Synergistic and complete reversal of the multidrug resistance of mitoxantrone hydrochloride by three-in-one multifunctional lipid-sodium glycocholate nanocarriers based on simultaneous BCRP and Bcl-2 inhibition.
Multidrug resistance (MDR) is a severe obstacle to successful chemotherapy due to its complicated nature that involves multiple mechanisms, such as drug efflux by transporters (P-glycoprotein and breast cancer resistance protein, BCRP) and anti-apoptotic defense (B-cell lymphoma, Bcl-2). To synergistically and completely reverse MDR by simultaneous inhibition of pump and non-pump cellular resistance, three-in-one multifunctional lipid-sodium glycocholate (GcNa) nanocarriers (TMLGNs) have been designed for controlled co-delivery of water-soluble cationic mitoxantrone hydrochloride (MTO), cyclosporine A (CsA - BCRP inhibitor), and GcNa (Bcl-2 inhibitor). GcNa and dextran sulfate were incorporated as anionic compounds to enhance the encapsulation efficiency of MTO (up to 97.8%±1.9%) and sustain the release of cationic MTO by electrostatic interaction. The results of a series of in vitro and in vivo investigations indicated that the TMLGNs were taken up by the resistant cancer cells by an endocytosis pathway that escaped the efflux induced by BCRP, and the simultaneous release of CsA with MTO further efficiently inhibited the efflux of the released MTO by BCRP; meanwhile GcNa induced the apoptosis process, and an associated synergistic antitumor activity and reversion of MDR were achieved because the reversal index was almost 1.0.
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Guixia
G
Ling
Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Tianhong
T
Zhang
Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Peng
P
Zhang
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Jin
J
Sun
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Zhonggui
Z
He
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002966:Clathrin / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004705:Endocytosis; D006000:Glycocholic Acid / Q000008:administration & dosage*; D006801:Humans; D020128:Inhibitory Concentration 50; D008055:Lipids / Q000737:chemistry* / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000188:drug therapy; D061986:MCF-7 Cells; D008297:Male; D008942:Mitoxantrone / Q000008:administration & dosage*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010316:Particle Size; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D002966:Clathrin; D008055:Lipids; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D008942:Mitoxantrone; D006000:Glycocholic Acid
B-cell lymphoma; breast cancer resistance protein; mitoxantrone hydrochloride; multidrug resistance; sodium glycocholate; three-in-one multifunctional lipid-GcNa nanocarriers