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

• 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
• 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

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.

项目摘要： 胰腺导管腺癌（PDA）是一种高致死性癌症，5年生存率低于9%。 需要安全有效的PDA新治疗方法。目前，化疗（例如， 吉西他滨、白蛋白结合型紫杉醇）是优选的治疗，因为大多数患者（80%）的肿瘤是 初次诊断时手术不可切除。然而，即使这些治疗选择也具有有限的功效 由于高度免疫抑制的肿瘤微环境和由于低免疫抑制性而导致的肿瘤渗透性差， 血管密度和致密间质。为了克服这些治疗障碍，申请人最近 开发了一种基于吉西他滨（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NLG 919。初步数据 结果表明，PGEM载体渗透到实验肿瘤的核心，重要的是， 亲水性GEM和具有不同性质的多种疏水性试剂可以负载到PGEM胶束上。 事实上，与PTX和NLG 919共负载的PGEM诱导了改善的抗肿瘤免疫应答，并且在小鼠中表达。 在PANC 02异种移植模型中高度有效地抑制肿瘤生长，最可能是通过协同 PTX和GEM的肿瘤杀伤作用，以及NLG 919在逆转IDO介导的肿瘤细胞凋亡中的作用， 免疫抑制在本申请中，申请人提出通过以下方式进一步改进PGEM载体： 优化每个构建基序的单元（目标1）。此外，申请人将测试体内靶向 使用紧密模拟人PDA的肿瘤模型，比较不同PGEM纳米载体的效率。的 纳米制剂的药代动力学、生物分布和渗透性（目的2），以及它们的治疗性 将评估效果和潜在机制（目标3）。 成功地实现拟议的目标不仅将为改善人权提供一个有效的制度， PDA免疫化疗，而且还提供了一个载体平台，可以扩展到靶向共递送 多种不同的亲水性和疏水性试剂，用于各种联合治疗。