OTHER FUNCTIONS - R&D BIOMEDICAL (BASIC RESEARCH)

其他功能-R

• 批准号: 8564720
• 负责人: CHARLES NOBLE
• 金额: $ 21.6万
• 依托单位: ZONEONE PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2013-06-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8564720
• 关键词: 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin; Basic Science; Biodistribution; Blood Circulation; Bone Marrow; Cancer cell line; Data; Development Plans; Dose; Drug Controls; Drug Formulations; Drug Kinetics; Encapsulated; Evaluation; Extravasation; Future; Generations; Growth; Hepatic; Human; In Vitro; Lead; Lipids; Liposomes; Maximum Tolerated Dose; Mus; Nausea; Pharmaceutical Preparations; Phase; Plasma; Property; Protocols documentation; Reporting; Screening procedure; Serum; Solid Neoplasm; Specific qualifier value; Sterols; Therapeutic; Time; Toxic effect; Tumor Tissue; Xenograft Model; design; gastrointestinal; in vivo; inhibitor/antagonist; liver function; meetings; nanoliposome; nanosized; research and development; tumor; tumor xenograft

The Hsp90 inhibitor 17-DMAG will be encapsulated in a nano-sized liposome formulation that is long-circulating with controlled drug release properties in tumor tissue. Reformulation of 17-DMAG in a nanoliposome will increase the dose intensity of 17-DMAG in solid tumors while reducing the hepatic, gastrointestinal, nausea and bone marrow toxicity. The key is devising a nanoliposome composition that will retain the drug in circulation and release the drug from the nanoliposome at an appropriate rate after accumulation in the tumor. ZoneOne Pharma will use a new class of sterol-modified lipids (SML) that enable a wide and predictable range of drug release rates from the nanoliposome to encapsulate 17-DMAG using a remote loading protocol. In this development plan, ZoneOne Pharma will design nanoliposome compositions of 17-DMAG for evaluation by loading efficiency, in vitro plasma stability, in vivo pharmacokinetic and biodistribution studies. These formulations will be evaluated for tumor release effect on therapeutic activity in a proof-of-concept efficacy study at the end of Phase 1. A single formulation will be selected from confirmation efficacy studies as the first step of a future Phase II project.

Hsp90 抑制剂 17-DMAG 将被封装在纳米级脂质体制剂中，该制剂可在肿瘤组织中长期循环并具有受控药物释放特性。在纳米脂质体中重新配制 17-DMAG 将增加实体瘤中 17-DMAG 的剂量强度，同时减少肝脏、胃肠道、恶心和骨髓毒性。关键是设计一种纳米脂质体组合物，该组合物将药物保留在循环中，并在肿瘤中积聚后以适当的速率从纳米脂质体中释放药物。 ZoneOne Pharma 将使用一类新型甾醇修饰脂质 (SML)，该脂质体能够通过远程加载协议封装 17-DMAG，使纳米脂质体的药物释放速率范围广泛且可预测。在该开发计划中，ZoneOne Pharma 将设计 17-DMAG 纳米脂质体组合物，通过装载效率、体外血浆稳定性、体内药代动力学和生物分布研究进行评估。第一阶段结束时，将在概念验证功效研究中评估这些制剂的肿瘤释放对治疗活性的影响。将从确认功效研究中选择单一制剂，作为未来第二阶段项目的第一步。