TOWARD TRANSLATION OF NANFORMULATED PACLITAXEL-PLATINUM COMBINATION

纳米制剂紫杉醇-铂组合的转化

• 批准号: 10306113
• 负责人: ALEXANDER V KABANOV
• 金额: $ 61.31万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306113
• 关键词: Address; Advanced Development; Animal Model; Animals; Anthracycline; Antigens; Biodistribution; Biological Assay; Breast Cancer Patient; CD2 gene; Carboplatin; Cisplatin; Clinic; Clinical; Clinical Data; Clinical Oncology; Combined Modality Therapy; Crossover Design; Data; Development; Disease; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Excipients; Genetically Engineered Mouse; Goals; Human; Hydrophobicity; Immune; Immune checkpoint inhibitor; Immunotherapeutic agent; Immunotherapy; In complete remission; Investigational Therapies; Isogenic transplantation; Lead; Macaca mulatta; Malignant Neoplasms; Medical; Micelles; Modeling; Mus; Nanotechnology; Neoadjuvant Therapy; Neoplasm Metastasis; Paclitaxel; Pathologic; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I/II Trial; Plasma; Platinum; Polymers; Positron-Emission Tomography; Postoperative Period; Pre-Clinical Model; Procedures; Prodrugs; Prognosis; Rattus; Recurrence; Reproducibility; Resources; Rodent; Safety; Sampling; Solubility; Study models; TP53 gene; Taxes; Technology; Testing; Therapeutic; Translations; Treatment outcome; Vertebral column; Visceral metastasis; Work; antitumor effect; base; cancer cell; cancer subtypes; chemotherapy; copolymer; drug development; good laboratory practice; human disease; improved; malignant breast neoplasm; mouse model; nanoformulation; nanoparticle; nanotherapeutic; nonhuman primate; novel; novel strategies; pre-clinical; programs; response; small molecule; standard of care; success; synergism; taxane; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

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.

纳米制剂紫杉醇-铂组合的转化 该提案的目标是获得临床前数据，以实现基于纳米技术的新型药物的转化 治疗三阴性乳腺癌（TNBC）的药物组合。 TNBC 占乳腺癌的 10-20% 且与相对较差的预后、较早的疾病复发和较高的内脏数量相关。 转移。化疗，特别是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，但很大一部分患者患有早期 TNBC 不幸的是发生转移性疾病。使用铂酸盐和紫杉烷的联合治疗被证明可以 提高 TNBC 的病理完全缓解率并提高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 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 影响。为了解决许多纳米颗粒中铂酸盐和紫杉烷的混溶性和载药量差的问题，我们建议 使用聚（2-恶唑啉）（POx）嵌段共聚物的高容量聚合物胶束（PM）来结合 药物。在前期工作中，我们开发了 POXOL-CP PM，它是 PTX 和疏水性顺铂的组合 前药共同负载在 POx 嵌段共聚物胶束中，显示出溶解的药理学协同作用 与药物相比，这两种药物能够更好地递送至肿瘤，并且在几种动物模型中的疗效得到提高 小分子药物或其组合单独施用。该提案的目标是获得 我们的新组合纳米疗法在啮齿动物和非人类灵长类动物 (NHP) 中的额外 GLP 前数据 模型，开发 POXOL-CP PM 的经过验证的检测方法和程序，进一步证明其安全性和 疗效并为 TNBC 患者将 POXOL-CP PM 转化为临床建立途径。项目 实现以下目标： 1) 制造可重复、稳定且安全的 POXOL-CP PM，验证其安全性 并改善了 TNBC 小鼠模型中肿瘤的药物输送； 2) 展示 POXOL-CP PM 的活性 与原位同基因移植 (OST) 和基因工程小鼠的护理标准相比 概括人类疾病的 TNBC 模型 (GEMM)。 3) 评估 POXOL-CP 的安全性和 PK 概况 大鼠和 NHP 模型中的 PM。我们将遵循良好实验规范（GEP）进行数据保存和记录 制定标准操作程序 (SOP) 并遵循临床和转化小组的指导。如果 该项目的成功结果将有助于形成数据包以支持良好实验室规范 (GLP) 和良好生产规范 (GMP) 为 NCI 实验疗法 (NExT) 工作和竞争 计划和/或其他资源，以促进 POXOL-CP PM 的开发，以改善临床效果 TNBC 患者的治疗结果。