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.

项目总结