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具有治疗包括癌症在内的多种疾病的潜力。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通常会产生毒性。由于缺乏能够控制细胞因子分布的有效局部递送策略，细胞因子治疗无法影响癌症免疫治疗。该项目提出了一种新颖的递送技术，其中在瘤内 (i.t) 注射之前，将有效的重组细胞因子白细胞介素 12 (IL-12) 与称为壳聚糖的可生物降解多糖进行化学连接。这种新策略有望在肿瘤微环境中提供持续、高浓度的 IL-12，同时最大限度地减少潜在有害的全身传播。拟议的项目由三个目标组成，重点是在临床前肿瘤模型中开发和评估 IL-12-壳聚糖生物缀合物。第一个目标是合成新型 IL-12-壳聚糖生物缀合物并在体外评估其生物活性。溶剂可及氨基酸的突变将允许 IL-12 与壳聚糖进行位点特异性缀合。目标 2 将评估安全性通过记录 IL-12-壳聚糖生物缀合物的时空分布以及与 IL-12-壳聚糖施用相关的任何潜在毒性。目标 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。该项目的总体目标是确定与壳聚糖缀合是否可以维持 IL-12 的有效抗肿瘤活性，同时减轻毒性问题。从长远来看，这种细胞因子-壳聚糖递送平台的验证可能为癌症免疫治疗中的其他细胞因子疗法铺平道路。