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

项目摘要 该项目解决了抗去势前列腺癌治疗的迫切需要。 (CRPC)通过提议设计和开发一种新型的纳米结构药物 (P-TRIS5)，它将靶向肿瘤细胞，并提供两种有效的协同疗法(和 SiRNA和一个小分子)来抑制雄激素受体和RUNX，这两种通常 CRPC中涉及的转录因子。 我们将使用体外和体内模型来研究这种新化合物，这些模型已经为 CRPC和Seek展示了1)有效的体外靶向和细胞摄取，以及2)有效 在两种异种移植小鼠模型中的传递和疗效。Parabon NanoLabs具有重要的 有开发和验证合理设计的纳米结构的经验 并将利用现有的基础设施、专业知识和协作来 调查拟议的CRPC靶向药物的可能性。 我们的合成方法始于使用Parabon的EsSemblix™药物设计P-TRIS5 开发平台，是计算机辅助设计(CAD)软件的强大组合 设计自组装DNA纳米载体及其专利纳米制造方法 制作。接下来，这两种疗法和一个靶向多肽将与 使用商业上可获得的化合物的纳米载体，并通过标准方案进行纯化。 我们将通过监测P-TRIS5上的荧光标签来衡量P-TRIS5的性能 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。脱靶细胞毒性也将在体内进行测量，以 展示对肿瘤的选择性靶向。死后切除的组织将被分析以 在动物模型中确定下游靶点的抑制程度。 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。我们的关注点是CRPC，一种前列腺癌 对新疗法的迫切需求，是由对分子的丰富知识推动的 涉及的生物学以及小分子和siRNA的组合形成的协同作用 目标是这种致命疾病最危险变种的司机。

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.