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

• 批准号: 10672877
• 负责人: Robert A. Casero
• 金额: $ 44.75万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-11 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672877
• 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; Oncogenes; 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 Proteins; Up-Regulation; Woman; Work; Xenograft Model; analog; anti-cancer; anti-cancer therapeutic; anti-tumor immune response; anticancer activity; antitumor effect; 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; microRNA delivery; nanomaterials; nanoparticle; nanoparticle delivery; nanoshell; neoplastic cell; particle; preclinical safety; response; restoration; self assembly; small molecule; therapeutic miRNA; trafficking; tumor; tumor progression; tumor xenograft; tumorigenesis

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.

该建议的目的是使用自组装的纳米材料改善结肠癌的全身疗法 可以输送有效的抗癌miRNA，然后在癌细胞中降解为活跃的小分子调节剂 多胺代谢失调。尽管具有巨大的治疗潜力，但miRNA的临床翻译 面临主要未解决的药物交付挑战。由于多个突变参与 肿瘤发生和肿瘤进展，miRNA与多胺代谢调节剂的组合具有 巨大的治疗潜力。多胺代谢在许多癌基因和 肿瘤抑制途径使其成为这种组合miRNA治疗方法的逻辑靶标。我们的 目的是开发多胺前药（PAPS），以调节失调的多胺代谢和 封装并系统地传递抗癌miR-34a。假设是基于 多胺代谢的调节剂将向肿瘤传递miR-34a，这将导致增强 由于肿瘤多胺生物合成的下调和多胺分解代谢的上调而引起的组合效应 以及由于miR-34a而导致的重要细胞生长和死亡调节功能的恢复。我们将完成 目的三个特定目的：（1）我们将优化肿瘤渗透PAP/miR-34a的配方 提供miRNA并调节多胺代谢的纳米颗粒。基于鼓励体内活性的抗癌 在我们的初步研究中，我们假设用肿瘤穿透IRGD肽和 通过稳定的超疏水性氟化部分将导致有效的全身传递。 （2）我们会的 确定PAP/miR-34a纳米颗粒在体外的作用机理。我们的结果表明PAP有效 在减少肿瘤细胞的生长和凋亡的诱导中，但确切的作用机理 纳米颗粒及其与细胞内贩运，拆卸和多胺类似物释放速率的关系 未知。我们将确定行动的机制，并确定哪些组成策略最多 有效产生强大的抗肿瘤作用。 （3）我们将测试颗粒在结肠癌中的体内功效 使用人类肿瘤异种移植物和促合型肿瘤模型。我们将进行全面 在与人类疾病相关的模型中，评估PAP/MIR-34A的抗癌活性和生存优势。 还将研究抗肿瘤免疫原性对功效的贡献，这是由于已知的已知作用 多胺类似物对增加抗肿瘤免疫反应。我们预计我们将能够准备 具有改善抗癌活性并长期存活的纳米颗粒。提出的综合方法是创新的 由于PAP聚合物作为多胺代谢和miRNA的调节剂的双重功能设计 载体。这项研究很重要，因为它将解决开发药物/核酸的主要障碍 用于癌症系统治疗的纳米技术，并建立一个广泛适用的通用平台 靶向多胺代谢作为改善抗癌疗法的一种组合输送系统。

项目成果

Identification of a Novel Substrate-Derived Spermine Oxidase Inhibitor.

• DOI: 10.32607/actanaturae.10992
• 发表时间: 2020-07
• 期刊: Acta naturae
• 影响因子: 2
• 作者: Dunston TT;Khomutov MA;Gabelli SB;Stewart TM;Foley JR;Kochetkov SN;Khomutov AR;Casero RA Jr
• 通讯作者: Casero RA Jr