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

项目摘要

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.

项目概要尽管最近取得了成功，但治疗耐药性仍然是胰腺癌治疗的主要挑战。在几种人类癌症类型的免疫检查点治疗中，胰腺癌对免疫检查点治疗的反应较差越来越多的证据表明，胰腺癌中的致密基质屏障会阻碍药物治疗基质的物理屏障和生物屏障。免疫抑制反应进一步限制浸润效应 T 细胞的数量和功能。该项目的目的是开发一种新的免疫治疗策略，通过肿瘤穿透和我们的创新性 uPAR 靶向和基质免疫调节治疗纳米颗粒和 PD-L1 抑制剂。断裂配体由uPA的氨基末端片段(ATF)和基质的催化结构域组成金属蛋白酶-14 (ATFmmp14) 靶向肿瘤中的多种细胞类型并促进纳米颗粒/药物的作用。迁移穿过基质和细胞外基质屏障到达 ATFmmp14 结合的磁性肿瘤细胞。携带阿霉素或 SN38 的氧化铁纳米颗粒 (IONP) 启用磁共振成像 (MRI) 引导纳米粒子/药物在肿瘤中的靶向递送，对胰腺癌患者具有强大的治疗效果值得注意的是，异种移植（PDX）和 Kras 驱动的转基因小鼠肿瘤模型的靶向递送。治疗诊断 IONP 促进免疫效应细胞的肿瘤浸润并减少免疫抑制细胞，将免疫“冷”胰腺肿瘤转化为“热”肿瘤。我们进一步开发了超小型 IONP。 PD-L1 抑制剂 (Nano-iPD-L1) 使用工程化的 PD-L1 阻断肽我们展示了 Nano-iPD-L1。 Nano-iPD-L1 与全身递送后选择性地积聚在胰腺肿瘤中。 ATFmmp14-IONP/药物增强小鼠瘤内递送并显着抑制肿瘤生长因此，我们通过共同努力改善胰腺肿瘤的药物输送。基质穿透 ATFmmp14-IONP/SN38 和 Nano-iPD-L1 的施用可产生强大的治疗效果通过直接杀伤肿瘤细胞、调节免疫抑制基质和阻断 PD-L1 功能来发挥功效在拟议的研究中，我们将首先研究和优化细胞毒性 T 细胞产生强烈反应。 ATFmmp14-IONP/SN38 和 Nano-iPD-L1 联合递送小鼠胰腺的剂量和疗效癌症模型（目标1），然后进行非侵入性 MRI 评估治疗诊断 IONP 输送和肿瘤反应。在转基因小鼠和胰腺中使用 ATFmmp14-IONP/SN38 和 Nano-iPD-L1 联合治疗后癌症 PDX 模型（目标 2）。最后，ATFmmp14- 瘤内积累增强的影响。 IONP/SN38 和 Nano-iPD-L1 促进效应免疫细胞浸润，调节基质将在转基因小鼠中研究免疫抑制细胞和因子以及激活细胞毒性 T 细胞胰腺肿瘤模型（目标 3）。这项研究的结果应该为我们提供新的靶向治疗 IONP。以及免疫疗法，以转化这种针对晚期胰腺癌的新疗法。