title: siRNA capsulated brain-targeted nanoparticles specifically knock down OATP2B1 in mice: a mechanism for acute morphine tolerance suppression.
abstract: Regulating main brain-uptake transporter of morphine may restrict its tolerance generation, then modify its antinociception. In this study, more than 2 fold higher intracellular uptake concentrations for morphine and morphine-6-glucuronide (M6G) were observed in stable expression cells, HEK293-hOATP2B1 than HEK293-MOCK. Specifically, the Km value of morphine to OATP2B1 (57.58 ± 8.90 μM) is 1.4-time more than that of M6G (80.31 ± 21.75 μM); Cyclosporine A (CsA), an inhibitor of OATP2B1, can inhibit their intracellular accumulations with IC50 = 3.90 ± 0.50 μM for morphine and IC50 = 6.04 ± 0.86 μM for M6G, respectively. To further investigate the role of OATP2B1 in morphine brain transport and tolerance, the novel nanoparticles of DGL-PEG/dermorphin capsulated siRNA (OATP2B1) were applied to deliver siRNA into mouse brain. Along with OATP2B1 depressed, a main reduction was found for each of morphine or M6G in cerebrums or epencephalons of acute morphine tolerance mice. Furthermore, calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) in mouse prefrontal cortex (mPFC) underwent dephosphorylation at Thr286. In conclusion, OATP2B1 downregulation in mouse brain can suppress tolerance via blocking morphine and M6G brain transport. These findings might help to improve the pharmacological effects of morphine.
authors.affiliation: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Zi-Zhao
authors.initials: ZZ
authors.lastname: Yang
authors.affiliation: Zhejiang Provincial Key Laboratory of Geriatrics &Geriatrics Institute of Zhejiang Province, Zhejiang Hospital, 12 Lingyin Road, Hangzhou, Zhejiang Province 310013, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Ming-Cheng
authors.initials: MC
authors.lastname: Xu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Sai
authors.initials: S
authors.lastname: An
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: School of Life Sciences, Jilin Univeristy, Changchun, 130012, China.
authors.forename: Jing-Kai
authors.initials: JK
authors.lastname: Gu
authors.affiliation: Department of Biopharmaceutical Sciences, University of Illinois, 833 S. Wood Street, Chicago, IL 60612, USA.
authors.forename: Zai-Jie Jim
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Lu-Shan
authors.initials: LS
authors.lastname: Yu
authors.affiliation: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009020:Morphine / Q000378:metabolism* / Q000494:pharmacology; D009022:Morphine Derivatives / Q000378:metabolism / Q000494:pharmacology; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; C529569:CAMK2N1 protein, human; D009022:Morphine Derivatives; D027361:Organic Anion Transporters; D011506:Proteins; C000610580:Slco2b1 protein, mouse; C035349:morphine-6-glucuronide; D009020:Morphine; D016572:Cyclosporine