pH sensitive elastin-like-peptides for tumor targeting

描述（由申请人提供）：本提案的目标是通过向肿瘤提供更多治疗而不增加剂量限制性副作用来提高癌症生存率。假设是，静脉注射携带治疗货物的蛋白质可以在肿瘤内的低pH区域聚集，形成抗肿瘤仓库。部分由于缺氧区域内乳酸的积累，许多实体瘤的血管外区域pH值较低，约为6.7，而血液和健康组织的pH值为7.4。pH触发弹性蛋白样肽（ELP）将由重复五肽（VPGXG）工程化。由X位氨基酸的选择决定，ELP表现出尖锐的相变温度，在此温度以上，它们聚集成微米大小的聚集体。ELP具有遗传可编码、易于生物合成、单分散、免疫耐受和可生物降解的特点，是一个有吸引力的治疗平台。为验证这一假设而设计的具体目标是：1)设计pH依赖性ELP，并在pH为7时发生相变；2)将治疗货物偶联到ELP；3)检测ELP在小鼠模型中的生物分布和肿瘤消退。如果成功，这种方法可以改善全身范围内原发性和转移性肿瘤的治疗。

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.