Development of nucleic acid delivery platform based on polymeric CXCR4 antagonists

基于聚合CXCR4拮抗剂的核酸递送平台的开发

• 批准号: 9045744
• 负责人: Jing Li
• 金额: $ 34.75万
• 依托单位: BOHEMICA PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2019-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045744
• 关键词: Address; Adjuvant; CXCR4 gene; Characteristics; Cholangiocarcinoma; Clinical Research; Combined Modality Therapy; Complex; DNA; Development; Disease; Exhibits; Family; Formulation; Generations; Goals; Histocompatibility Testing; In Vitro; Incidence; Inflammatory; Inflammatory Bowel Diseases; Lead; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Medical; Mendelian disorder; Methods; MicroRNAs; Modeling; Neoadjuvant Therapy; Neoplasm Metastasis; Nucleic Acids; Patients; Pharmacologic Substance; Phase; Play; Positioning Attribute; Preparation; Primary Neoplasm; Psoriasis; Public Health; Quality of life; Rattus; Research; Resistance; Rodent; Role; Safety; Small Interfering RNA; System; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Tumor Burden; Work; anticancer activity; base; cancer type; chemokine; chemokine receptor; chemotherapy; design; human disease; improved; in vivo; inhibitor/antagonist; innovation; malignant breast neoplasm; melanoma; mortality; nanoparticle; novel; novel strategies; novel therapeutics; nucleic acid inhibitor; physical property; pre-clinical; public health relevance; research study; safety study; standard of care; success; therapeutic miRNA; therapy outcome; treatment strategy; vector

 DESCRIPTION (provided by applicant): Therapeutics based on nucleic acids (NA) promise to revolutionize treatment of multiple diseases but their widespread use is currently limited by the lack of efficient delivery methods. We have recently developed a new NA delivery platform based on polymeric CXCR4 inhibitors (PCX) suitable as dual-function systems for simultaneous NA delivery and inhibition of CXCR4 chemokine receptor. The objective of this 1-year Phase I project is to use the PCX platform to develop an innovative combination treatment of cholangiocarcinoma using PCX/microRNA nanoparticles. Clinical and experimental studies show that CXCR4 expression is associated with more aggressive disease, higher primary tumor burden, more metastases, and shorter overall survival in cholangiocarcinoma. The hypothesis of this project is that using PCX to deliver miR106b inhibitor, identified in our preliminary studies s potential target in cholangiocarcinoma, will lead to improved overall anticancer activity. We will accomplish the objectives through pursuing the following specific aims: 1) optimize PCX/microRNA formulation parameters to obtain nanoparticles capable of simultaneous CXCR4 inhibition and microRNA delivery in cholangiocarcinoma and 2) determine if delivery of miR106b inhibitor by PCX improves overall survival in orthotopic rat model of cholangiocarcinoma. The approach is innovative because of the dual-function design of nanoparticles with CXCR4 inhibitory activity and microRNA delivery. The proposed research is significant because it will establish widely applicable and versatile NA delivery platform that target chemokine networks as a way of improving therapeutic outcomes in cancer and other diseases with involvement of CXCR4.

 描述（由申请人提供）：基于核酸（NA）的治疗有望彻底改变多种疾病的治疗，但其广泛使用目前受到缺乏有效递送方法的限制。我们最近开发了一种新的NA传递平台的基础上聚合物CXCR 4抑制剂（PCX）适合作为双功能系统，同时NA传递和抑制CXCR 4趋化因子受体。这个为期1年的I期项目的目标是使用PCX平台开发一种使用PCX/microRNA纳米颗粒的胆管癌创新组合治疗。临床和实验研究表明，CXCR 4表达与胆管癌的侵袭性更强、原发肿瘤负荷更高、转移更多和总生存期更短相关。该项目的假设是，使用PCX来递送miR 106 b抑制剂，在我们的初步研究中确定了胆管癌的潜在靶点，将导致整体抗癌活性的改善。我们将通过追求以下具体目标来实现这些目标：1）优化PCX/microRNA制剂参数以获得能够在胆管癌中同时抑制CXCR 4和递送microRNA的纳米颗粒，以及2）确定通过PCX递送miR 106 b抑制剂是否改善胆管癌原位大鼠模型中的总体存活率。该方法是创新的，因为具有CXCR 4抑制活性和microRNA递送的纳米颗粒的双功能设计。这项研究具有重要意义，因为它将建立广泛适用和通用的NA递送平台，靶向趋化因子网络，作为改善癌症和其他涉及CXCR 4的疾病治疗结果的一种方式。

项目成果

Cholangiocarcinoma therapy with nanoparticles that combine downregulation of MicroRNA-210 with inhibition of cancer cell invasiveness.

• DOI: 10.7150/thno.26506
• 发表时间: 2018
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Xie Y;Wang Y;Li J;Hang Y;Jaramillo L;Wehrkamp CJ;Phillippi MA;Mohr AM;Chen Y;Talmon GA;Mott JL;Oupický D
• 通讯作者: Oupický D