title: Multidrug resistance: Physiological principles and nanomedical solutions.
abstract: Multidrug resistance (MDR) is a pathophysiological phenomenon employed by cancer cells which limits the prolonged and effective use of chemotherapeutic agents. MDR is primarily based on the over-expression of drug efflux pumps in the cellular membrane. Prominent examples of such efflux pumps, which belong to the ATP-binding cassette (ABC) superfamily of proteins, are Pgp (P-glycoprotein) and MRP (multidrug resistance-associated protein), nowadays officially known as ABCB1 and ABCC1. Over the years, several strategies have been evaluated to overcome MDR, based not only on the use of low-molecular-weight MDR modulators, but also on the implementation of 1-100(0) nm-sized drug delivery systems. In the present manuscript, after introducing the most important physiological principles of MDR, we summarize prototypic nanomedical strategies to overcome multidrug resistance, including the use of carrier materials with intrinsic anti-MDR properties, the use of nanomedicines to modify the mode of cellular uptake, and the co-formulation of chemotherapeutic drugs together with low- and high-molecular-weight MDR inhibitors within a single drug delivery system. While certain challenges still need to be overcome before such constructs and concepts can be widely applied in the clinic, the insights obtained and the progress made strongly suggest that nanomedicine formulations hold significant potential for improving the treatment of multidrug-resistant malignancies.
authors.affiliation: Department of Experimental Molecular Imaging, Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Sijumon
authors.initials: S
authors.lastname: Kunjachan
authors.affiliation: Cytometry Lab, Department of Molecular Biophysics, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland.
authors.forename: Błażej
authors.initials: B
authors.lastname: Rychlik
authors.affiliation: Department of Controlled Drug Delivery, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, PO Box 217, 7500 AE, Enschede, The Netherlands.|Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Department of Experimental Molecular Imaging, Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.affiliation: Department of Experimental Molecular Imaging, Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.|Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.|Department of Controlled Drug Delivery, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, PO Box 217, 7500 AE, Enschede, The Netherlands.
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000502:physiology; D006801:Humans; D058990:Molecular Targeted Therapy; D050997:Nanomedicine / Q000379:methods*; D049329:Nanostructures / Q000737:chemistry*; D009928:Organ Specificity; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry; D021381:Protein Transport; D013379:Substrate Specificity
chemical_list: D018528:ATP-Binding Cassette Transporters; D004337:Drug Carriers; D004364:Pharmaceutical Preparations
keywords: ABC transporters; Drug efflux pumps; Drug targeting; MDR; MRP; Multidrug resistance; Nanomedicine; Pgp; Pluronics; siRNA