July 3, 2006
Hybrid Nanoparticles Increase Anticancer Activity in Multiple Drug Resistant Tumor Cells
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 and the Journal of Pharmacology and Experimental Therapeutics.
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.
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.
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.
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.
The nanoparticle formulation and cytotoxicity studies are detailed in a paper titled, “A new polymer-lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells.” This paper was published online in advance of print publication. An abstract of this paper is available through PubMed.
The work examining the mechanism of enhanced toxicity is detailed in a paper titled, “A mechanistic study of enhanced doxorubicin uptake and retention in multidrug resistant breast cancer cells using a polymer-lipid hybrid nanoparticle system.” This paper was published online in advance of print publication. An abstract of this paper is available through PubMed.