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By-passing of P-glycoprotein using immunoliposomes
Jörg Huwyler1, Andrin Cerletti, Gert Fricker
1Department of Research, University Hospital/Kantonsspital, Basel, Switzerland.
Journal of Drug Targeting
|May 9, 2002
Summary
Immunoliposomes bypass multidrug resistance by using receptor-mediated endocytosis to deliver drugs. This novel drug delivery system overcomes P-glycoprotein efflux, enhancing drug uptake in target cells.
Area of Science:
- Nanotechnology
- Pharmacology
- Cell Biology
Background:
- Multidrug resistance (MDR) in cancer is often mediated by P-glycoprotein (P-gp) efflux pumps.
- Conventional strategies to overcome MDR involve co-administering P-gp inhibitors, which can have systemic side effects.
Purpose of the Study:
- To investigate immunoliposomes as an alternative strategy to overcome P-gp-mediated MDR.
- To assess if immunoliposomes can bypass P-gp efflux via receptor-mediated endocytosis.
Main Methods:
- Targeted immunoliposomes were constructed using the OX26 monoclonal antibody against the transferrin receptor.
- Radiolabeled digoxin was encapsulated within OX26-immunoliposomes.
- Cellular uptake studies were performed on RBE4 rat brain capillary endothelial cells.
- Experiments included P-gp inhibition (ritonavir) and endocytosis inhibition (nocodazole).
Main Results:
- OX26-immunoliposomes enhanced digoxin cellular uptake by 25-fold compared to free digoxin.
- Liposomal digoxin uptake was unaffected by P-gp inhibition (ritonavir) but sensitive to endocytosis inhibition.
- Free digoxin uptake was enhanced by ritonavir, confirming P-gp activity.
- Confocal microscopy and acid wash assays confirmed efficient cellular internalization and endosomal escape.
Conclusions:
- Immunoliposome-based drug delivery systems can effectively bypass P-glycoprotein efflux pumps.
- Receptor-mediated endocytosis facilitates the intracellular delivery of drugs encapsulated in immunoliposomes.
- This approach offers a promising strategy for overcoming MDR in cancer therapy.