title: Evaluation of dual P-gp-BCRP inhibitors as nanoparticle formulation.
abstract: Overcoming multidrug resistance (MDR) in cancer is a major challenge and efforts are on-going to develop inhibitors against the most characterized and ubiquitous MDR transporters: P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP1) and breast cancer resistance protein (BCRP). Recently reported, two 4-anilinoquinazolines (compounds 1 and 2), demonstrate potential MDR reversal activity against BCRP and to a lesser extent, P-gp. In this work, we formulated the compounds as polymeric nanoparticles (NPs) and assessed their MDR inhibitory activity in relevant BCRP and P-gp over-expressing cell line models. Particles in the size range 300-365nm with a loading efficiency of 69% (compound 1 NP) and 77% (compound 2 NP) respectively were obtained. BCRP inhibition was observed in Hoechst 33342 and pheophorbide A assays while P-gp inhibition was evaluated in calcein AM and rhodamine-123 assays. In cytotoxicity studies, while BCRP expressing cells showed complete reversal of drug resistance in nearly all treatment groups (both compounds and their respective NP); a higher reversal in NP treated group was obtained as compared with inhibitory compound treated group in P-gp expressing cells. These results demonstrate promising inhibitory activity of both formulations, especially against P-gp expressing cells; which is possibly due to a prolonged presence of encapsulated compounds in NPs and consequently a prolonged sensitization of transmembrane drug transporter. These formulations can therefore be considered as dual-transporter inhibitors and it is imperative to investigate both inhibitors in animal models of MDR owing to the presence of multiple efflux transporters in several cancer models.
authors.affiliation: Pharmaceutical Institute, University of Bonn, Pharmaceutical Technology and Biopharmaceutics, Gerhard-Domagk-Str. 3, 53121 Bonn, Germany.
authors.forename: Manu Smriti
authors.initials: MS
authors.lastname: Singh
authors.affiliation: Pharmaceutical Institute, University of Bonn, Pharmaceutical Chemistry II, An der Immenburg 4, 53121 Bonn, Germany; Indian Institute of Technology Gandhinagar, Department of Chemistry, VGEC Complex, Chandkheda, 382424 Ahmedabad, India.
authors.forename: Kapil
authors.initials: K
authors.lastname: Juvale
authors.affiliation: Pharmaceutical Institute, University of Bonn, Pharmaceutical Chemistry II, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Pharmaceutical Institute, University of Bonn, Pharmaceutical Technology and Biopharmaceutics, Gerhard-Domagk-Str. 3, 53121 Bonn, Germany; Laboratory of Pharmaceutical Engineering, University of Franche-Comté, Besançon, France. Electronic address: alf.lamprecht@uni-bonn.de.
authors.forename: Alf
authors.initials: A
authors.lastname: Lamprecht
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000378:metabolism; D004285:Dogs; D004317:Doxorubicin / Q000494:pharmacology; D000077146:Irinotecan; D061985:Madin Darby Canine Kidney Cells; D018613:Microscopy, Confocal; D053758:Nanoparticles; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D020112:Rhodamine 123 / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D002734:Chlorophyll; D020112:Rhodamine 123; D000077146:Irinotecan; D004317:Doxorubicin; C032623:pheophorbide a; C017807:bisbenzimide ethoxide trihydrochloride; D002166:Camptothecin
keywords: BCRP; Cancer; MDR; Nanoparticle; P-gp