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(申请人提供)：这项提案的目标是在不增加剂量限制副作用的情况下，通过对肿瘤提供更多的治疗来提高癌症存活率。假设是静脉注射。携带治疗货物的注射蛋白可以在肿瘤内低pH区聚集，形成抗肿瘤仓库。部分由于乳酸在含氧量较低的区域积聚，许多实体肿瘤的血管外区域的pH值较低，约为6.7，而血液和健康组织的pH值为7.4。PH触发的弹性蛋白样肽(ELP)将由重复五肽(VPGXG)改造而来。由X位氨基酸的选择决定，ELP表现出强烈的相变温度，在此温度以上，它们聚集成微米级的聚集体。ELP是一种有吸引力的治疗平台，具有基因可编码、易于生物合成、单分散、免疫耐受和可生物降解等特点。为验证这一假设而设计的具体目标是：1)设计pH依赖的ELP，在pH值为7的情况下进行相变；2)将治疗货物连接到ELP；3)在小鼠模型中测试ELP的生物分布和肿瘤消退。如果成功，这种方法可以改善对遍及全身的多种原发和转移肿瘤的治疗。