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.

纳米紫杉醇-铂组合物的转化研究