Engineering novel biomolecular materials for therapeutic peptide payload delivery

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Hematological cancers, including leukemia and lymphoma, are estimated to cause the death of 58,000 people in the United States in 2018 and account for 9.5% of all cancer-related deaths. The currently available clinical treatments, including chemotherapy and antibody therapy, are inadequate due to the high mortality rate and deleterious side effects of treatment. New peptide drug candidates in development are poised to address this need for new therapeutics. However, the delivery of a peptide to cells in the blood stream poses unique challenges due to low bioavailability, rapid clearance, and enzymatic degradation. By conjugating a lipid to a peptide, peptide amphiphiles (PAs) are produced. PAs can self-assemble into micelles (PAMs), producing a modular nanoparticle. PAMs have been shown to address the issues of peptide stability and clearance in the blood stream. I have designed a modular PAM that is easily produced and displays a cell-targeting aptamer, and utilized a recently discovered cell-targeting DNA aptamer capable of selectively associating with leukemia and lymphoma over healthy lymphocytes and found it to retain cell-targeting potential even when displayed on the surface of micelles. Additionally, through the development of a novel disulfide-linked peptide amphiphile, aptamer-displaying micelles capable of aptamer-specific association to deliver a therapeutically effective peptide are described and evaluated. A second technology in hematological drug delivery described here is that of lipidated, highly hydrophobic poly(amino acid)s. These lipidated poly(amino acid)s self-assemble similarly to peptide amphiphiles and are able to entrap therapeutics when nanoprecipitated through a dump-and-stir method. A method is described to display aptamer on the surface of these poly(amino acid) nanoprecipitates for delivery of therapeutic levels of the chemotherapeutic doxorubicin to lymphoma cells.