This lecture will cover the molecular design of conjugates and fusions of genetically encoded stimulus responsive elastin-like polypeptides (ELPs) for drug delivery applications. Below a characteristic inverse transition temperature (Tt), ELPs are soluble in aqueous solution, but when the temperature is raised above their Tt, they desolvate and undergo phase separation. This family of self-assembling ELPs provides rich opportunities for application in medicine. In one example of the utility of ELPs for drug delivery, I will show how conjugation of multiple copies of the cancer drugs doxorubicin or paclitaxel via a pH-sensitive linker to the end of an ELP spontaneously triggers their self-assembly into near-monodisperse nanoparticles that induce near complete tumor regression in a murine cancer model following a single dose. We have also designed diblock ELPs that self-assemble into monodisperse micelles in response to a thermal trigger, wherein self-assembly in the narrow temperature range between 37 �C (normal body temperature) and 42 �C (highest temperature approved for mild clinical hyperthermia) results in the multivalent presentation of a functional cell penetrating peptide (CPP) motif. The presentation of a functional CPP only at 42 �C, but not at 37 �C opens the way to convert CPPs which are powerful yet promiscuous agents to promote the uptake of drugs into cells, into a thermally targeted system for cancer drug delivery. Finally, I will describe Protease Operated Depots (PODs) for the delivery of peptide drugs that consist of two linked modules �an ELP with a Tt below body temperature fused to multiple copies of a peptide drug with intervening protease cleavage sites. I will show that PODs of glucagon-like peptide-1 form a depot upon s.c. injection that allows control of blood glucose level in a diabetic mouse model for 5 days after a single injection of a POD.

Genetically engineered polypeptide conjugates and fusions for drug delivery

246th National Meeting (2013)

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