Novel Gold nanocarriers conjugates for microRNA delivery in ovarian cancer

新型金纳米载体缀合物用于卵巢癌中的 microRNA 递送

• 批准号: 9977255
• 负责人: GABRIEL Luis BARLETTA
• 金额: $ 9.48万
• 依托单位: UNIVERSITY OF PUERTO RICO AT HUMACAO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-07 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977255
• 关键词: Animals; Applications Grants; Autoimmune Diseases; Award; Blood; Cancer Patient; Cause of Death; Cell membrane; Chemicals; Cisplatin; Clinical; Complex; Cytoplasm; Data; Death Rate; Development; Diagnosis; Disease; Drug Delivery Systems; Drug Formulations; Drug resistance; Engineering; Folic Acid; Gene Expression; Genetic Transcription; Goals; Gold; Health; Human; Hydrophobicity; Implant; Individual; Laboratories; Lead; Life; Ligands; Literature; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Medicine; MicroRNAs; Mission; Modeling; Mus; Neurodegenerative Disorders; Normal Cell; Oligonucleotides; Oncogenes; Ovarian Carcinoma; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Process; Public Health; RNA Interference; Reagent; Reporting; Research; Resistance; Serum; Small Interfering RNA; Solid; Surface; System; Temperature; Testing; Therapeutic; Therapeutic Agents; Tissues; Translating; Treatment Efficacy; United States National Institutes of Health; Untranslated RNA; Virus Diseases; Western World; anti-cancer therapeutic; base; c-myc Genes; cancer cell; cancer initiation; cancer therapy; chemotherapy; design; disulfide bond; drug development; evidence base; expectation; experimental study; folate-binding protein; human disease; improved; in vivo; innovation; mouse model; nanoGold; nanocarrier; nanomaterials; nanoparticle; neoplastic cell; neurotensin mimic 2; novel; ovarian neoplasm; small molecule; targeted delivery; trend; tumor; tumor growth

PROJECT SUMMARY In vivo delivery of MicroRNAs (miRNA)-based therapeutics is an important, but currently challenging aspect of the drug development process for a variety of diseases, including cancer, viral infections, and autoimmune and neurodegenerative disorders. Our long-term goal is to develop evidence-based clinically-useful delivery systems for miRNAs to improve therapies for human disease, in particular for cancer. The objective for this SC3 application is to synthetize and test a nanocarrier reagent to deliver an oligonucleotide miRNA mimic (OMM) of miR-18a (miR-18a-OMM), in ovarian cancer tumors implanted in mice. Experiments showed that miR-18a-OMM reduced the proliferation of ovarian cancer cells, an effect that was in part due to the reduction of c-MYC expression (c-MYC is an oncogene highly abundant in ovarian cancer cells). Our central hypothesis is that a host - and – guest model, consisting of a host molecule covalently bound to a solid gold nanoparticle (AuNP) and a guest molecule attached to the cargo molecule (OMM and/or a tumor-cell-targeting ligand), will form a strong host-guest nanocarrier complex for the efficient delivery of miR-18a-OMM. This hypothesis was formulated based on the existing literature and on preliminary data produced in the PI’s and the collaborator’s laboratories. The rationale for this project is that successful completion of these studies is likely to yield a new nanoparticle reagent for delivering and transfecting specific miRNAs in vivo. Guided by preliminary data, this hypothesis will be tested pursuing two specific aims: 1) To synthetize and characterize new multifunctional gold nanocarriers for delivering of miR-18a OMMs; and 2) To determine the therapeutic efficacy of miR- 18a-OMM-gold nanocarriers in vivo. For the first aim, the approach involves modifying the surface of Au nanoparticles with a guest molecule, and the miRNA and other ligands (needed for improving the stability and delivery efficiency of the complex) with a molecule (a “guest”) that forms strong inclusion complexes with the host molecule on the Au surface. To support proof of concept, under the second aim, we will target mir-18a with an OMMin in ovarian cancer mouse model. This contribution will be significant because it is expected to constitute an important step in a continuum of research that will ultimately lead to the development of a clinically useful nanoparticle system to treat ovarian cancer. The proposed research is potentially innovative because it represents a substantial departure from the status quo by introducing a new type of nanoparticle reagent specifically designed to deliver oligonucleotide mimic in vivo, to silence a specific target inside the ovarian cancer cells in live animals. This, in turn, should translate to better therapy for humans.

项目概要 基于 MicroRNA (miRNA) 的疗法的体内递送是一个重要但目前具有挑战性的方面 针对多种疾病的药物开发过程，包括癌症、病毒感染、自身免疫性疾病和 神经退行性疾病。我们的长期目标是开发基于证据的临床有用的输送系统 miRNA 可以改善人类疾病的治疗，特别是癌症的治疗。 SC3 的目标 应用是合成和测试纳米载体试剂，以传递寡核苷酸 miRNA 模拟物 (OMM) miR-18a (miR-18a-OMM)，在植入小鼠卵巢癌肿瘤中。实验表明miR-18a-OMM 减少卵巢癌细胞的增殖，这种作用部分是由于 c-MYC 的减少 表达（c-MYC 是卵巢癌细胞中高度丰富的癌基因）。我们的中心假设是 主体和客体模型，由共价结合到固体金纳米颗粒 (AuNP) 的主体分子组成 和附着在货物分子（OMM和/或肿瘤细胞靶向配体）上的客体分子将形成 强大的主客体纳米载体复合物，用于有效递送 miR-18a-OMM。这个假设是 根据现有文献以及 PI 和合作者的初步数据制定 实验室。该项目的基本原理是成功完成这些研究可能会产生新的 用于体内递送和转染特定 miRNA 的纳米颗粒试剂。根据初步数据，本 将测试假设以实现两个具体目标：1）合成和表征新的多功能 用于递送 miR-18a OMM 的金纳米载体； 2) 确定 miR-的治疗效果 体内 18a-OMM-金纳米载体。对于第一个目标，该方法涉及修改 Au 的表面 具有客体分子、miRNA 和其他配体的纳米颗粒（需要提高稳定性和 复合物的递送效率）与分子（“客体”）形成强包合物 Au 表面上的主体分子。为了支持概念验证，在第二个目标下，我们将瞄准 mir-18a 在卵巢癌小鼠模型中使用 OMMin。这一贡献将是巨大的，因为预计 构成连续研究中的重要一步，最终将导致临床治疗的发展 有用的纳米颗粒系统可治疗卵巢癌。拟议的研究具有潜在的创新性，因为它 通过引入新型纳米颗粒试剂，与现状有了很大的不同 专门设计用于在体内递送寡核苷酸模拟物，以沉默卵巢癌内的特定靶标 活体动物的细胞。反过来，这应该转化为对人类更好的治疗。