Reversal of multidrug resistance by the inhibition of ATP-binding cassette pumps employing "Generally Recognized As Safe" (GRAS) nanopharmaceuticals: A review.
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.
The Group of Biomaterials and Nanotechnology for Improved Medicines (BIONIMED), Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina; National Science Research Council (CONICET), Argentina; Department of Materials Science and Engineering, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel. Electronic address: alesosnik@gmail.com.
Alejandro
A
Sosnik
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005079:Excipients / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry
D018528:ATP-Binding Cassette Transporters; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D004337:Drug Carriers; D005079:Excipients
ABC; ART; ATP-binding casette superfamily pumps (ABCs); ATP-binding cassette superfamily; AUC; Antiretroviral therapy; Area-Under-the-Curve; BCRP; BCS; Biopharmaceutic Classification System; Breast cancer resistance protein; CD; CFR; CMC; Cancer; Code of Federal Regulations; Critical Micellar Concentration; Cyclodextrins; DDS; Dox; Doxorubicin; Drug Delivery Systems; FDC; Fixed Dose Combinations; GRAS; Generally Recognized As Safe; HBV; HIV; HLB; Hepatitis B virus; Human Immunodeficiency Virus; Hydrophilic–Lipophilic Balance; IV; Infectious diseases; Intravenous; MDM; MDR; MRP; Monocyte-derived macrophages; Multidrug resistance; Multidrug resistance-associated protein; Multidrug-resistant; NBD; NRTIs; Nanopharmaceuticals; Nucleoside reverse transcriptase inhibitors; Nucleotide-binding domain; P-glycoprotein; P-gp; PAMAM; PCL; PEG; PEO-PPO; PI; PLA; Poly(epsilon-caprolactone); Poly(ethylene glycol); Poly(ethylene oxide)-poly(propylene oxide) block copolymer; Poly(lactic acid); Polyamidoamines; Polymeric amphiphiles; Protease inhibitor; R123; Rhodamine 123; TB; Tuberculosis; U.S. Food and Drug Administration; US-FDA; “Generally Recognized As Safe” (GRAS) pharmaceutical excipients