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Intracellular Distribution-based Anticancer Drug Targeting: Exploiting a Lysosomal Acidification Defect Associated with Cancer Cells
Ndolo, Rosemary A. Jacobs, Damon T. Forrest, M. Laird Krise, Jeffrey P.
Ndolo, Rosemary A.
Jacobs, Damon T.
Forrest, M. Laird
Krise, Jeffrey P.
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Abstract
The therapeutic usefulness of anticancer agents relies on their ability to exert maximal toxicity to cancer cells and minimal toxicity to normal cells. The difference between these two parameters defines the therapeutic index of the agent. Towards this end, much research has focused on the design of anticancer agents that have optimized potency against a variety of cancer cell types; however, much less effort is spent on the design of drugs that are minimally toxic to normal cells. We have previously described a concept for a novel drug delivery platform that relies on the propensity of drugs with optimal physicochemical properties to distribute differently in normal versus cancer cells due to differences in intracellular pH gradients. Specifically, we demonstrated in vitro that certain weakly basic anticancer agents had the propensity to distribute to intracellular locations in normal cells that prevent interaction with the drug target, and to intracellular locations in cancer cells that promote drug-target interactions. We refer to this concept broadly as intracellular distribution-based drug targeting. Here we will discuss current in vivo work from our laboratory that examined the role of lysosome pH on the intracellular distribution and toxicity of inhibitors of the Hsp90 molecular chaperone in mice.
Description
This is the published version, also available here: http://mcpharmacol.com/index.php/Journals/article/view/103.
Date
2010-09-09
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Publisher
LumiText Publishing
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Keywords
Intracellular, Drug Delivery, Drug Targeting, Lysosomes, Anticancer, Heat shock proteins
Citation
Ndolo, Rosemary A., Jacobs, Damon T., Forrest, M. Laird., Krise, Jeffrey P. "Intracellular Distribution-based Anticancer Drug Targeting: Exploiting a Lysosomal Acidification Defect Associated with Cancer Cells." Molecular and Cellular Pharmacology, Vol 2, No 4 (2010).