Original articles
Jingyi Li, Yaqi Zhang, Miaorong Yu, Aohua Wang, Yu Qiu, Weiwei Fan, Lars Hovgaard, Mingshi Yang, Yiming Li, Rui Wang, Xiuying Li, Yong Gan. The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1460-1472

The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery
Jingyi Lia,b, Yaqi Zhangb,c, Miaorong Yub, Aohua Wangb,c, Yu Qiub,c, Weiwei Fanb, Lars Hovgaardd, Mingshi Yange, Yiming Lia, Rui Wanga, Xiuying Lif, Yong Ganb,c,g
a. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;
b. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
c. University of Chinese Academy of Sciences, Beijing 100049, China;
d. Oral Formulation Development, Novo Nordisk A/S, Maalov 2760, Denmark;
e. Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark;
f. University of Texas at Dallas, Richardson, TX 75080, USA;
g. NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, National Institutes for Food and Drug Control, Beijing 100050, China
Abstract:
Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores. In this study, we demonstrate that the upregulated intestinal transporter (PCFT), which reaches a maximum of 12.3-fold expression in the intestinal epithelial cells of diabetic rats, mediates the uptake of the folic acid-grafted nanoparticles (FNP). Specifically, the upregulated PCFT could exert its function to mediate the endocytosis of FNP and efficiently stimulate the traverse of FNP across enterocytes by the lysosome-evading pathway, Golgi-targeting pathway and basolateral exocytosis, featuring a high oral insulin bioavailability of 14.4% in the diabetic rats. Conversely, in cells with relatively low PCFT expression, the positive surface charge contributes to the cellular uptake of FNP, and FNP are mainly degraded in the lysosomes. Overall, we emphasize that the upregulated intestinal transporters could direct the uptake of ligand-modified nanoparticles by mediating the endocytosis and intracellular trafficking of ligand-modified nanoparticles via the transporter-mediated pathway. This study may also theoretically provide insightful guidelines for the rational design of transporter-targeted nanoparticles to achieve efficient drug delivery in diverse diseases.
Key words:    Ligand-modified nanoparticles    Transporter    Proton-coupled folate transporter    Expression level    Endocytosis    Intracellular trafficking    Diabetes    Oral insulin delivery   
Received: 2021-05-17     Revised: 2021-07-10
DOI: 10.1016/j.apsb.2021.07.024
Funds: The authors thank the financial support from the National Natural Science Foundation of China (NSFC, No. 81773651, 82025032, and 81803445, China), NN-CAS foundation, National Key R&D Program of China (No. 2020YFE0201700, China), and Major International Joint Research Project of Chinese Academy of Sciences (No. 153631KYSB20190020, China). We would like to thank Dr. Ulrik Lytt Rahbek from Novo Nordisk A/S, Denmark, for helpful discussion about folate receptors and transporters. We also thank the National Center for Protein Science Shanghai for two-photon intravital imaging of experimental rats.
Corresponding author: Rui Wang,E-mai:wr@shutcm.edu.cn;Xiuying Li,E-mai:Xiuying.Li@utdallas.edu;Yong Gan,E-mai:ygan@simm.ac.cn     Email:wr@shutcm.edu.cn;Xiuying.Li@utdallas.edu;ygan@simm.ac.cn
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Jingyi Li
Yaqi Zhang
Miaorong Yu
Aohua Wang
Yu Qiu
Weiwei Fan
Lars Hovgaard
Mingshi Yang
Yiming Li
Rui Wang
Xiuying Li
Yong Gan

References:
[1] Lundquist P, Artursson P. Oral absorption of peptides and nanoparticles across the human intestine: opportunities, limitations and studies in human tissues. Adv Drug Deliv Rev 2016; 106: 256-276
[2] Safari H, Kelley WJ, Saito E, Kaczorowski N, Carethers L, Shea LD, et al. Neutrophils preferentially phagocytose elongated particles-an opportunity for selective targeting in acute inflammatory diseases. Sci Adv 2020; 6: eaba1474
[3] Bellini M, Riva B, Tinelli V, Rizzuto MA, Salvioni L, Colombo M, et al. Engineered ferritin nanoparticles for the bioluminescence tracking of nanodrug delivery in cancer. Small 2020; 16: e2001450
[4] Wang SH, Dormidontova EE. Nanoparticle design optimization for enhanced targeting: monte carlo simulations. Biomacromolecules 2010; 11: 1785-1795
[5] Qu Y, Wu ZT, Liu Y, Lin JH, Zhang L, Luo XL. Impact of double-chain surfactant stabilizer on the free active surface sites of gold nanoparticles. Mol Catal 2021; 501: 111377
[6] Webster P, Saito K, Cortez J, Ramirez C, Baum MM. Concentrative nucleoside transporter 3 is located on microvilli of vaginal epithelial cells. ACS Omega 2020; 5: 20882-20889
[7] Hu NJ, Iwata S, Cameron AD, Drew D. Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT. Nature 2011; 478: 408-411
[8] Park J, Choi JU, Kim K, Byun Y. Bile acid transporter mediated endocytosis of oral bile acid conjugated nanocomplex. Biomaterials 2017; 147: 145-154
[9] Fan WW, Xia DN, Zhu QL, Li XY, He SF, Zhu CL, et al. Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery. Biomaterials 2018; 151: 13-23
[10] Drozdzik M, Czekawy I, Oswald S, Drozdzik A. Intestinal drug transporters in pathological states: an overview. Pharmacol Rep 2020; 72: 1173-1197
[11] Erdmann P, Bruckmueller H, Martin P, Busch D, Haenisch S, Muller J, et al. Dysregulation of mucosal membrane transporters and drug-metabolizing enzymes in ulcerative colitis. J Pharm Sci 2019; 108: 1035-1046
[12] Jahnel J, Fickert P, Hauer AC, Hogenauer C, Avian A, Trauner M. Inflammatory bowel disease alters intestinal bile acid transporter expression. Drug Metab Dispos 2014; 42: 1423-1431
[13] Lloret-Linares C, Miyauchi E, Luo HL, Labat L, Bouillot JL, Poitou C, et al. Oral morphine pharmacokinetic in obesity: the role of P-glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 jejunal contents and obesity-associated biomarkers. Mol Pharm 2016; 13: 766-773
[14] Miyauchi E, Tachikawa M, Decleves X, Uchida Y, Bouillot JL, Poitou C, et al. Quantitative atlas of cytochrome P450, UDP-glucuronosyltransferase, and transporter proteins in jejunum of morbidly obese subjects. Mol Pharm 2016; 13: 2631-2640
[15] Sugimoto R, Watanabe H, Ikegami K, Enoki Y, Imafuku T, Sakaguchi Y, et al. Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism. Kidney Int 2017; 91: 658-670
[16] Pan Y, Omori K, Ali I, Tachikawa M, Terasaki T, Brouwer KLR, et al. Altered expression of small intestinal drug transporters and hepatic metabolic enzymes in a mouse model of familial Alzheimer’s disease. Mol Pharm 2018; 15: 4073-4083
[17] Pote MS, Viswanathan G, Kesavan V. Increased intestinal folate absorption in experimental diabetes. J Clin Biochem Nutr 1998; 25: 25-30
[18] Said HM, Ghishan FK, Murrell JE. Intestinal transport of 5-methyltetrahydrofolate in streptozotocin-induced diabetes mellitus in the rat. Diabetes Res 1986; 3: 363-367
[19] Kamen BA, Smith AK. A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev 2004; 56: 1085-1097
[20] Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 2006; 127: 917-928
[21] Sarmento B, Martins S, Ferreira D, Souto EB. Oral insulin delivery by means of solid lipid nanoparticles. Int J Nanomedicine 2007; 2: 743-749
[22] Pan D, Das A, Liu D, Veazey RS, Pahar B. Isolation and characterization of intestinal epithelial cells from normal and SIV-infected rhesus macaques. PLoS One 2012; 7: e30247
[23] Yang SJ, Lin FH, Tsai KC, Wei MF, Tsai HM, Wong JM, et al. Folic acid-conjugated chitosan nanoparticles enhanced protoporphyrin IX accumulation in colorectal cancer cells. Bioconjugate Chem 2010; 21: 679-689
[24] Diebold Y, Jarrin M, Saez V, Carvalho ELS, Orea M, Calonge M, et al. Ocular drug delivery by liposome-chitosan nanoparticle complexes (LCS-NP). Biomaterials 2007; 28: 1553-1564
[25] Jing LJ, Shao SM, Wang Y, Yang YB, Yue XL, Dai ZF. Hyaluronic acid modified hollow prussian blue nanoparticles loading 10-hydroxycamptothecin for targeting thermochemotherapy of cancer. Theranostics 2016; 6: 40-53
[26] Chen F, Goel S, Valdovinos HF, Luo H, Hernandez R, Barnhart TE, et al. In vivo integrity and biological fate of chelator-free zirconium-89-labeled mesoporous silica nanoparticles. Acs Nano 2015; 9: 7950-7959
[27] Lin YH, Mi FL, Chen CT, Chang WC, Peng SF, Liang HF, et al. Preparation and characterization of nanoparticles shelled with chitosan for oral insulin delivery. Biomacromolecules 2007; 8: 146-152
[28] Furumiya M, Yamashiro T, Inoue K, Nishijima C, Ohta K, Hayashi Y, et al. Sustained inhibition of proton-coupled folate transporter by myricetin. Drug Metab Pharmacokinet 2015; 30: 154-159
[29] Yamashiro T, Ohta K, Inoue K, Furumiya M, Hayashi Y, Yuasa H. Kinetic and time-dependent features of sustained inhibitory effect of myricetin on folate transport by proton-coupled folate transporter. Drug Metab Pharmacokinet 2015; 30: 341-346
[30] Roger E, Lagarce F, Garcion E, Benoit JP. Lipid nanocarriers improve paclitaxel transport throughout human intestinal epithelial cells by using vesicle-mediated transcytosis. J Controlled Release 2009; 140: 174-181
[31] Jintapattanakit A, Junyaprasert VB, Kissel T. The role of mucoadhesion of trimethyl chitosan and PEGylated trimethyl chitosan nanocomplexes in insulin uptake. J Pharm Sci 2010; 98: 4818-4830
[32] Zhao RB, Diop-Bove N, Visentin M, Goldman ID. Mechanisms of membrane transport of folates into cells and across epithelia. Annu Rev Nutr 2011; 31: 177-201
[33] Alam C, Hoque MT, Finnell RH, Goldman ID, Bendayan R. Regulation of reduced folate carrier (RFC) by vitamin D receptor at the blood-brain barrier. Mol Pharm 2017; 14: 3848-3858
[34] Boshnjaku V, Shim KW, Tsurubuchi T, Ichi S, Szany EV, Xi GF, et al. Nuclear iocalization of folate receptor alpha: a new role as a transcription factor. Sci Rep 2012; 2: 980
[35] Biabanikhankahdani R, Alitheen NBM, Ho KL, Tan WS. pH-Responsive virus-like nanoparticles with enhanced tumour-targeting ligands for cancer drug delivery. Sci Rep 2016; 6: 37891
[36] Jones SK, Sarkar A, Feldmann DP, Hoffmann P, Merkel OM. Revisiting the value of competition assays in folate receptor-mediated drug delivery. Biomaterials 2017; 138: 35-45
[37] Jin H, Pi J, Yang F, Jiang JH, Wang XP, Bai HH, et al. Folate-chitosan nanoparticles loaded with ursolic acid confer anti-breast cancer activities in vitro and in vivo. Sci Rep 2016; 6: 30782
[38] Zhou Y, Chen JH, Wang H, Wang CX, Zhang JY, Tao YW, et al. Synthesis and characterization of folate-poly(ethylene glycol) chitosan graft-polyethylenimine as a non-viral carrier for tumor-targeted gene delivery. Afr J Biotechnol 2011; 10: 6120-6129
[39] Chanphai P, Konka V, Tajmir-Riahi HA. Folic acid-chitosan conjugation: a new drug delivery tool. J Mol Liq 2017; 238: 155-159
[40] Yang CX, Gao S, Kjems J. Folic acid conjugated chitosan for targeted delivery of siRNA to activated macrophages in vitro and in vivo. J Mater Chem B 2014; 2: 8608-8615
[41] Yamashiro T, Yasujima T, Ohta K, Inoue K, Yuasa H. Identification of the amino acid residue responsible for the myricetin sensitivity of human proton-coupled folate transporter. Sci Rep 2019; 9: 18105
[42] Peng SF, Tseng MT, Ho YC, Wei MC, Liao ZX, Sung HW. Mechanisms of cellular uptake and intracellular trafficking with chitosan/DNA/poly(γ-glutamic acid) complexes as a gene delivery vector. Biomaterials 2011; 32: 239-248
[43] Kaksonen M, Roux A. Mechanisms of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol 2018; 19: 313-326
[44] Zhang XW, Qi JP, Lu Y, He W, Li XY, Wu W. Biotinylated liposomes as potential carriers for the oral delivery of insulin. Nanomedicine 2014; 10: 167-176
[45] He ZY, Santos JL, Tian HK, Huang HH, Hu YZ, Liu LX, et al. Scalable fabrication of size-controlled chitosan nanoparticles for oral delivery of insulin. Biomaterials 2017; 130: 28-41
[46] Shrestha N, Araujo F, Shahbazi MA, MaKila E, Gomes MJ, Herranz-Blanco B, et al. Drug delivery: thiolation and cell-penetrating peptide surface functionalization of porous silicon nanoparticles for oral delivery of insulin. Adv Funct Mater 2016; 26: 3374
[47] Yeh TH, Hsu LW, Tseng MT, Lee PL, Sonjae K, Ho YC, et al. Mechanism and consequence of chitosan-mediated reversible epithelial tight junction opening. Biomaterials 2011; 32: 6164-6173
[48] Linz G, Djeljadini S, Steinbeck L, Kose G, Kiessling F, Wessling M. Cell barrier characterization in transwell inserts by electrical impedance spectroscopy. Biosens Bioelectron 2020; 165: 112345
[49] Bharali DJ, Lucey DW, Jayakumar H, Pudavar HE, Prasad PN. Folate-receptor-mediated delivery of InP quantum dots for bioimaging using confocal and two-photon microscopy. J Am Chem Soc 2005; 127: 11364-11371
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