Diversity Supplement - TOWARD TRANSLATION OF NANFORMULATED PACLITAXEL-PLATINUM COMBINATION

紫杉醇-铂纳米复合物的翻译 该提案的目标是获得临床前数据，以使一种新的基于纳米技术的 治疗三阴性乳腺癌（TNBC）的药物组合。TNBC占乳腺癌的10%-20% 并且与相对较差的预后、较早的疾病复发和较高数量的内脏 转移化疗，特别是蒽环类和紫杉烷类，仍然是主要的医疗手段。 早期和转移性TNBC的管理，但相当比例的早期TNBC患者 不幸地发展成转移性疾病。使用铂酸盐和紫杉烷的组合治疗显示出 增加TNBC的病理完全缓解率，并改善新辅助治疗环境中的生存率。 我们建议使用纳米技术，通过共同递送铂和紫杉烷来改善TNBC的治疗 在同一纳米颗粒中的药物以协同方式攻击癌细胞， 效果为了解决铂酸盐和紫杉烷类药物在许多纳米颗粒中的溶解性和载药量差的问题，我们提出了 使用聚（2-恶唑啉）（POx）嵌段共聚物的高容量聚合物胶束（PM）来掺入 毒品在初步工作中，我们开发了POXOL-CP PM，PTX和疏水顺铂的组合 共负载在POx嵌段共聚物胶束中的前药已经显示出溶解的前药的药理学协同作用。 药物，更好地将两种药物递送到肿瘤，并且在几种动物模型中的功效与 小分子药剂或它们的组合分开给药。该提案的目的是获得 我们的新型复方纳米颗粒在啮齿动物和非人灵长类动物（NHP）中的其他GLP前数据 模型，开发经验证的POXOL-CP PM检测方法和程序，进一步证明其安全性， P0 X 0 L-CP PM的有效性，并建立将P0 X 0 L-CP PM转化为TNBC患者的临床的路径。项目 目的：1）生产可重复、稳定、安全的POXOL-CP PM，验证其安全性 以及在TNBC的小鼠模型中改善药物向肿瘤的递送; 2）证明POXOL-CP PM的活性 与原位同基因移植（OST）和基因工程小鼠中的标准治疗相比 概括人类疾病的TNBC模型（GEMM）。3)评估POXOL-CP的安全性和PK特征 大鼠和NHP模型中的PM。我们将遵循良好实验规范（GEP）保存和记录数据 制定标准操作规程（SOP），并遵循临床和翻译小组的指导。如果 该项目的成功结果将允许形成数据包，以支持药物非临床研究质量管理规范 (GLP)和良好生产规范（GMP）的工作和竞争的NCI实验治疗（NExT） 计划和/或其他资源，以推进POXOL-CP PM在临床上的发展， 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.