A multitargeted nanocarrier inhibitor of undruggable transcription factors for treating castration resistant prostate cancer

用于治疗去势抵抗性前列腺癌的不可成药转录因子的多靶点纳米载体抑制剂

• 批准号: 10252316
• 负责人: Steven L Armentrout
• 金额: $ 25.05万
• 依托单位: PARABON NANOLABS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252316
• 关键词: Address; Affect; Androgen Receptor; Animal Model; Antiandrogen Therapy; Antigen Targeting; Autopsy; Binding; Biological Assay; CWR22Rv1; Castration; Cell Count; Cell Differentiation process; Cell Line; Cell Survival; Cells; Charge; Collaborations; Complex; Computer-Aided Design; Confocal Microscopy; Core-Binding Factor; DNA; Dangerousness; Data; Dependence; Development; Diagnosis; Disease; Drug Efflux; Drug Targeting; Dyes; Engineering; Ensure; FOLH1 gene; Genetic Transcription; Glioblastoma; Image; In Vitro; Infrastructure; Interruption; Knowledge; Label; Lead; Length; Ligands; Luciferases; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Messenger RNA; Methodology; Methods; Molecular Biology; Monitor; Mus; Nanostructures; Nuclear Receptors; Patients; Peptides; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preclinical Testing; Production; Prostate Cancer therapy; Proteins; Protocols documentation; RNA Splicing; Resistance; Shapes; Site; Small Business Technology Transfer Research; Small Interfering RNA; Software Design; Surface; Technology; Testing; Therapeutic; Tissues; Tracer; Tumor Burden; United States National Institutes of Health; VCaP; Validation; Variant; Visualization; Xenograft procedure; androgen deprivation therapy; cancer drug resistance; castration resistant prostate cancer; cell growth; cell type; cyanine dye 5; cytotoxicity; design; docetaxel; drug development; drug efficacy; effective therapy; experience; fluorophore; improved; in vivo; in vivo Model; in vivo evaluation; inhibitor/antagonist; innovation; microscopic imaging; mouse model; nanocarrier; nanodrug; nanofabrication; neoplastic cell; novel; novel therapeutics; prostate cancer cell; protein protein interaction; self assembly; small molecule; standard of care; steroid hormone; success; synergism; targeted delivery; testing uptake; therapeutic target; therapy outcome; therapy resistant; transcription factor; tumor; tumor growth; uptake

Project Summary This project addresses the critical need for treatments of castration resistant prostate cancer (CRPC) by proposing to engineer and develop a novel, nanostructured pharmaceutical (P-TRIS5) which will target tumor cells and deliver two potent, synergistic therapeutics (an siRNA and a small molecule) to inhibit the androgen receptor and RUNX, two commonly implicated transcription factors in CRPC. We will study the new compound using in vitro and in vivo models that are well-established for CRPC and seek to show 1) effective in vitro targeting and cellular uptake, and 2) effective delivery and efficacy in two xenograft mouse models. Parabon NanoLabs has significant experience in the development and validation of rationally designed, nanostructured pharmaceuticals and will leverage existing infrastructure, expertise, and collaborations to investigate the potential for the proposed CRPC targeted drug. Our synthesis methodology begins with the design of P-TRIS5 using Parabon’s Essemblix™ Drug Development Platform, a powerful combination of computer-aided design (CAD) software for designing self-assembling DNA nanocarriers and proprietary nanofabrication methods for their production. Next, the two therapeutics and a targeting peptide will be conjugated to the nanocarrier using commercially available compounds and purified by standard protocols. We will measure the performance of P-TRIS5 by monitoring a fluorescent label on the compound for targeting (via fluorescent confocal microscopy in vitro) and tumor growth via bioluminescent full-body live imaging. Off-target cytotoxicity will also be measured in vivo to demonstrate selective targeting of the tumor. Post-mortem excised tissues will be analyzed to determine the extent of inhibition of downstream targets in the animal model. The success of this project will create new avenues to rationally design nanostructured pharmaceuticals against many kinds of cancer. Our focus on CRPC, a prostate cancer with a critical need for new therapies, is driven by an abundance of knowledge about the molecular biology involved and the synergy formed by a combination of small molecules and siRNA to target drivers of the most dangerous variants of this deadly disease.

项目摘要 该项目解决了去势抵抗性前列腺癌治疗的迫切需求 （CRPC）提出设计和开发一种新型的纳米结构药物， （P-TRIS 5），它将靶向肿瘤细胞，并提供两种有效的协同治疗剂（一种 siRNA和一种小分子）来抑制雄激素受体和RUNX，这两种通常 CRPC中的转录因子。 我们将使用体外和体内模型研究这种新化合物，这些模型已经建立， CRPC并试图显示1）有效的体外靶向和细胞摄取，以及2）有效的 在两种异种移植小鼠模型中的递送和功效。Parabon NanoLabs具有显著的 在开发和验证合理设计的，纳米结构的 制药，并将利用现有的基础设施，专业知识和合作， 研究拟议的CRPC靶向药物的潜力。 我们的合成方法从使用Parabon的P-TRIS ™药物设计P-TRIS 5开始。 开发平台，一个强大的计算机辅助设计（CAD）软件的组合， 设计自组装DNA纳米载体和专有的纳米制造方法， 生产接下来，将两种治疗剂和靶向肽缀合至靶向肽。 使用市售化合物制备纳米载体并通过标准方案纯化。 我们将通过监测P-TRIS 5上的荧光标记来测量P-TRIS 5的性能。 用于靶向的化合物（通过体外荧光共聚焦显微镜）和肿瘤生长， 生物发光全身活体成像还将在体内测量脱靶细胞毒性， 显示出对肿瘤的选择性靶向。将分析死后切除的组织， 确定动物模型中下游靶标的抑制程度。 该项目的成功将为合理设计纳米结构开辟新的途径。 治疗多种癌症的药物。我们专注于CRPC，一种前列腺癌， 对新疗法的迫切需求，是由丰富的分子生物学知识驱动的。 所涉及的生物学和由小分子和siRNA的组合形成的协同作用， 针对这种致命疾病最危险变种的驱动因素。