Self-immolative prodrug/miRNA nanoparticle combinations for cancer treatment

用于癌症治疗的自毁前药/miRNA纳米颗粒组合

基本信息

批准号：
10084282
负责人：
Robert A. Casero
金额：
$ 45.66万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-11 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084282
关键词：
Address Affect Anabolism Apoptotic Artificial nanoparticles Biodistribution Cancer Model Cell Death Cells Charge Clinical Trials Colon Colon Carcinoma Combined Modality Therapy DNA Damage Data Down-Regulation Drug Delivery Systems Drug Kinetics Encapsulated Evaluation Face Formulation Gene Mutation Goals Human Immunocompetent In Vitro Induction of Apoptosis Intervention Ligands Malignant Neoplasms Metabolism MicroRNAs Microfluidics Modeling Modification Mutation Nanotechnology Nature Nucleic Acids Oncogenic Pathway interactions Penetration Peptides Performance Pharmaceutical Preparations Pharmacologic Substance Plasma Polyamine Catabolism Polyamines Polymers Prodrugs Production Property Publishing Reactive Oxygen Species Research Scheme System Systemic Therapy TP53 gene Testing Therapeutic Toxic effect Tumor Suppressor Genes Up-Regulation Woman Work Xenograft Model analog anti-cancer anti-cancer therapeutic anti-tumor immune response anticancer activity antitumor effect base cancer cell cancer heterogeneity cancer therapy cancer type cell growth clinical translation colon cancer treatment design efficacious treatment human disease immunogenicity improved in vivo in vivo evaluation innovation lipophobicity men nanomaterials nanoparticle nanoparticle delivery neoplastic cell particle preclinical safety response restoration small molecule therapeutic miRNA trafficking tumor tumor progression tumor xenograft tumorigenesis

项目摘要

The goal of this proposal is to improve systemic therapies of colon cancer using self-assembled nanomaterials that can deliver potent anticancer miRNA and then degrade in cancer cells to active small molecule modulators of dysregulated polyamine metabolism. Despite tremendous therapeutic potential, clinical translation of miRNA faces major unsolved pharmaceutical delivery challenges. Due to the involvement of multiple mutations in tumorigenesis and tumor progression, combination of miRNAs with modulators of polyamine metabolism has significant therapeutic potential. The fact that polyamine metabolism is downstream from many oncogenes and tumor suppressor pathways make it a logical target for such combination miRNA therapy approaches. Our objective is to develop polyamine prodrugs (PaPs) that can modulate dysregulated polyamine metabolism and encapsulate and systemically deliver anticancer miR-34a. The hypothesis is that self-immolative PaPs based on modulators of polyamine metabolism will deliver miR-34a to the tumors, which will result in enhanced combination effect due to the downregulation of tumor polyamine biosynthesis and upregulation of polyamine catabolism and restoration of important cell growth and death-regulatory functions due to miR-34a. We will accomplish the objectives in three specific aims: (1) we will optimize formulation of tumor-penetrating PaP/miR-34a nanoparticles that deliver miRNA and modulate polyamine metabolism. Based on encouraging anticancer in vivo activity in our preliminary studies, we hypothesize that particle modification with tumor-penetrating iRGD peptide and with stabilizing superhydrophobic fluorinated moieties will result in efficient systemic delivery. (2) we will determine the mechanism of action of PaP/miR-34a nanoparticles in vitro. Our results indicate that PaPs are effective in reducing tumor cell growth and induction of apoptosis, but the precise mechanism of action of the nanoparticles and how it relates to their intracellular trafficking, disassembly and rate of polyamine analog release is unknown. We will ascertain the mechanisms of action and determine which composition strategies are most effective in producing strong antitumor effect. (3) we will test the in vivo efficacy of the particles in colon cancer using human tumor xenografts and syngeneic immune competent tumor models. We will conduct comprehensive evaluation of anticancer activity and survival advantage of PaP/miR-34a in models relevant for human disease. Contribution of the antitumor immunogenicity to the efficacy will be also studied due to known effects of polyamine analogs on increasing the antitumor immune response. We predict that we will be able to prepare nanoparticles with improved anticancer activity and prolonged survival. The proposed integrative approach is innovative because of the dual-function design of the PaP polymers as modulators of polyamine metabolism and miRNA carriers. The research is significant because it will address major barriers in developing drug/nucleic acid nanotechnology for systemic treatment of cancer and establish a widely applicable and versatile platform for combination delivery systems that target polyamine metabolism as a way of improving anticancer therapies.

该提案的目标是利用自组装纳米材料改善结肠癌的全身治疗可以传递有效的抗癌 miRNA，然后在癌细胞中降解为活性小分子调节剂多胺代谢失调。尽管具有巨大的治疗潜力，miRNA 的临床转化面临着尚未解决的重大药物输送挑战。由于涉及多种突变肿瘤发生和肿瘤进展中，miRNA 与多胺代谢调节剂的组合具有显着的治疗潜力。事实上，多胺代谢是许多癌基因的下游，肿瘤抑制途径使其成为此类组合 miRNA 治疗方法的合理目标。我们的目标是开发可以调节失调的多胺代谢和多胺前药（PaP）封装并系统地递送抗癌 miR-34a。假设自焚 PaP 是基于多胺代谢调节剂会将 miR-34a 递送至肿瘤，从而增强由于肿瘤多胺生物合成下调和多胺分解代谢上调而产生的联合效应以及 miR-34a 导致的重要细胞生长和死亡调节功能的恢复。我们将完成三个具体目标：（1）我们将优化肿瘤穿透性 PaP/miR-34a 的配方递送 miRNA 并调节多胺代谢的纳米颗粒。基于鼓励体内抗癌活性在我们的初步研究中，我们假设用肿瘤穿透 iRGD 肽进行颗粒修饰并具有稳定的超疏水性氟化部分将导致有效的全身递送。 (2) 我们将确定 PaP/miR-34a 纳米颗粒的体外作用机制。我们的结果表明 PaP 是有效的减少肿瘤细胞生长和诱导细胞凋亡，但其确切的作用机制纳米颗粒及其与细胞内运输、分解和多胺类似物释放速率的关系未知。我们将确定作用机制并确定哪种组合策略最有效有效产生强烈的抗肿瘤作用。 (3)我们将测试颗粒对结肠癌的体内功效使用人类肿瘤异种移植物和同基因免疫活性肿瘤模型。我们将全面开展在人类疾病相关模型中评估 PaP/miR-34a 的抗癌活性和生存优势。由于已知的作用，还将研究抗肿瘤免疫原性对功效的贡献。多胺类似物可增强抗肿瘤免疫反应。我们预测我们将能够做好准备纳米颗粒具有改善的抗癌活性和延长的生存期。所提出的综合方法具有创新性由于 PaP 聚合物作为多胺代谢和 miRNA 调节剂的双重功能设计载体。这项研究意义重大，因为它将解决开发药物/核酸的主要障碍纳米技术用于癌症的系统治疗，并建立一个广泛适用的多功能平台以多胺代谢为目标的联合给药系统作为改善抗癌治疗的一种方式。