Diversity Supplement - TOWARD TRANSLATION OF NANFORMULATED PACLITAXEL-PLATINUM COMBINATION

多样性补充 - 纳米配方紫杉醇-铂组合的转化

• 批准号: 10529457
• 负责人: ALEXANDER V KABANOV
• 金额: $ 5.01万
• 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/10529457
• 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.

向纳米形的紫杉醇 - 白斑组合翻译 该提案的目的是获取亲链接数据以翻译 治疗三重阴性乳腺癌（TNBC）的药物组合。 并通过相对池的预后，早期的疾病复发和较高的内脏数量抗拒 转移疗法，尤其是蒽环类药物和紫杉烷 早期和公制的TNBC的管理，但早期TNBC患者的明显建议 不幸的是，使用柏拉图酯和紫杉虫进行转移性疾病。 提高TNBC的病理完整反应率，并在新辅助tereatment环境中新辅助的新adjuval生存。 我们建议使用纳米技术通过共同塑造铂和紫杉烷来改善TNBC的处理 同一纳米颗粒中的药物以协同的方式攻击癌细胞，并产生更大的抗肿瘤 效果。 对我们来说，聚（2-恶唑）（POX）块共聚物的高容量聚合物胶束（PMS）合并 药物。 前药共同加载在痘块共聚物胶束中 药物，两种药物递送到肿瘤的更好的递送以及在几种模型中的提高疗效比较了 小分子剂或其组合分别给药。 我们在啮齿动物和非人类灵长类动物（NHP）中新组合纳米治疗的其他前GLP数据 模型，开发有验证的内乐-CP PM的测定法和程序，进一步证明了其安全性和 功效并为TNBC患者的诊所转化为毒素CP PMS的疗效 解决以下目的：1）生产可重现，稳定和安全的内乐CP PMS，验证其安全性 并改善了TNBC小鼠模型中肿瘤的药物递送； 与原位同性移植（OST）和尼斯工程的鼠标中的护理标准相比 tnbc的模型（GEMM）重新分配人类疾病。 大鼠和NHP模型中的PM。 并制定标准操作程序（SOP），并遵循临床和翻译面板的指导。 成功的结果将允许成立数据包来支持良好的实验室实践 （GLP）和良好的制造实践（GMP）工作并竞争NCI实验治疗（下一项） 程序，和/或/或其他其他资源，以在 TNBC患者的治疗结果。