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：
10415002
负责人：
Steven L Armentrout
金额：
$ 14.95万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415002
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 antagonist cancer drug resistance castration resistant prostate cancer cell growth cell type cyanine dye 5 cytotoxicity design docetaxel drug development drug efficacy effective therapy enzalutamide experience fluorophore improved in vivo in vivo Model in vivo evaluation inhibitor innovation microscopic imaging mouse model nanocarrier nanodrug nanofabrication neoplastic cell novel novel therapeutics prostate cancer cell protein protein interaction rational design 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.

项目摘要该项目解决了对抑制前列腺癌治疗的关键需求（CRPC）提议工程师并开发一种新颖的纳米结构制药（p-Tris5）将靶向肿瘤细胞并提供两种有效的协同疗法（一个 siRNA和一个小分子）以抑制雄激素受体和runx，两个通常 CRPC中实施的转录因子。我们将使用体外和体内模型研究新化合物的新化合物 CRPC并寻求显示1）有效的体外靶向和细胞摄取，2）有效两种Xenographotic Mouse模型的传递和效率。 Parabon Nanolabs具有重要的在理性设计，纳米结构的开发和验证方面的经验药品，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。我们的合成方法从Parabon's Essemblix™药物的P-Tris5设计开始开发平台是计算机辅助设计（CAD）软件的强大组合为其设计自组装DNA纳米载体和专有纳米制作方法生产。接下来，将两种治疗剂和一个靶肽结合到纳米载体使用市售化合物，并通过标准协议纯化。我们将通过监视荧光标签来测量P-Tris5的性能用于靶向的化合物（通过荧光共聚焦显微镜在体外）和肿瘤生长通过生物发光全身现场成像。脱靶细胞毒性也将在体内测量证明肿瘤的选择性靶向。验尸后出色的组织将被分析为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创造新的途径针对多种癌症的药物。我们专注于CRPC，这是一种前列腺癌对新疗法的关键需求是由大量有关分子的知识驱动的涉及的生物学以及由小分子和siRNA的组合形成的协同作用这种致命疾病最危险变体的目标驱动因素。