title: Multifunctional nanoassemblies for vincristine sulfate delivery to overcome multidrug resistance by escaping P-glycoprotein mediated efflux.
abstract: Multifunctional nanoassemblies (MNAs) were successfully developed for controlled delivery of water-soluble cationic vincristine sulfate (VCR) to overcome multidrug resistance (MDR). The incorporation of anionic small molecule of phosphatidylserine (PS) significantly enhanced the encapsulation efficiency of VCR in MNAs up to 94.4% by electrostatic interaction. Obvious sustained-release characteristics were found in VCR-loaded MNAs (VCR-MNAs) as the cumulative release of VCR was 83.2% at 96 h, and burst-release was effectively diminished. In vivo pharmacokinetics in rats following intravenous administration demonstrated that VCR-MNAs had higher AUC and longer t(1/2) than VCR solution (VCR-Sol). To investigate the MDR reversal effect and clarify the possible mechanism induced by MNAs, the cytotoxicity, cellular uptake and uptake mechanism experiments were performed in MCF-7 and P-glycoprotein over-expressing MCF-7/Adr cells, respectively. Compared with VCR-Sol, VCR-MNAs efficiently enhanced the cytotoxicity to 36.5-fold by increasing the cellular accumulation of VCR (12.6-fold higher) in MCF-7/Adr cells. The results of endocytosis inhibition experiment proved that VCR-MNAs were uptaken into the resistant cancer cells by clathrin- and caveolae-mediated endocytosis pathways, which escaped the efflux induced by P-gp transporter and thereby overcame the MDR of VCR.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Guixia
authors.initials: G
authors.lastname: Ling
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.forename: Tianhong
authors.initials: T
authors.lastname: Zhang
authors.forename: Yue
authors.initials: Y
authors.lastname: Yuan
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Sun
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Wang
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D019344:Lactic Acid / Q000737:chemistry; D054709:Lecithins / Q000737:chemistry; D008297:Male; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar; D055672:Static Electricity; D014018:Tissue Distribution; D044366:Transition Temperature; D014750:Vincristine / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D054709:Lecithins; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D014750:Vincristine