pH sensitive elastin-like-peptides for tumor targeting

用于肿瘤靶向的 pH 敏感弹性蛋白样肽

• 批准号: 7262427
• 负责人: John Andrew MacKay
• 金额: $ 4.88万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7262427
• 关键词: Acids; Adverse effects; Amino Acid Repetitive Sequences; Amino Acid Sequence; Amino Acids; Animals; Area; Behavior; Biodistribution; Blood; Body Temperature; Disease regression; Disseminated Malignant Neoplasm; Dose-Limiting; Doxorubicin; Elastin; Engineering; Environmental Engineering technology; Exhibits; Extracellular Space; Figs - dietary; Goals; Heating; Human; Hydrazones; In Vitro; Localized; Malignant Neoplasms; Measures; Methods; Modeling; Molecular Biology; Mus; Neoplasm Metastasis; Organ; Peptides; Phase Transition; Polymer Chemistry; Polymers; Positioning Attribute; Proline; Proteins; Range; Research; Site; Solid Neoplasm; Solutions; Temperature; Testing; Therapeutic; Therapeutic Agents; Thermodynamics; Tissues; Toxic effect; Transition Temperature; Water; base; design; improved; in vivo; intravenous administration; mathematical model; mouse model; size; tumor

DESCRIPTION (provided by applicant): The goal of this proposal is to improve cancer survival by delivering more therapeutic to the tumor without increasing dose-limiting side effects. The hypothesis is that an i.v. injected protein carrying therapeutic cargo can aggregate within regions of low pH inside tumors, forming an anti-tumor depot. Due in part to lactate accumulation within poorly oxygenated areas, many solid tumors have extravascular regions of low pH, around 6.7, in contrast to blood and healthy tissues at pH 7.4. pH triggered elastin-like-peptides (ELP) will be engineered from repeating pentapeptides (VPGXG). Determined by the choice of X position amino acids, ELP exhibit sharp phase transition temperatures, above which they coalesce into micron-sized aggregates. An attractive therapeutic platform, ELP are genetically encodable, easily biosynthesized, monodisperse, immuno-tolerated, and biodegradable. The specific aims designed to test this hypothesis are: 1) engineer pH dependent ELP with a phase transition at pH 7; 2) conjugate therapeutic cargo to the ELP; 3) test ELP biodistribution and tumor regression in a mouse model. If successful, this approach could improve the treatment of a wide range of both primary and metastatic tumors located throughout the body.

描述（由申请人提供）：该提案的目的是通过为肿瘤提供更多的治疗性而不增加剂量限制副作用来改善癌症生存。假设是i.v.注射蛋白质的携带治疗货物可以在肿瘤内pH值低的区域内聚集，从而形成抗肿瘤仓库。部分原因是含氧区域内的乳酸积累，许多实体瘤的血管外区域低于6.7，与pH 7.4处的血液和健康组织相反。 pH触发的弹性蛋白样肽（ELP）将通过重复的五肽（VPGXG）进行设计。通过选择X位置氨基酸的选择，ELP表现出尖锐的相过渡温度，在上面，它们将其合并为微米大小的聚集体。 ELP是一个有吸引力的治疗平台，具有遗传编码，易于生物合成，单分散，免疫耐受性和可生物降解。旨在检验此假设的特定目的是：1）在pH 7处具有相变的工程pH依赖性ELP； 2）将治疗性货物连接到ELP； 3）在小鼠模型中测试ELP生物分布和肿瘤回归。如果成功的话，这种方法可以改善整个体内的多种原发性和转移性肿瘤的处理。