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: 10225464
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225464
• 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.

项目摘要 基于microRNA（miRNA）的体内递送是一个重要但目前具有挑战性的方面 各种疾病的药物开发过程，包括癌症，病毒感染和自身免疫性和 神经退行性疾病。我们的长期目标是开发基于证据的临床用途交付系统 miRNA改善人类疾病的疗法，尤其是癌症的疗法。 SC3的目标 应用是合成和测试纳米载体试剂以提供寡核苷酸miRNA模拟（OMM） miR-18a（miR-18a-omm），植入小鼠的卵巢癌肿瘤中。实验表明miR-18a-ommomm 减少了卵巢癌细胞的增殖，这种作用部分是由于C-Myc的减少 表达（C-Myc是一种高度丰富的癌细胞中的癌基因）。我们的中心假设是 宿主 - 和 - 客体模型，由宿主分子共价结合到固体金纳米粒子（AUNP） 以及附着在货物分子（OMM和/或靶向肿瘤靶向配体）的来宾分子将形成一个 强大的宿主纳米载体复合物，可有效地递送miR-18a-omm。这个假设是 根据现有文献和PI和合作者的初步数据制定 实验室。该项目的理由是，这些研究的成功完成可能会产生新的 用于在体内输送和转染特定miRNA的纳米颗粒试剂。在初步数据的指导下， 假设将进行测试，以追求两个具体的目的：1）合成和表征新的多功能 用于交付miR-18a oumms的金纳米载体； 2）确定mir-的治疗效率 18A寄给体内的纳米载体。对于第一个目标，该方法涉及修改AU的表面 带有宾客分子的纳米颗粒以及miRNA和其他配体（改善稳定性和 与分子（“访客”）形成强大的包容络合物的分子的递送效率） 宿主分子在AU表面上。为了支持概念证明，在第二个目标下，我们将以Mir-18a为目标 与卵巢癌小鼠模型中的Ommin。这项贡献将是重要的，因为它有望 构成了连续研究的重要一步，最终将导致诊所的发展 有用的纳米颗粒系统治疗卵巢癌。拟议的研究可能具有创新性，因为它 通过引入一种新型的纳米颗粒试剂，代表了与现状的实质性不同 专门设计用于在体内输送寡核苷酸的模拟物，以使卵巢癌内部的特定靶标保持 活动物中的细胞。反过来，这应该转化为对人类的更好疗法。