CAREER: Development of acid-cleavable linkers for drug delivery

University Of California-San Diego, La Jolla CA

Investigators

Abstract

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). The Organic and Macromolecular Chemistry Program in the Chemistry Division at the National Science Foundation supports Professor Jerry Yang at the University of California San Diego whose research will evaluate and optimize the hydrolytic properties of a new class of cid-cleavable linkers that can be used for the controlled release of therapeutics from drug delivery systems (DDSs). These pH-sensitive linkers are designed to exploit the lower pH of the endosomes or lysosomes to trigger the release of therapeutic agents from suitable delivery vessels upon internalization in cells. The specific aims of this research are: 1) to synthesize and to evaluate the pH-dependent hydrolytic properties of several derivatives of N-ethoxybenzylimidazoles (NEBIs) that can be used to conjugate therapeutics to drug delivery vessels, 2) to construct model drug delivery systems comprising cancer cell-targeting antibodies carrying cancer therapeutics via the proposed pH-sensitive NEBI linkers, 3) to evaluate the specificity, uptake, and intracellular localization of the proposed drug delivery systems in cultured cells, and 4) to evaluate the utility of the proposed NEBI linkers for the selective delivery of anticancer agents to human breast cancer cells. The outcome of this research will be the development of a general strategy to covalently attach therapeutics to drug delivery systems for improved efficacy of drugs for a broad range of diseases. The broader impacts of this research are enhanced by the versatility, tunability, and predictability of this linker system. This, combined with its accessibility in practical scales, provides an ideal platform for creating a general method to covalently attach an array of drugs to a range of drug-delivery systems for effective treatment of disease. The educational activities described in this proposal will also have a broad impact in the training of the next generation of interdisciplinary scientists. The application of fundamental chemical concepts to important biomedical problems is a common theme that is reinforced by Professor Yang both in the classroom and in research. By including students from diverse scientific backgrounds and levels of education (i.e., from the high school to the postdoctoral levels), students are forced to think of problems from many different angles, and in as simple terms as possible, so that they can effectively communicate and develop innovative solutions across multiple disciplines.