Chemotherapy delivery with nanoparticles for targeted induction of immunogenic cell death

使用纳米粒子进行化疗，靶向诱导免疫原性细胞死亡

基本信息

批准号：
10468237
负责人：
Yoon Yeo
金额：
$ 39.98万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468237
关键词：
Affect Animal Model Animals Benchmarking Biodistribution Blood Circulation Cancer Patient Cancer Remission Cell Death Induction Cells Complement Cytotoxic T-Lymphocytes Development Disease remission Dose Dose-Limiting Drug Carriers Drug Delivery Systems Drug Kinetics Endothelium Evaluation Formulation Goals Grant Immune Immune system Immunity Immunocompromised Host Immunologic Memory Immunotherapy Ionizing radiation Label Ligands Literature Methods Mission Molecular Oncolytic viruses Paclitaxel Patients Pattern Performance Pharmaceutical Preparations Public Health Radiation Radiobiology Regimen Research Research Personnel Resources Role Safety Signal Transduction Small Interfering RNA Surface System T-Lymphocyte Therapeutic Toxic effect Toxicity due to chemotherapy Tumor Antibodies Tumor Antigens Tumor Immunity Tumor Suppression United States National Institutes of Health Variant anti-PD-1/PD-L1 anti-PD-L1 antibodies anti-cancer anti-tumor immune response base cancer cell cancer immunotherapy cancer therapy chemotherapy clinical translation drug testing human disease immune checkpoint blockade immunogenic cell death immunogenicity improved in vivo innovation nanomedicine nanoparticle nanoparticle delivery nanoparticle drug neoantigens neoplastic cell novel therapeutics pharmacokinetics and pharmacodynamics polyphenol prevent programmed cell death ligand 1 response side effect systemic toxicity tumor tumor growth tumor immunology tumor microenvironment uptake

项目摘要

ABSTRACT Immune checkpoint blockade (ICB) aims to reactivate cytotoxic T-cell activities against tumors. Current ICB therapy has had a dramatic therapeutic impact, but only about 20% of patients have long-term tumor-free survival. A potential reason for the limited response rate is the lack of dominant neoantigens for T-cell recogni- tion. Several chemotherapeutic drugs have been identified as effective inducers of immunogenic cell death (ICD) and actively investigated in combination with ICB agents as off-label indications. However, a main chal- lenge in using chemotherapy as an ICD inducer is the dose-limiting side effects, including the toxicity to im- mune cells that will directly compromise cancer immunotherapy. In order to enhance ICB with ICD-inducing chemotherapy, a delivery system that specifically and efficiently affect tumor cells is necessary. With the ongo- ing R01 support (R01EB017791) we have developed nanoparticle (NP) systems with good circulation stability and high drug loading capacity that deliver more chemotherapeutic drugs to tumors and achieve greater anti- tumor efficacy relative to commercial benchmark products. We have also demonstrated that localized ionizing radiation (IR) further increased NP delivery to tumors. In this renewal application, we propose to use the NPs and IR to enhance their potential to induce ICD in tumors thereby sensitizing the tumors to ICB ther- apy. Our central hypothesis is that NPs will concentrate the drug in tumors without increasing systemic toxicity to induce ICD and help retain the released damage-associated molecular patterns and tumor antigens to gen- erate durable anti-tumor immune responses. We will combine NPs with high drug loading capacity and good circulation stability as well as surface modifiers that have contributed to in vivo performance of NPs in order to obtain optimal NPs for tumor delivery and intracellular uptake and retention. The activity of ICD-inducing NPs will be evaluated via the ability to promote anti-tumor immune responses (Aim 1); and their anti-cancer effect will be evaluated in combination with local ionizing radiation (Aim 2). To investigate the contribution of ICD-in- ducing NPs to ICB therapy, they will be combined with siRNA targeting PD-L1 or anti-PD-1/PD-L1 antibodies and evaluated in animal models of tumors with known (in)sensitivity to immunotherapy (Aim 3). The innovative aspect of this strategy is that it explores the untapped utility of NPs as a way of increasing the potential of chemotherapy to induce ICD and the role of carriers in cancer immunotherapy. With successful completion of this project, we expect to have developed a new therapeutic regimen with durable anti-cancer effects and high complete remission rates.

抽象的免疫检查点阻滞（ICB）旨在重新激活针对肿瘤的细胞毒性T细胞活性。当前的 ICB治疗具有巨大的治疗作用，但只有大约20％的患者长期无肿瘤生存。反应率有限的潜在原因是缺乏T细胞识别的主要新抗原。 tion。几种化学治疗药物已被确定为免疫原性死亡的有效诱导剂（ICD）并积极研究与ICB代理作为标签外指示。但是，一个主要的chal- 使用化学疗法作为ICD诱导剂的LENGE是剂量限制的副作用，包括对IM的毒性穆恩细胞将直接损害癌症免疫疗法。为了通过ICD诱导增强ICB 化学疗法是一种特殊有效地影响肿瘤细胞的输送系统。与ongo- ING R01支持（R01EB017791）我们开发了纳米颗粒（NP）系统，具有良好的循环稳定性和高药物负荷能力，可为肿瘤提供更多的化学治疗药物，并获得更大的抗相对于商业基准产品的肿瘤功效。我们还证明了局部电离辐射（IR）进一步增加了NP向肿瘤的递送。在此续订应用程序中，我们建议使用NP 和IR增强其在肿瘤中诱导ICD的潜力，从而使肿瘤对ICB治疗敏感 APY。我们的中心假设是，NP将在肿瘤中集中药物而不会增加全身毒性诱导ICD并有助于保留释放的损伤相关的分子模式和肿瘤抗原耐用的抗肿瘤免疫反应。我们将将NP与较高的药物负载能力和良好结合在一起循环稳定性以及有助于NP的体内性能的表面修饰符获得最佳的NP，用于肿瘤递送以及细胞内摄取和保留率。 ICD诱导NP的活性将通过促进抗肿瘤免疫反应的能力进行评估（AIM 1）；和他们的反癌效应将与局部电离辐射结合评估（AIM 2）。调查ICD-IN-的贡献将NP插入ICB治疗，它们将与靶向PD-L1或抗PD-1/PD-L1抗体的siRNA结合并在对免疫疗法敏感的肿瘤动物模型中进行了评估（AIM 3）。创新该策略的各个方面是，它探讨了NP的未开发的效用，以提高化学疗法诱导ICD和携带者在癌症免疫疗法中的作用。成功完成这个项目，我们希望已经开发出一种具有持久抗癌作用的新治疗方案，并且很高完全缓解率。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Meta-Analysis of Drug Delivery Approaches for Treating Intracellular Infections.

DOI：
10.1007/s11095-022-03188-z
发表时间：
2022-06
期刊：
Pharmaceutical research
影响因子：
3.7
作者：
Shin S;Kwon S;Yeo Y
通讯作者：
Yeo Y

Sustained delivery of carfilzomib by tannic acid-based nanocapsules helps develop antitumor immunity.

DOI：
10.1021/acs.nanolett.9b04147
发表时间：
2019-10
期刊：
Nano letters
影响因子：
10.8
作者：
Maie S. Taha;Gregory M. Cresswell;Joonyoung Park;Wooin Lee;T. Ratliff;Y. Yeo
通讯作者：
Maie S. Taha;Gregory M. Cresswell;Joonyoung Park;Wooin Lee;T. Ratliff;Y. Yeo

Radiation-enhanced delivery of plasmid DNA to tumors utilizing a novel PEI polyplex.