Tumor-permeable nanoparticles for enhanced pancreatic cancer immunochemotherapy

用于增强胰腺癌免疫化疗的肿瘤可渗透纳米颗粒

基本信息

批准号：
10316236
负责人：
Jingjing Sun
金额：
$ 17.97万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-09 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316236
关键词：
Animal Model Antineoplastic Agents Biodistribution Biological Biological Availability Blood Circulation Blood Vessels CD8-Positive T-Lymphocytes Cancer Model Cells Clinical Combined Modality Therapy Cytidine Deaminase Data Development Diagnosis Dioxygenases Drug Combinations Drug Kinetics Engineering Enzymes Exhibits Experimental Neoplasms Extravasation Formulation Human Hydrophobicity Immune Immuno-Chemotherapy Immunosuppression Immunotherapy In Vitro Kynurenine Lead Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Micelles Modeling Morphology Mus Operative Surgical Procedures Oral Oxidation-Reduction Paclitaxel Pancreatic Ductal Adenocarcinoma Patients Penetration Permeability Pharmaceutical Preparations Pharmacotherapy Polymers Property Radiation therapy Regimen Regulatory T-Lymphocyte Safety Solubility Survival Rate Therapeutic Therapeutic Effect Tissues Transgenic Model Treatment Efficacy Tryptophan Tryptophan 2,3 Dioxygenase Unresectable Water Xenograft Model Xenograft procedure anti-tumor immune response base cancer therapy chemotherapy cytotoxicity density design effector T cell extracellular gemcitabine hydrophilicity improved in vivo in vivo evaluation inhibitor mouse model nanocarrier nanoformulation nanoparticle novel therapeutics overexpression pancreatic neoplasm patient derived xenograft model recruit side effect treatment strategy tumor tumor growth tumor-immune system interactions

项目摘要

Project Summary: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a 5-year survival rate less than 9%. New treatments for PDA that are both safe and effective are needed. Currently, chemotherapy (e.g. gemcitabine, nab-paclitaxel) is the preferred treatment, as the tumors in majority of patients (80%) are surgically non-resectable at initial diagnosis. However, even these therapeutic choices have limited efficacy because of the highly immunosuppressive tumor microenvironment and poor tumor penetration due to low density of blood vessels and dense stroma. To overcome these treatment obstacles, the applicant recently developed an immunochemotherapy regimen based on co-delivery of gemcitabine (GEM), paclitaxel (PTX) and indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor NLG919 through a PGEM nanocarrier. Preliminary data showed that the PGEM carrier penetrated to the core of experimental tumors, and, importantly, both hydrophilic GEM and multiple hydrophobic agents with distinct properties could be loaded onto PGEM micelles. Indeed, PGEM co-loaded with PTX and NLG919 induced an improved anti-tumor immune response and was highly efficacious in inhibiting tumor growth in PANC02 xenograft model, most likely through a synergistic tumor killing effect of PTX and GEM, as well as the effect of NLG919 in reversing IDO-mediated immunosuppression. In this application, the applicant proposes to further improve the PGEM carrier by optimizing the units of each constructing motif (Aim 1). In addition, the applicant will test the in vivo targeting efficiency of different PGEM nanocarriers using tumor models that closely mimic human PDA. The pharmacokinetics, biodistribution and penetration of the nanoformulations (Aim 2), as well as their therapeutic effect and the underlying mechanism (Aim 3) will be evaluated. The successful completion of the proposed aims will not only provide an effective regimen for improved PDA immunochemotherapy, but also provide a carrier platform that can be extended to targeted co-delivery of multiple distinct hydrophilic and hydrophobic agents for various combination therapies.

项目概要：胰腺导管腺癌（PDA）是一种高度致命的癌症，5年生存率低于9%。需要安全有效的 PDA 新疗法。目前，化疗（例如吉西他滨（吉西他滨、白蛋白结合型紫杉醇）是首选治疗方法，因为大多数患者 (80%) 的肿瘤是初步诊断时不可手术切除。然而，即使这些治疗选择的疗效也有限由于高度免疫抑制的肿瘤微环境和低肿瘤渗透性血管和致密基质的密度。为了克服这些治疗障碍，申请人最近开发了基于吉西他滨（GEM）、紫杉醇（PTX）联合给药的免疫化疗方案和吲哚胺 2, 3-双加氧酶 1 (IDO1) 抑制剂 NLG919（通过 PGEM 纳米载体）。初步数据表明 PGEM 载体渗透到实验肿瘤的核心，而且重要的是，亲水性 GEM 和多种具有不同特性的疏水剂可以负载到 PGEM 胶束上。事实上，PGEM 与 PTX 和 NLG919 共同负载可诱导改善的抗肿瘤免疫反应，并且在 PANC02 异种移植模型中非常有效地抑制肿瘤生长，很可能是通过协同作用 PTX和GEM的肿瘤杀伤作用，以及NLG919逆转IDO介导的肿瘤作用免疫抑制。在本申请中，申请人提出进一步改进PGEM载体：优化每个构建基序的单元（目标 1）。此外，申请人还将测试体内靶向性使用非常模仿人类 PDA 的肿瘤模型来研究不同 PGEM 纳米载体的效率。这纳米制剂的药代动力学、生物分布和渗透（目标 2）及其治疗作用将评估效果和潜在机制（目标 3）。成功完成拟议目标不仅将为改进提供有效的方案 PDA免疫化疗，还提供了一个载体平台，可以扩展到靶向联合递送用于各种联合疗法的多种不同的亲水性和疏水性药剂。