Reversal of multidrug resistance by the inhibition of ATP-binding cassette pumps employing “Generally Recognized As Safe” (GRAS) nanopharmaceuticals: A review

Department of Materials Science and Engineering, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel. Electronic address: .
Advanced drug delivery reviews (Impact Factor: 12.71). 09/2013; DOI: 10.1016/j.addr.2013.09.002
Source: PubMed

ABSTRACT Pumps of the ATP-binding cassette superfamily (ABCs) regulate the access of drugs to the intracellular space. In this context, the overexpression of ABCs is a well-known mechanism of multidrug resistance (MDR) in cancer and infectious diseases (e.g., viral hepatitis and the human immunodeficiency virus) and is associated with therapeutic failure. Since their discovery, ABCs have emerged as attractive therapeutic targets and the search of compounds that inhibit their genetic expression and/or their functional activity has gained growing interest. Different generations of pharmacological ABC inhibitors have been explored over the last four decades to address resistance in cancer, though clinical results have been somehow disappointing. "Generally Recognized As Safe" (GRAS) is a U.S. Food and Drug Administration designation for substances that are accepted as safe for addition in food. Far from being "inert", some amphiphilic excipients used in the production of pharmaceutical products have been shown to inhibit the activity of ABCs in MDR tumors, emerging as a clinically translatable approach to overcome resistance. The present article initially overviews the classification, structure and function of the different ABCs, with emphasis on those pumps related to drug resistance. Then, the different attempts to capitalize on the activity of GRAS nanopharmaceuticals as ABC inhibitors are discussed.

Download full-text


Available from: Alejandro Sosnik, Jul 01, 2015
1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer is the most common non-cutaneous malignancy in American men. Docetaxel is a useful chemotherapeutic agent for prostate cancer that has been available for over a decade, but the length of the treatment and systemic side effects hamper compliance. Additionally, docetaxel resistance invariably emerges, leading to disease relapse. Docetaxel resistance is either intrinsic or acquired by adopting various mechanisms that are highly associated with genetic alterations, decreased influx and increased efflux of drugs. Several combination therapies and small P-glycoprotein inhibitors have been proposed to improve the therapeutic potential of docetaxel in prostate cancer. Novel therapeutic strategies that may allow reversal of docetaxel resistance include alterations of enzymes, improving drug uptake and enhancement of apoptosis. In this review, we provide the most current docetaxel reversal approaches utilizing nanotechnology. Nanotechnology mediated docetaxel delivery is superior to existing therapeutic strategies and a more effective method to induce P-glycoprotein inhibition, enhance cellular uptake, maintain sustained drug release, and improve bioavailability.
    Drug Resistance Updates 04/2014; DOI:10.1016/j.drup.2014.04.001 · 8.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract All polymeric chemosensitizers proposed thus far have a linear poly(ethylene glycol) (PEG) hydrophilic block. To testify whether precisely this chemical structure and architecture of the hydrophilic block is a prerequisite for chemosensitization, a series of novel block copolymers containing a hyperbranched polyglycerol segment as a hydrophilic block (PPO-NG copolymers) was tested on multidrug resistant (MDR) tumor cells in culture. PPO-NG copolymers inhibited MDR of three cell lines, indicating that the linear PEG can be substituted for a hyperbranched polyglycerol block without loss of the polymers´ chemosensitizing activity. The extent of MDR reversal increased with the polymers affinity towards the cells and the expression level of P-glycoprotein. In contrast to Pluronic L61, which increases viability of tumor cells in the absence of drugs, PPO-NG chemosensitizers are completely devoid of this property undesired in cancer therapy, making them promising candidates for application as novel MDR reversal agents.
    Biomacromolecules 06/2014; 15(7). DOI:10.1021/bm500521j · 5.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Irinotecan loaded nanostructured lipid carrier (NLC-Ir) was surface decorated with hyaluronic acid graft polymer. Hyaluronic acid is a biocompatible, non-antigenic and hydrophilic, CD-44 ligand that can impart many useful features to the nanocarrier for anticancer drug delivery. The present investigation demonstrated that hyaluronic acid coated HA-NLC had significantly lower haemolytic potential as compared to uncoated NLC. Further, HA-NLC had a reduced plasma protein interaction and low macrophage uptake. The in vivo tumor targeting and pharmacodynamics efficacy of HA-NLC was studied in Ehrlich's Ascites Tumor (EAT) allograft model. Radio scintigraphic biodistribution studies revealed that HA-NLC carrier got accumulated in the tumor tissues in good proportion. Additionally, the content of radioactivity associated with tumor tissues remained constant at 2, 4 and 24h (2.41, 2.48 and 2.47%, respectively), while it got reduced in other organs. Furthermore, tumor to muscle ratio of radioactivity suggested a better accumulation of HA-NLC in tumor tissues that was significantly enhanced (P<0.05) with time. In vivo antitumor activity of hyaluronan coated HA-NLC-Ir was 5.8 and 2.6 times higher as compared to control and free drug solution respectively. Furthermore, encapsulation of irinotecan in HA-NLC-Ir nanocarrier was found to have reduced the thrombocytopenia and neutropenia associated with free irinotecan. Thus, it can be inferred that the hyaluronic acid decorated nanocarrier can provide a haemo-compatible, non-toxic and target based delivery system for the effective management of cancer. Copyright © 2014 Elsevier B.V. All rights reserved.
    Colloids and surfaces B: Biointerfaces 10/2014; DOI:10.1016/j.colsurfb.2014.09.061 · 4.29 Impact Factor