| Posted: July 3, 2006 |
Hybrid nanoparticles increase anticancer activity in multiple drug resistant tumor cells |
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(Nanowerk News) A novel combination of lipids, a negatively charged polymer, and the anticancer drug doxorubicin has yielded a new nanoparticle that can kill breast cancer cells that are normally resistant to this drug. Additional studies with this nanoparticulate formulation then identified what could be a new approach to overcoming an important drug resistance mechanism common in tumors. The results of this research appear in papers published in Pharmaceutical Research ("A New Polymer-Lipid Hybrid Nanoparticle System Increases Cytotoxicity of Doxorubicin Against Multidrug-Resistant Human Breast Cancer Cells.") and the Journal of Pharmacology and Experimental Therapeutics ("A Mechanistic Study of Enhanced Doxorubicin Uptake and Retention in Multidrug Resistant Breast Cancer Cells Using a Polymer-Lipid Hybrid Nanoparticle System").
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To create this polymer-lipid hybrid nanoparticle, Xiao Yu Wu, Ph.D., and her colleagues at the University of Toronto, first synthesized a new type of negatively charged polymer from the lipid component of soybean oil. They then mixed this polymer with doxorubicin and stearic acid, a waxy lipid obtained from animal fat or coconut oil, among other sources. These biocompatible and biodegradable substances self-assemble into solid nanoparticles with diameters as small as 50 nanometers. These nanoparticles contain nearly 80% of the doxorubicin that the researchers used in the formulation mixture, with doxorubicin accounting for about 5% of the final mass of each nanoparticle.
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Drug release studies showed that half of the loaded doxorubicin diffused out of the nanoparticles over a two- to four-hour period. When the researchers dosed drug-resistant breast cancer cells with the doxorubicin-loaded nanoparticles, they observed that the drug-loaded nanoparticles were eight times more toxic than doxorubicin alone. There was little difference in cell-killing activity in non-resistant tumor cells. The investigators also found that resistant cells retained twice as much doxorubicin when it was loaded in the nanoparticle.
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In further studies, the researchers then examined the mechanism by which these nanoparticles enhance the activity of doxorubicin in drug-resistant tumor cells. To conduct these studies, the investigators used breast tumor cells that overexpress p-glycoprotein (Pgp), a protein that sits in the cell membrane and pumps anticancer drugs out of a cell almost immediately after they enter the cell.
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The results of these experiments showed that drug loaded into nanoparticles entered the drug-resistant cells via endocytosis, which enabled the drug to bypass the p-glycoprotein pump. In contrast, free drug appeared to enter the cell via simple diffusion across the cell membrane, leaving it available to the p-glycoprotein pump. The researchers also found that more doxorubicin ended up in the cell nucleus, where it exerts its cell-killing activity, when the drug was entrapped in nanoparticles.
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