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. ? ? ? ?
Showing the most recent 10 out of 11 publications
