Biopolymer-based strategies for local delivery of cytokine therapeutics

基于生物聚合物的细胞因子治疗局部递送策略

基本信息

批准号：
8697520
负责人：
David Zaharoff
金额：
$ 30.14万
依托单位：
UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
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：
2014-06-03 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697520
关键词：
Adverse effects Amino Acids Biochemical Biocompatible Biopolymers Blood Chemical Analysis Cell membrane Charge Chitosan Clinical Clinical Research Complete Blood Count Cytotoxic T-Lymphocytes Delayed Hypersensitivity Development Disease Dose Dose-Limiting Drug Kinetics Evaluation Extracellular Matrix Proteins Flow Cytometry Generations Goals Human Immune System Diseases Immune response Immunity Immunohistochemistry Immunotherapeutic agent Immunotherapy In Vitro Inflammation Inflammatory Injection of therapeutic agent Interleukin-12 Link Lysine Malignant Neoplasms Mediating Modeling Molecular Weight Monitor Mutation Organ Polysaccharides Pre-Clinical Model Production Property Recombinant Cytokines Relative (related person)Safety Scientist Serum Signal Transduction Site Solvents System T-Lymphocyte Technology Testing Therapeutic Time Tissues Toxic effect Toxicology Tumor-Infiltrating Lymphocytes Validation base cancer immunotherapy clinical application cytokine design fluorescence imaging immune function in vivo mutant novel novel strategies paracrine pre-clinical preclinical study prevent public health relevance response spatiotemporal tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Cytokine-based immunotherapies have the potential to treat a wide range of diseases including cancer. Unfortunately, pro-inflammatory cytokines with potent antitumor activity are frequently toxic upon systemic exposure. The lack of effective local delivery strategies capable of controlling the distribution cytokines has prevented cytokine therapeutics from impacting cancer immunotherapy. This project proposes a novel delivery technology in which a potent recombinant cytokine, interleukin-12 (IL-12), is chemically-linked to a biodegradable polysaccharide called chitosan prior to intratumoral (i.t.) injection. This novel strategy is expected to provide sustained, high concentrations of IL-12 in the tumor microenvironment, while minimizing potentially harmful systemic dissemination. The proposed project is comprised of three aims focusing on the development and evaluation of IL-12-chitosan bioconjugates in preclinical tumor models. In the first aim, novel IL-12-chitosan bioconjugates will be synthesized and evaluated in vitro for bioactivity. The mutation of solvent accessible amino acids will allow for site-specific conjugation of IL-12 to chitosan. Aim 2 will assess safety by documenting the spatiotemporal distribution of IL-12-chitosan bioconjugates and any potential toxicities associated with IL-12-chitosan administration. Aim 3 will evaluate antitumor efficacy of IL-12-chitosan bioconjugates as well as the elaboration of tumor-specific immunity in relevant preclinical models. The overall goal of this project is to determine if conjugation to chitosan can maintain the potent antitumor activity of IL-12 while alleviating toxicity concerns. I the long-term, validation of this cytokine-chitosan delivery platform may pave the way for additional cytokine therapeutics in cancer immunotherapy.

描述（由申请人提供）：基于细胞因子的免疫疗法有可能治疗包括癌症在内的多种疾病。不幸的是，具有有效抗肿瘤活性的促炎细胞因子在全身暴露后经常有毒。缺乏能够控制分布细胞因子的有效局部分娩策略阻止了细胞因子疗法对癌症免疫疗法的影响。该项目提出了一种新型的递送技术，其中有效的重组细胞因子白介素12（IL-12）在注射肿瘤内（I.T.）注射之前将化学连接到可生物降解的多糖类的可生物降解多糖。预计这种新型策略将在肿瘤微环境中提供持续的高浓度IL-12，同时最大程度地减少潜在有害的全身传播。拟议的项目由三个目的组成，重点是临床前肿瘤模型中IL-12-壳聚糖生物缀合物的开发和评估。在第一个目标中，新型的IL-12-壳聚糖生物偶联物将在体外合成并评估生物活性。溶剂可访问氨基酸的突变将允许IL-12与壳聚糖的位点特异性结合。 AIM 2将评估安全通过记录IL-12-chitosan生物缀合物的时空分布以及与IL-12-壳聚糖给药相关的任何潜在毒性。 AIM 3将评估IL-12-壳聚糖生物缀合物的抗肿瘤功效，以及在相关临床前模型中阐述肿瘤特异性免疫力。该项目的总体目标是确定与壳聚糖的共轭是否可以在减轻毒性问题的同时保持IL-12的有效抗肿瘤活性。我的长期验证该细胞因子 - 核递送平台可能为癌症免疫疗法中的其他细胞因子疗法铺平了道路。