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（由适用提供）：基于核酸（NA）的治疗学有望彻底改变多种疾病的治疗，但目前其宽度的使用受到缺乏有效的递送方法的限制。我们最近开发了一个基于聚合物CXCR4抑制剂（PCX）作为双功能系统的新NA输送平台，可简单地传递和抑制CXCR4趋化因子受体。这个为期一年的I期项目的目的是使用PCX平台使用PCX/microRNA纳米颗粒来开发胆管癌的创新组合处理。临床和实验研究表明，CXCR4的表达与胆管癌瘤中更侵略性疾病，更高的原发性肿瘤燃烧，更多的转移和整体生存相关。该项目的假设是，在我们的初步研究中，使用PCX提供MiR106b抑制剂在胆管癌的潜在目标中确定，将导致总体抗癌活性改善。我们将通过追求以下特定目的来实现目标：1）优化PCX/microRNA公式参数，以获取能够在胆管癌中能够简单的CXCR4抑制和MicroRNA传递的纳米颗粒，2）2）确定是否通过PCX通过PCX递送MiR106b抑制剂是否可以通过PCX的整体生存在cholopopic Ratopic Ratopic of cholancorancocarmoma中的整体生存。该方法具有创新性，因为具有CXCR4抑制活性和microRNA递送的纳米颗粒的双功能设计。拟议的研究之所以重要，是因为它将建立广泛适用且多功能的NA输送平台，该平台以趋化因子网络为目标，以改善癌症和其他疾病的治疗结果，并参与CXCR4。

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