Intestinal OCTN2- and MCT1-targeted drug delivery to improve oral bioavailability

Banker, 1990 Gibaldi, 1991 Luo, 2015, A review of biodegradable polymeric systems for oral insulin delivery, Drug Deliv, 23, 1882 Zhang, 2014, Current prodrug strategies for improving oral absorption of nucleoside analogues, Asian J Pharm Sci, 9, 65, 10.1016/j.ajps.2013.12.006 Faivre, 2015, Phase i dose escalation and pharmacokinetic evaluation of two different schedules of LY2334737, an oral GEM prodrug, in patients with advanced solid tumors, Invest New Drugs, 33, 1206, 10.1007/s10637-015-0286-7 Bender, 2009, Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine, J Med Chem, 52, 6958, 10.1021/jm901181h Adema, 2012, Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126, Investig New Drugs, 30, 1908, 10.1007/s10637-011-9756-8 Bergman, 2011, Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models, Investig New Drugs, 29, 456, 10.1007/s10637-009-9377-7 Stuurman, 2013, Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors, Investig New Drugs, 31, 959, 10.1007/s10637-013-9925-z Minko, 2013, Nanotechnology approaches for personalized treatment of multidrug resistant cancers, Adv Drug Deliv Rev, 65, 1880, 10.1016/j.addr.2013.09.017 Bertrand, 2014, Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology, Adv Drug Deliv Rev, 66, 2, 10.1016/j.addr.2013.11.009 Yao, 2016, External-stimuli responsive systems for cancer theranostic, Asian J Pharm Sci, 11, 585, 10.1016/j.ajps.2016.06.001 Luo, 2014, Prodrug-based nanoparticulate drug delivery strategies for cancer therapy, Trends Pharmacol Sci, 35, 556, 10.1016/j.tips.2014.09.008 Mura, 2015, Lipid prodrug nanocarriers in cancer therapy, J Control Release, 208, 25, 10.1016/j.jconrel.2015.01.021 Lajoie, 2015, Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier, Annu Rev Pharmacol Toxicol, 55, 613, 10.1146/annurev-pharmtox-010814-124852 Bazak, 2015, Cancer active targeting by nanoparticles: a comprehensive review of literature, J Cancer Res Clin Oncol, 141, 769, 10.1007/s00432-014-1767-3 Tambe, 2017, Surface engineered dendrimers in sirna delivery and gene silencing, Curr Pharm Des, 23, 2952, 10.2174/1381612823666170314104619 Yan, 2011, Bifunctional peptidomimetic prodrugs of didanosine for improved intestinal permeability and enhanced acidic stability: synthesis, transepithelial transport, chemical stability and pharmacokinetics, Mol Pharm, 8, 319, 10.1021/mp100376q Sun, 2008, Synthesis, transport and pharmacokinetics of 5′-amino acid ester prodrugs of 1-β-D-arabinofuranosylcytosine, Mol Pharm, 6, 315, 10.1021/mp800200a Cao, 2013, Propylene glycollinked amino acid/dipeptide diester prodrugs of oleanolic acid for pept1-mediated transport: synthesis, intestinal permeability, and pharmacokinetics, Mol Pharm, 10, 1378, 10.1021/mp300647m Trauner, 2003, Bile salt transporters: molecular characterization, function, and regulation, Physiol Rev, 83, 633, 10.1152/physrev.00027.2002 Swaan, 1997, Enhanced transepithelial transport of peptides by conjugation to cholic acid, Bioconjug Chem, 8, 520, 10.1021/bc970076t Margarida, 2013, Intestinal drug transporters: an overview, Adv Drug Deliv Rev, 65, 1340, 10.1016/j.addr.2012.09.042 Guan, 2019, Morris. Cellular uptake of MCT1 inhibitors AR-C155858 and AZD3965 and their effects on MCT-mediated transport of L-lactate in murine 4T1 breast tumor cancer cells, AAPS J, 21, 13, 10.1208/s12248-018-0279-5 Krajcsi, 2013, Drug-transporter interaction testing in drug discovery and development, World J Pharmacol, 2, 35, 10.5497/wjp.v2.i1.35 Han, 1998, 5′-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter, Pharm Res, 15, 1154, 10.1023/A:1011919319810 Sugawara, 2000, Transport of valganciclovir, a ganciclovirprodrug, via peptide transporters PEPT1 and PEPT2, J Pharm Sci, 89, 781, 10.1002/(SICI)1520-6017(200006)89:6<781::AID-JPS10>3.0.CO;2-7 Li, 2006, Transport of levovirin prodrugs in the human intestinal Caco 2 cell line, J Pharm Sci, 95, 1318, 10.1002/jps.20434 Yan, 2011, Bifunctional peptidomimetic prodrugs of didanosine for improved intestinal permeability and enhanced acidic stability: synthesis, transepithelial transport, chemical stability and pharmacokinetics, Mol Pharm, 8, 319, 10.1021/mp100376q Sun, 2008, Synthesis, transport and pharmacokinetics of 5′-amino acid ester prodrugs of 1-β-D-arabinofuranosylcytosine, Mol Pharm, 6, 315, 10.1021/mp800200a Fan, 2018, Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery, Biomaterials, 151, 13, 10.1016/j.biomaterials.2017.10.022 Yuqian, 2018, Dipeptide-modified nanoparticles to facilitate oral docetaxel delivery: new insights into PepT1-mediated targeting strategy, Drug Deliv, 25, 1403, 10.1080/10717544.2018.1480675 Wang, 2017, Combination of l-carnitine with lipophilic linkage-donating gem derivatives as intestinal novel organic cation transporter 2-targeting oral prodrugs, J Med Chem, 60, 2552, 10.1021/acs.jmedchem.7b00049 Kou, 2017, Cotransporting ion is a trigger for cellular endocytosis of transporter-targeting nanoparticles: a case study of high efficiency SLC22A5 (OCTN2)-mediated carnitine-conjugated nanoparticles for oral delivery of therapeutic drugs, Adv Healthc Mater, 6, 10.1002/adhm.201700165 Zhang, 2002, Modeling of active transport systems, Adv Drug Deliv Rev, 54, 329, 10.1016/S0169-409X(02)00007-8 Cao, 2012, Advances in research of PepT1-targeted prodrug, Asian J Pharm Sci, 7, 110 Rautio, 2008, Prodrugs: design and clinical applications, Nat Rev Drug Discov, 7, 255, 10.1038/nrd2468 Hu, 2004, Prodrugs: effective solutions for solubility, permeability and targeting challenges, Invest Drugs J, 7, 736 Tsirigos, 2017, Topology of membrane proteins-predictions, limitations and variations, Curr Opin Struct Biol, 50, 9, 10.1016/j.sbi.2017.10.003 Ohashi, 2002, Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein, J Pharmacol Exp Ther, 302, 1286, 10.1124/jpet.102.036004 Wang, 2000, Abnormal sodium stimulation of carnitine transport in primary carnitine deficiency, J Biol Chem, 275, 20782, 10.1074/jbc.M000194200 Seth, 1999, Mutations in novel organic cation transporter (OCTN2), an organic cation/carnitine transporter, with differential effects on the organic cation transport function and the carnitine transport function, J Biol Chem, 274, 33388, 10.1074/jbc.274.47.33388 Muoio Deborah, 2012, Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility, Cell Metab, 15, 764, 10.1016/j.cmet.2012.04.005 Clark, 2012, Bioinformatics analysis reveals transcriptome and microRNA signatures and drug repositioning targets for IBD and other autoimmune diseases, Inflamm Bowel Dis, 18, 2315, 10.1002/ibd.22958 Adeva-Andany, 2017, Significance of L-carnitine for human health, IUBMB Life, 69, 578, 10.1002/iub.1646 Mescka, 2015, L-carnitine supplementation decreases DNA damage in treated VIPD patients, Mutation Res Fundam Mol Mech Mutagen, 775, 43, 10.1016/j.mrfmmm.2015.03.008 Tamai, 1998, Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2, J Biol Chem, 273, 20378, 10.1074/jbc.273.32.20378 Bremer, 1983, Carnitine–metabolism and functions, Physiol Rev, 63, 1420, 10.1152/physrev.1983.63.4.1420 Rebouche, 1992, Carnitine function and requirements during the life cycle, FASEB J, 6, 3379, 10.1096/fasebj.6.15.1464372 Inazu, 2006, Functional expression of the organic cation/carnitine transporter 2 in rat astrocytes, J Neurochem, 97, 424e34, 10.1111/j.1471-4159.2006.03757.x Schomig, 1998, Molecular cloning and characterization of two novel transport proteins from rat kidney, FEBS Lett, 425, 79e86, 10.1016/S0014-5793(98)00203-8 Wu, 1998, cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family, Biochem Biophys Res Commun, 246, 589e95, 10.1006/bbrc.1998.8669 Tamai, 2000, Molecular and functional characterization of organic cation/carnitine transporter family in mice, J Biol Chem, 275, 40064e72, 10.1074/jbc.M005340200 Nakanishi, 2011, Organic cation transporter-mediated renal secretion of ipratropium and tiotropium in rats and humans, Drug Metab Dispos, 39, 117, 10.1124/dmd.110.035402 Nakamura, 2009, Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation /carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption, Mol Pharm, 7, 187, 10.1021/mp900206j Mo, 2014, L-carnitine ester of prednisolone: pharmacokinetic and pharmacodynamic evaluation of a type I prodrug, Int J Pharm, 475, 123, 10.1016/j.ijpharm.2014.08.049 Tune, 1994, Toxicity of cephaloridine to carnitine transport and fatty acid metabolism in rabbit renal cortical mitochondria: structure–activity relationships, J Pharmacol Exp Ther, 270, 873 Hirano, 2006, Mechanism of the inhibitory effect of zwitterionic drugs (levofloxacin and grepafloxacin) on carnitine transporter (OCTN2) in Caco-2 cells, Biochim Biophys Acta Biomembr, 1758, 1743, 10.1016/j.bbamem.2006.07.002 Tamai, 2013, Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and SLC22a21), Biopharm Drug Dispos, 34, 29, 10.1002/bdd.1816 Tamai, 2001, Tsuji. Na+-coupled transport of L-carnitine via high-affinity carnitine transporter OCTN2 and its subcellular localization in kidney, Biochim Biophys Acta, 1512, 273, 10.1016/S0005-2736(01)00328-5 Koepsell, 2007, Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications, Pharm Res, 24, 1227, 10.1007/s11095-007-9254-z Gong, 2002, Identification of OCT6 as a novel organic cation transporter preferentially expressed in hematopoietic cells and leukemias, Exp Hematol, 30, 1162, 10.1016/S0301-472X(02)00901-3 Srinivas, 2007, Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB0,+, Am J Physiol Gastrointest Liver Physiol, 293, G1046, 10.1152/ajpgi.00233.2007 Grube, 2011, Selective regulation of cardiac organic cation transporter novel type 2 (OCTN2) in dilated cardiomyopathy, Am J Pathol, 178, 2547, 10.1016/j.ajpath.2011.02.020 Qu, 2013, Different involvement of promoter methylation in the expression of organic cation/carnitine transporter 2 (OCTN2) in cancer cell lines, PLoS ONE, 8, e76474, 10.1371/journal.pone.0076474 Kato, 2006, Organic cation/carnitine transporter OCTN2 (Slc22a5) is responsible for carnitine transport across apical membranes of small intestinal epithelial cells in mouse, Mol Pharmacol, 70, 829, 10.1124/mol.106.024158 Meier, 2007, Regional distribution of solute carrier mRNA expression along the human intestinal tract, Drug Metab Dispos, 35, 590, 10.1124/dmd.106.013342 Ohashi, 1999, Na(+)- dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance, J Pharmacol Exp Ther, 291, 778 Ohashi, 2002, Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein, J Pharmacol Exp Ther, 302, 1286, 10.1124/jpet.102.036004 Diao, 2011, Synthesis and in vitro characterization of drug conjugates of L-carnitine as potential prodrugs that target human Octn2, J Pharm Sci, 100, 3802, 10.1002/jps.22557 Miller, 2004, Cellular and physiological effects of short-chain fatty acids, Mini Rev Med Chem, 4, 839, 10.2174/1389557043403288 Scheppach, 2004, The butyrate story: old wine in new bottles?, Curr Opin Clin Nutr Metab Care, 7, 563, 10.1097/00075197-200409000-00009 Cavaglieri, 2003, Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes, Life Sci, 73, 1683, 10.1016/S0024-3205(03)00490-9 Kinoshita, 2002, Butyrate reduces colonic paracellular permeability by enhancing PPARgamma activation, Biochem Biophys Res Commun, 293, 827, 10.1016/S0006-291X(02)00294-2 Tong, 2004, Butyrate suppresses Cox-2 activation in colon cancer cells through HDAC inhibition, Biochem Biophys Res Commun, 317, 463, 10.1016/j.bbrc.2004.03.066 Thibault, 2007, Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation, Gastroenterology, 133, 1916, 10.1053/j.gastro.2007.08.041 Cetinkaya, 2006, Effects of L-carnitine on oxidant/antioxidant status in acetic acid-induced colitis, Dig Dis Sci, 51, 488, 10.1007/s10620-006-3160-9 Giancaterini, 2001, Effects of propyonil-L-carnitine topical irrigation in distal ulcerative colitis: a preliminary report, Am J Gastroenterol, 96, 2275, 10.1111/j.1572-0241.2001.03988.x Pasut, 2008, Antitumoral activity of PEG-gemcitabine prodrugs targeted by folic acid, J Control Release, 127, 239, 10.1016/j.jconrel.2008.02.002 Wang, 2014, Enhanced tumor delivery of gemcitabine via PEG-DSPE/TPGS mixed micelles, Mol Pharm, 11, 1140, 10.1021/mp4005904 Zhang, 2013, Systemic delivery of gemcitabine triphosphate via LCP nanoparticles for NSCLC and pancreatic cancer therapy, Biomaterials, 34, 3447, 10.1016/j.biomaterials.2013.01.063 Sun, 2009, Synthesis, transport and pharmacokinetics of 5′-amino acid ester prodrugs of 1-beta-D-arabinofuranosylcytosine, Mol Pharm, 6, 315, 10.1021/mp800200a Kim, 2016, Paclitaxel and curcumin co-bound albumin nanoparticles having antitumor potential to pancreatic cancer, Asian J Pharm Sci, 11, 708, 10.1016/j.ajps.2016.05.005 Halestrap, 1999, The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation, Biochem J, 343, 281, 10.1042/bj3430281 Kyte, 1982, A simple method for displaying the hydropathic character of a protein, J Mol Biol, 157, 105, 10.1016/0022-2836(82)90515-0 Hofmann, 1993, Tmbase-A database of membrane spanning protein segments, Biol Chem Hoppe Seyler, 374, 166 Saier, 1994, Computer-aided analyses of transport protein sequences: gleaning evidence concerning function, structure, biogenesis, and evolution, Microbiol Rev, 58, 71, 10.1128/MR.58.1.71-93.1994 Rahman, 1999, Helix 8 and helix 10 are involved in substrate recognition in the rat monocarboxylate transporter MCT1, Biochemistry, 38, 11577, 10.1021/bi990973f Kim, 1992, cDNA cloning of MEV, a mutant protein that facilitates cellular uptake of mevalonate, and identification of the point mutation responsible for its gain of function, J Biol Chem, 267, 23113, 10.1016/S0021-9258(18)50064-8 Garcia, 1994, cDNA cloning of the human monocarboxylate transporter 1 and chromosomal localization of the SLC16A1 locus to 1p 13.2-p 12, Genomics, 23, 500, 10.1006/geno.1994.1532 Poole, 1992, Identification and partial purification of the erythrocyte lactate transporter, Biochem J, 283, 855, 10.1042/bj2830855 Gali, 2003, The loop between helix 4 and helix 5 in the monocarboxylate transporter MCT1 is important for substrate selection and protein stability, Biochem J, 376, 413, 10.1042/bj20030799 Schuster, 1996, Cloning of the rabbit homologue of mouse ‘basigin’ and rat ‘OX-47’: kidney cell type-specific expression, and regulation in collecting duct cells, Biochim Biophys Acta, 1311, 13, 10.1016/0167-4889(95)00186-7 Kirk, 2000, CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression, EMBO J, 19, 3896, 10.1093/emboj/19.15.3896 Warburg, 1956, On respiratory impairment in cancer cells, Science, 124, 269, 10.1126/science.124.3215.269 Halestrap, 2012, The monocarboxylate transporter family-Structure and functional characterization, IUBMB Life, 64, 1, 10.1002/iub.573 Dimmer, 2000, The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells, Biochem J, 3501, 219, 10.1042/bj3500219 Chiche, 2012, In vivo pH in metabolic-defective Ras- transformed fibroblast tumors: key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH, Int J Cancer, 130, 1511, 10.1002/ijc.26125 Cuff, 2002, Substrate-induced regulation of the human colonic monocarboxylate transporter, MCT1, J Physiol, 539, 361, 10.1113/jphysiol.2001.014241 Halestrap, 2004, The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond, Pflüg Arch Eur J Physiol, 447, 619, 10.1007/s00424-003-1067-2 Pérez-Escuredo, 2016, Monocarboxylate transporters in the brain and in cancer, Biochim Biophys Acta Mol Cell Res, 1863, 2481, 10.1016/j.bbamcr.2016.03.013 Garcia, 1995, cDNA cloning of MCT2, a second monocarboxylate transporter expressed in different cells than MCT1, J Biol Chem, 270, 1843, 10.1074/jbc.270.4.1843 Garcia, 1994, Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle, Cell, 76, 865, 10.1016/0092-8674(94)90361-1 Johannsson, 1997, Cellular and subcellular expression of the monocarboxylate transporter MCT1 in rat heart: a high-resolution immunogold analysis, Circ Res, 80, 400, 10.1161/01.res.0000435856.47954.71 Jackson, 1996, The kinetics, substrate, and inhibitor specificity of the monocarboxylate (lactate) transporter of rat liver cells determined using the fluorescent intracellular pH indicator, 2’,7’-bis(carboxyethyl)-5(6)-carboxyfluores cein, J Biol Chem, 271, 861, 10.1074/jbc.271.2.861 Kirat, 2007, Monocarboxylate transporter 1 (MCT1) in the liver of pre-ruminant and adult bovines, Vet J, 173, 124, 10.1016/j.tvjl.2005.07.005 Ritzhaupt, 1998, Identification and characterization of a monocarboxylate transporter (MCT1) in pig and human colon: its potential to transport L-lactate as well as butyrate, J Cell Physiol, 513, 719 Orsenigo, 1999, A monocarboxylate transporter MCT1 is located at the basolateral pole of rat jejunum, Exp Physiol, 84, 1033, 10.1111/j.1469-445X.1999.01918.x Kirat, 2006, Monocarboxylate transporter 1 gene expression in the ovine gastrointestinal tract, Vet J, 171, 462, 10.1016/j.tvjl.2004.12.009 Welter, 2008, Expression of the monocarboxylate transporter 1 (MCT1) in cells of the porcine intestine, Cell Biol Int, 32, 638, 10.1016/j.cellbi.2008.01.008 Eilertsen, 2014, Monocarboxylate transporters 1-4 in NSCLC: MCT1 is an independent prognostic marker for survival, PLoS ONE, 9, 10.1371/journal.pone.0105038 Bonen, 2001, The expression of lactate transporters (MCT1 and MCT4) in heart and muscle, Eur J Appl Physiol, 86, 6, 10.1007/s004210100516 Lu, 2015, Electro-acupuncture up-regulates astrocytic MCT1 expression to improve neurological deficit in middle cerebral artery occlusion rats, Life Sci, 134, 68, 10.1016/j.lfs.2015.05.014 Cuff, 2002, Substrate induced regulation of the human colnic monocarboxylate transporter, MCT1, J Physiol, 539, 361, 10.1113/jphysiol.2001.014241 Shimoyama, 2007, Expression of monocarboxylate transporter 1 (MCT1) in the dog intestine, J Vet Med Sci, 69, 599, 10.1292/jvms.69.599 Welter, 2008, Expression of the monocarboxylate transporter 1 (MCT1) in cells of the porcine intestine, Cell Biol Int, 32, 599, 10.1016/j.cellbi.2008.01.008 Halestrap, 2013, The SLC16 gene family-structure, role and regulation in health and disease, Mol Aspects Med, 34, 337, 10.1016/j.mam.2012.05.003 Doherty, 2014, Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis, Cancer Res, 74, 908, 10.1158/0008-5472.CAN-13-2034 Itoh, 1998, Transport of phenethicillin into rat intestinal brush border membrane vesicles: role of the monocarboxylic acid transport system, Int J Pharm, 172, 103, 10.1016/S0378-5173(98)00196-3 Utoguchi, 2000, Carrier-mediated transport of valproic acid in BeWo cells, a human trophoblast cell line, Int J Pharm, 195, 115, 10.1016/S0378-5173(99)00398-1 Wu, 2000, Atorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and the proton-monocarboxylic acid cotransporter, Pharm Res, 17, 209, 10.1023/A:1007525616017 Okamura, 2002, Transport and uptake of nateglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1, Br J Pharmacol, 137, 391, 10.1038/sj.bjp.0704875 Cundy, 2004, XP13512 [(+/-)-1-([(alpha-isobutan oyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys, J Pharmacol Exp Ther, 311, 324, 10.1124/jpet.104.067959 Sun YX, Zhao DY, Wang G, Jiang QK, Guo MR, Kan QM, et al. A novel oral prodrug-targeting transporter MCT 1: 5-fluorouracil-dicarboxylate monoester conjugates. 2019; 10.1016/j.ajps. 2019.04.001. Pollack, 1998, Gabapentin as a potential treatment for anxiety disorders, Am J Psychiatry, 155, 992, 10.1176/ajp.155.7.992 Garcia-Borreguero, 2002, Treatment of restless legs syndrome with gabapentin: a doubleblind, cross-over study, Neurology, 59, 1573, 10.1212/WNL.59.10.1573 Guttuso, 2003, Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial, Obstet Gynecol, 101, 337 Wu, 2017, Bioinspired butyrate-functionalized nanovehicles for targeted oral delivery of biomacromolecular drugs, J Control Release, 262, 273, 10.1016/j.jconrel.2017.07.045 Paradis, 1994, Use of pluronic micelles to overcome multidrug resistance, Int J Oncol, 5, 1305 Kabanov, 2002, Pluronic (R) block copolymers as novel polymer therapeutics for drug and gene delivery, J Control Release, 82, 189, 10.1016/S0168-3659(02)00009-3 Batrakova, 2004, Effects of pluronic P85 on GLUT1 and MCT1 transporters in the blood-brain barrier, Pharm Res, 21, 1993, 10.1023/B:PHAM.0000048189.79606.6e