Electrically Mediated Delivery of Immunostimulatory DNA to Experimental Melanomas

电介导的免疫刺激 DNA 递送至实验性黑色素瘤

基本信息

批准号：
7140107
负责人：
Loree C Heller
金额：
$ 15.22万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7140107
关键词：
Electrically Mediated Delivery Immunostimulatory DNA

项目摘要

DESCRIPTION (provided by applicant): The broad, long term objectives of this proposal are to understand the physical and biological mechanisms for the immediate, long-term tumor regression generated after the electrically mediated delivery of non-coding, bacterially derived plasmid DNA. This effect requires neither therapeutic cDNA expression nor eukaryotic sequences within plasmids. The specific aims of this proposal are to test two hypotheses: The electroporation parameters for delivery of non-coding DNA can be manipulated to minimize the quantity of electricity delivered while maintaining efficient induction of tumor regression. The immediate tumor regression is due to a combination of the induction of apoptosis or necrosis and the induction of an immune response. This research derives its health relatedness from the possible use of this effect as a cancer therapy, as well as the possible consequences of this antitumor effect on electrically mediated therapeutic gene delivery in general. The research is designed to determine (a) which particular electroporation parameters are necessary to generate this strong antitumor effect, (b) if apoptosis and an induced immune response are responsible for tumor regression, (c) a possible signaling cascade, and (d) the immune cells and cytokines involved in the tumor regression process. The methods used include the manipulation of the electrical parameters and electrodes involved in the delivery, histological analysis to confirm the presence of apoptosis, and microarray analysis to implicate a possible signaling cascade. Specific antitumor immune mechanisms will be explored. The studies described in this proposal will characterize this effect and may have significant application for the development of efficacious gene delivery methods through electroporation that mediate clinically relevant antitumor responses.

描述（由申请人提供）：该提案的广泛、长期目标是了解在电介导的非编码、细菌来源的质粒 DNA 递送后产生的立即、长期肿瘤消退的物理和生物学机制。这种作用既不需要治疗性 cDNA 表达，也不需要质粒内的真核序列。该提案的具体目的是测试两个假设：可以操纵用于递送非编码DNA的电穿孔参数以最小化递送的电量，同时保持有效诱导肿瘤消退。肿瘤立即消退是由于细胞凋亡或坏死的诱导以及免疫反应的诱导的结合。这项研究的健康相关性源于这种效应可能用作癌症治疗，以及这种抗肿瘤效应对电介导的治疗性基因传递的一般可能后果。该研究旨在确定（a）哪些特定的电穿孔参数对于产生这种强抗肿瘤作用是必要的，（b）细胞凋亡和诱导的免疫反应是否是肿瘤消退的原因，（c）可能的信号级联，以及（d）免疫细胞和细胞因子参与肿瘤消退过程。使用的方法包括操纵参与递送的电参数和电极、组织学分析以确认细胞凋亡的存在，以及微阵列分析以暗示可能的信号级联。将探索特定的抗肿瘤免疫机制。本提案中描述的研究将表征这种效应，并可能对开发通过电穿孔介导临床相关抗肿瘤反应的有效基因递送方法具有重要应用。