pH sensitive elastin-like-peptides for tumor targeting

描述（由申请人提供）：该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存活率。该假说是静脉注射的携带治疗性货物的蛋白质可以在肿瘤内的低pH区域内聚集，形成抗肿瘤储库。部分由于乳酸盐在氧合不良区域内的积累，许多实体瘤具有低pH（约6.7）的血管外区域，而血液和健康组织的pH为7.4。pH触发的弹性蛋白样肽（ELP）将从重复五肽（VPGXG）工程化。由X位置氨基酸的选择确定，ELP表现出尖锐的相变温度，高于该温度，它们聚结成微米级的聚集体。ELP是一种有吸引力的治疗平台，具有遗传编码、易于生物合成、单分散、免疫耐受和生物可降解等优点。设计用于测试该假设的具体目的是：1）工程化pH依赖性ELP，其在pH 7下具有相变; 2）将治疗性货物缀合至ELP; 3）在小鼠模型中测试ELP生物分布和肿瘤消退。如果成功的话，这种方法可以改善广泛的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.