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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该项目解决了治疗去势抵抗性前列腺癌的迫切需求 (CRPC) 提议设计和开发一种新型纳米结构药物（P-TRIS5）将靶向肿瘤细胞并提供两种有效的协同疗法（一种 siRNA 和小分子）抑制雄激素受体和 RUNX，两种常见的 CRPC 中涉及的转录因子。我们将使用已建立的体外和体内模型来研究新化合物 CRPC 并试图证明 1) 有效的体外靶向和细胞摄取，以及 2) 有效 Parabon NanoLabs 在两种异种移植小鼠模型中的递送和功效具有显着性。开发和验证合理设计的纳米结构的经验药品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。我们的合成方法始于使用 Parabon 的 Essemblix™ Drug 设计 P-TRIS5 开发平台，计算机辅助设计 (CAD) 软件的强大组合设计自组装 DNA 纳米载体和专有的纳米制造方法接下来，两种治疗剂和一种靶向肽将与该药物缀合。纳米载体使用市售化合物并通过标准方案纯化。我们将通过监测 P-TRIS5 上的荧光标记来测量 P-TRIS5 的性能用于靶向（通过体外荧光共聚焦显微镜）和肿瘤生长的化合物生物发光全身实时成像也将在体内测量。证明对死后切除的组织进行选择性靶向。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途径我们的重点是 CRPC，一种患有前列腺癌的药物。对新疗法的迫切需求是由丰富的分子知识驱动的所涉及的生物学以及小分子和 siRNA 组合形成的协同作用针对这种致命疾病最危险的变异的驱动因素。