6-mercaptopurine (6-MP) and other thiopurines, such as 6-mecaptopurine ribozide (6-MPR) are some of the most important and most widely utilized anitleukemic and anti-inflammatory drugs. Conventional therapy with 6-mercaptopurine and its analogues is based on oral or intravenous administration of the compounds however 6-MP is susceptible to enzymatic degradation and inactivation, which results in poor bioavailability and potential for the development of increased resistance. In this collaborative application between the School of Engineering and Medical School of the University of Michigan we put forward a concept of the delivery of 6-MP and related compounds by using small gold nanoparticles (Au NPs). We intend to show that 6-mercaptopurine-9-2-D-ribofuraniside (6-MPR, a pro- drug of 6-MP) adsorbed on the surface of Au NPs has significantly enhanced anti-leukemia activity. It stems both from the greater tendency to penetrate the cells and extended life-time in circulation. The structure of the particle can be further modified to improve blood clearance time and cancer targeting. The fundamental and novel aspects of the project include (1) the verification of particle size in nanoscale being one of the primary factors determining the particle retention by reticular endothelial system, and (2) elucidation of the intracellular metabolism of NPs and their stabilizer shell. This information is relevant for many potential applications of Au NP as a vehicle to a large number of drugs as well as cancer imaging.
The Specific Aims (SAs) below will allow us to start validating the basic hypothesis and to obtain the proof-of-concept data allowing the scientific community to assess the potential of Au NPs as a delivery vehicle of mercaptopurines. SA1: Preparation of Au NP carrying 6-MPR and related drug delivery agents with cloaking and targeting functionalities. SA 2: In vitro evaluation of the clearance time using macrophages. SA3: Elucidation of the mechanism of 6-MPR delivery and release in leukemia cells. This project is based on the preliminary work done with the help of the seed grant from Children's Leukemia Research Association (investigator N. Kotov). The preliminary results give strong indications that 6- MPR-modified Au NPs have substantially increased anticancer activity as compared to free 6-MPR. We see the primary goal of this application in the accumulation of conceptually critical data and development of experimental tools for the transition into stages of more advanced testing of the drug delivery protocols with Au NPs.
Development of Au NPs for drug delivery of 6-MPR can substantially improve treatment of leukemia and reduce side-effects. The anticancer agent will also have longer span of activity and better efficacy.
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