Diversity Supplement - TOWARD TRANSLATION OF NANFORMULATED PACLITAXEL-PLATINUM COMBINATION

紫杉醇-铂纳米复合制剂的翻译研究 这项建议的目标是获得临床前数据，以使能够翻译一种基于纳米技术的新型 联合用药治疗三阴性乳腺癌(TNBC)。在10-20%的乳腺癌中，∼与TNBC有关 并与相对较差的预后、较早的疾病复发和较高的内脏数目有关 转移瘤。化疗，特别是使用蒽环类药物和紫杉烷类药物，仍然是主要的医疗手段。 早期和转移性TNBC的治疗，但早期TNBC患者的比例很大 不幸的是得了转移性疾病。使用铂酸盐和紫杉烷的联合治疗显示 提高TNBC的病理完全应答率，改善新辅助治疗环境下的存活率。 我们建议使用纳米技术通过共同输送铂和紫杉烷来改善TNBC的治疗 同一纳米颗粒中的药物以协同方式攻击癌细胞并产生更强的抗肿瘤作用 效果。为了解决铂和紫杉烷在许多纳米粒子中的不相容和载药量差的问题，我们提出了 使用高容量的聚(2-恶唑)(POX)嵌段共聚物的聚合物胶束(PM)来掺入 毒品。在前期工作中，我们开发了POXOL-CP PM，这是PTX和疏水顺铂的组合 前药共载于POX嵌段共聚胶束中，显示出增溶的药理协同作用 药物，这两种药物对肿瘤的更好的给药，以及在几个动物模型中与 小分子制剂或其组合单独给药。这项提议的目标是获得 我们在啮齿动物和非人灵长类动物(NHP)中进行纳米治疗的新组合的额外GLP前数据 模型，为POXOL-CP PM开发有效的分析和程序，进一步证明其安全性和 POXOL-CP PM用于TNBC患者的疗效和临床转译途径。该项目 1)研制可重复、稳定、安全的POXOL-CP PM，验证其安全性 在TNBC小鼠模型中改善对肿瘤的药物传递；2)展示POXOL-CP PM的活性 同种异体原位移植(OST)和基因工程小鼠护理标准的比较 概述人类疾病的TNBC模型(GEMM)。3)评价POXOL-CP的安全性和PK谱 PMS大鼠模型和NHP模型。我们将在数据保存和记录方面遵循良好的实验操作规范(GEP 并制定标准操作程序(SOP)，并遵循临床和翻译小组的指导。如果 该项目的成功将使形成支持良好实验室实践的数据包成为可能 (GLP)和良好制造规范(GMP)合作并竞争NCI实验治疗(NEXT) 计划和/或其他资源，以促进POXOL-CP PM的开发，使其走上临床改进的道路 TNBC患者的治疗结果。

TOWARD TRANSLATION OF NANFORMULATED PACLITAXEL-PLATINUM COMBINATION The goal of this proposal is to obtain pre-clinical data to enable the translation of a novel nanotechnology-based drug combination to treat triple negative breast cancer (TNBC). TNBC accounts for ∼10-20% of breast cancers and is associated with relatively poor prognosis, earlier disease recurrence and higher number of visceral metastases. Chemotherapy, in particular with anthracyclines and taxanes, remains the backbone medical management for both early and metastatic TNBC but a significant proportion of patients with early-stage TNBC unfortunately develop metastatic disease. Combination treatments using platinates and taxanes were shown to increase pathologic complete response rates in TNBC and improve survival in neoadjuvant treatment settings. We propose to use nanotechnology to improve the treatment of TNBC by co-delivering platinum and taxane drugs in the same nanoparticle to attack cancer cells in a synergistic fashion and produce greater antitumor effect. To address poor miscibility and drug loading of platinates and taxanes in many nanoparticles, we propose to use a high capacity polymeric micelles (PMs) of poly(2-oxazolne) (POx) block copolymers to incorporate drugs. In preliminary work we developed POXOL-CP PMs, a combination of PTX and hydrophobic cisplatin prodrug co-loaded in POx block copolymer micelles that has shown pharmacological synergy of solubilized drugs, better delivery of both drugs to tumors and improved efficacy in several animal models compared to the small molecule agents or their combination administered separately. The goal of this proposal is to obtain additional pre-GLP data for our new combination nanotherapeutic in rodent and non-human primate (NHP) models, develop validated assays and procedures for POXOL-CP PMs, further demonstrate its safety and efficacy and establish path for translation of POXOL-CP PMs to the clinic for TNBC patients. The project addresses the following aims: 1) Manufacture reproducible, stable, and safe POXOL-CP PMs, validate its safety and improved drug delivery to tumors in a mouse model of TNBC; 2) Demonstrate activity of POXOL-CP PMs compared to standard of care in Orthotopic Syngeneic Transplant (OST) and Genetically Engineered Mouse Models (GEMM) of TNBC that recapitulate the human disease. 3) Assess safety and PK profiles of POXOL-CP PMs in rat and NHP models. We will follow Good Experimental Practice (GEP) in data keeping and recording and develop Standard Operating Procedures (SOP) and follow guidance of a clinical and translational panel. If successful the results of this project will allow forming data package to support the Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) work and compete for NCI Experimental Therapeutics (NExT) program, and/or other resources to advance development of POXOL-CP PMs on a path to the clinic to improve treatment outcomes for patients with TNBC.