The delivery of therapeutics agents in the treatment of gram-negative bacterial infections and the various forms of brain cancers have one common, and yet deadly problem: penetration and retention. Gram-negative bacteria have been designed, and re-designed by evolution to prevent the penetration of bactericidal agents into its cytoplasm. Their complex outer membrane prevents common diffusion of said agents through the lipopolysaccharide layer upon the outer membrane. Entrance can only be achieved through either porin-channels or lipid-mediated transport, of which both are highly restrictive and slow. Likewise, the blood-brain barrier prevents common diffusion transport and only allows entrance through five-distinct transport mechanisms. When a cytotoxic agent penetrates either, or both systems, they are met with a highly selective and efficient removal mechanism; efflux pumps. While the construction and discovery of new novel single cytotoxic agents that are able to penetrate either barrier is possible, quick drug resistance can void said therapies rapidly. Given the current arsenal of cytotoxic agents currently in possession by the medical community, which unfortunately fail to possess penetrant properties towards either or both complex barriers, greats a unique opportunity. Our laboratory has undertaken a campaign to develop new chaperones that allow for transport and retention within either barrier when conjugated onto these untapped therapeutics. Through our investigations into numerous physicochemical properties, new trends have been identified that allow penetration that was once thought impossible. Current efforts have resulted in the construction of new small molecular chaperones, which upon conjugation onto non-penetrant species, has been observed to allow penetration into gram-negative bacteria or across the blood-brain barrier. To be presented is our current design into the investigations of the role physicochemical properties have upon penetration, combinational studies, evaluation, the first-generation chaperone construction, and overall findings.

Investigations into the development of new penetrating chaperones: Smuggling therapeutics across gram-negative bacteria and the blood-brain barrier

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.