Highlight on: “P-Glycoprotein-dependent trafficking of nanoparticle-drug conjugates”

by | Jun 12, 2014

The research article from Georgia Tech addresses an important issue in the current battle against cancer – the development of resistance to anticancer drugs, which leads to the loss of efficacy of chemotherapeutic treatment.

By Kiat Hwa Chan and Charlotte A. E. Hauser
Institute for Bioengineering and Nanotechnology, Singapore

SmallThe research article from Georgia Tech addresses an important issue in the current battle against cancer – the development of resistance to anticancer drugs, which leads to the loss of efficacy of chemotherapeutic treatment. Besides developing new anticancer drugs, it is equally important to discover how to reduce, if not circumvent, the development of resistance to anticancer drugs. Otherwise, efforts to develop new anticancer drugs would be made redundant due to resistance development. In order to tackle this critical issue, Dreaden et al. focus on one of the molecular targets that is responsible for resistance development, the multidrug resistance 1 P-glycoprotein (MDR1 P-gp). P-gp is a plasma membrane protein that effectuates the efflux of many xenobiotics, including anticancer drugs, out of cancerous cells. This efflux action renders the chemotherapeutics less efficacious at destroying the cancerous cells. While the efflux of small molecule drugs by P-gp is well-studied, the action of P-gp on gold nanoparticles (AuNPs) is unknown. This is evidently important to know given that AuNPs are gaining importance as an effective anticancer delivery platform, having have successfully undergone Phase I clinical trials.

In order to study the action of P-gp on AuNPs, Dreaden et al. coupled different macrolide antibiotics via poly(ethylene) glycol (PEG) linkers to gold nanorods (AuNRs). These macrolides are substrates for P-gp, so the adornment of the AuNRs with the macrolides would (1) enable the AuNRs to be taken up and (2) allow the intracellular trafficking of the AuNRs to be studied. Dreaden et al. demonstrate by various spectroscopic methods that the attachment of the macrolide antibiotics to the AuNRs is stable in biological medium. They also show with cell culture studies that the attachment of macrolides onto the AuNRs enhanced the uptake of AuNRs. More importantly, live-cell imaging showed that P-gp-dependent efflux of the macrolide-AuNR conjugate can be up to 5 times slower compared to the free macrolide, illustrating the ability of the AuNR to retard the efflux of the macrolide. Such a retardation effect is even more pronounced in the presence of P-gp inhibitors, leading to efflux retardation of up to 20 times. These results have important implications for the attachment of anticancer drugs to AuNPs to form anticancer drug-AuNP bioconjugates, which could be co-administered together with P-gp inhibitors in a chemotherapeutic cocktail as an effective way to overcome or slow down resistance development. This would certainly be a major advancement in the relentless fight against cancer.

KHChanKiat Hwa Chan received his BSc and MSc, both in chemistry, from the National University of Singapore (NUS) in 2003 and 2005 respectively. In NUS, he worked with Weng Kee Leong on the organometallic and bioorganometallic chemistry of osmium-cluster compounds. He received his PhD in chemistry from Princeton University in 2010, working with John T. Groves on the chemical biology of mycobactin (siderophore of Mycobacterium tuberculosis) trafficking in human macrophages. Since 2010, he has been a postdoctoral fellow at the Institute of Bioengineering and Nanotechnology (IBN), Agency for Science, Technology and Research (A*STAR). He is currently working with Charlotte A. E. Hauser on the materials chemistry of ultrashort peptide hydrogels, focusing on understanding the properties of these hydrogels with an eye to drug delivery applications.

HauserCharlotte A.E. Hauser did her Ph.D. in molecular biology at MIT. She worked at INSERM, Paris, and at the Max-Planck-Institute of Psychiatry in Munich, Germany. She is founder of Octagene, now Octapharma Biopharmaceuticals, a joint venture with Octapharma AG, Switzerland. She is currently a Team Leader and Principal Research Scientist at the Institute of Bioengineering and Nanotechnology (IBN). She has received awards from the German Federal Ministry of Science and Technology (BMFT), the French Société des Amis des Sciences, the Collège de France, and the Bavarian Research Foundation and was elected as a Société des Amis des Sciences Fellow. She is Fellow of the American Institute for Medical and Biological Engineers (AIMBE) and Adjunct Professor at Nanyang Technological University, Singapore.