Rational Design of Anticancer Drug Resistance Nanoparticles

University Of Wyoming, Laramie WY

Investigators

Abstract

0401982 Shen Drug resistance is a major problem in the treatment of cancer. Forms of resistance effectively reduce the cell drug concentration by mechanisms such as slowing drug uptake, ejecting drugs out of the cells by P-glycoprotein (P-gp) pumps, and bio-transforming. Thus, conventional dosages have low therapeutic efficacy, are very toxic and cause various side effects. Nanoparticles are ideal drug carriers because of their subcellular sizes, stability, and ability to evade the reticulo-endothelial systems. However, currently developed nanoparticles for cancer treatment generally have issues of premature drug burst release in the blood stream, but slow drug release and slow cellular uptake in cancer tissues. Coupled with drug resistance, these issues cause low drug concentration in the cancer cells and low therapeutic efficacy. The goal of this project is to design, synthesize, characterize and in vitro and in vivo evaluate nanoparticles that can overcome cancer drug resistance for effective chemotherapy. The hypothesis is that a fast release of a large amount of drugs inside the cancer cell cytoplasm would overwhelm P-gp pumps and other forms of drug resistance and thus build up a cell drug concentration higher than the cell killing threshold. To test this hypothesis, the investigators will use nanoparticles with no premature drug release as the drug-carrier, exploit the leaky nature of cancer capillary to have the nanoparticles preferentially trapped in cancer tissues, use electrostatic-interaction based adsorptive cellular uptake for efficient cell-internalization of the nanoparticles and use the lysosomal pH to trigger the rapid release of the drugs. This multidisciplinary research effort combines the elements of polymer synthesis and characterization, nanoscience, biomedical engineering, thermodynamics, and self-assembly. Results obtained may provide an effective new cancer therapeutic strategy for the war with cancer. Selected topics on biomedical applications of polymers and nanoparticles would be developed for a variety of courses.