title: Overcoming cellular multidrug resistance using classical nanomedicine formulations.
abstract: Over the past few decades, many different types of nanomedicines have been evaluated, both in vitro and in vivo. In general, nanomedicines are designed to improve the in vivo properties of low-molecular-weight (chemo-) therapeutic drugs, i.e. their biodistribution and the target site accumulation, and to thereby improve the balance between their efficacy and toxicity. A significant number of studies have also addressed the in vitro properties of nanomedicines, showing e.g. their ability to overcome cellular multidrug resistance (MDR). Particularly promising results in this regard have been reported for 'pharmacologically active' carrier materials, such as Pluronics, which are able to directly inhibit drug efflux pumps and other cellular detoxification mechanisms. In the present report, we have set out to evaluate the ability of classical (and pharmacologically inactive) carrier materials to overcome MDR. To this end, four different drug-sensitive and drug-resistant cancer cell lines were treated with increasing concentrations of free doxorubicin, of polymer-bound doxorubicin, of micellar doxorubicin and of liposomal doxorubicin, and resistance indices (IC(50) in resistant cells/IC(50) in sensitive cells) were determined. In addition, the cellular uptake of the four formulations was evaluated using fluorescence microscopy. It was found that the carrier materials did manage to overcome MDR to some extent, but that the overall benefit was quite small; only for polymer-bound doxorubicin in A431 cells, a significant (4-fold) reduction in the resistance index was observed. These findings indicate that the ability of classical nanomedicines to overcome cellular MDR should not be overestimated.
authors: Department of Experimental Molecular Imaging, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors: Sijumon
authors: S
authors: Kunjachan
authors: Andrzej
authors: A
authors: Błauż
authors: Diana
authors: D
authors: Möckel
authors: Benjamin
authors: B
authors: Theek
authors: Fabian
authors: F
authors: Kiessling
authors: Tomas
authors: T
authors: Etrych
authors: Karel
authors: K
authors: Ulbrich
authors: Louis
authors: L
authors: van Bloois
authors: Gert
authors: G
authors: Storm
authors: Grzegorz
authors: G
authors: Bartosz
authors: Błażej
authors: B
authors: Rychlik
authors: Twan
authors: T
authors: Lammers
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000008:administration & dosage / Q000737:chemistry; D000178:Acrylamides / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008081:Liposomes; D051379:Mice; D008823:Micelles; D050997:Nanomedicine; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000178:Acrylamides; D000970:Antineoplastic Agents; D008081:Liposomes; D008823:Micelles; D010714:Phosphatidylethanolamines; C482378:N-(2-hydroxypropyl)methacrylamide co-polymer-doxorubicin conjugate; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols; D004317:Doxorubicin