蛋白和肽类物质跨血脑屏障转运研究进展
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摘要
血脑屏障是外周循环系统与大脑组织之间的一个动态的屏障,其对多肽类药物的通透性直接影响了药物作用于中枢神经系统的疗效。随着神经科学、遗传工程等技术的发展,大量蛋白质或多肽类药物得以应用于神经系统疾病,许多蛋白或多肽类药物均有对中枢神经系统的生物活性,而血脑屏障的存在,阻碍了这些物质进入中枢神经系统发挥疗效。本文总结概括了肽类物质的转运机制、促进多肽类药物跨血脑屏障能力的途径以及介绍了已知的能透过血脑屏障蛋白及多肽,希望为蛋白及多肽类中枢神经系统药物提供一些方向。
The blood-brain barrier( BBB) is a dynamic barrier between the peripheral circulatory system and brain tissue,whose permeability to polypeptide drugs has a direct impact on the effect of drugs on the central nervous system( CNS). With the development of neuroscience and genetic engineering technology,a large number of protein and polypeptide drugs have been applied to the treatment of nervous system diseases. Many protein and polypeptide drugs have biological activities on the CNS,but the BBB prevents these substances from entering the CNS and exerting therapeutic effects. The mechanisms of transport of peptides and ways of promoting the penetration of the BBB by polypeptide drugs are summarized in this article and proteins or peptides known to penetrate the BBB are introduced. It is hoped that this paper will provide some direction for the development of CNS drugs.
The blood-brain barrier( BBB) is a dynamic barrier between the peripheral circulatory system and brain tissue,whose permeability to polypeptide drugs has a direct impact on the effect of drugs on the central nervous system( CNS). With the development of neuroscience and genetic engineering technology,a large number of protein and polypeptide drugs have been applied to the treatment of nervous system diseases. Many protein and polypeptide drugs have biological activities on the CNS,but the BBB prevents these substances from entering the CNS and exerting therapeutic effects. The mechanisms of transport of peptides and ways of promoting the penetration of the BBB by polypeptide drugs are summarized in this article and proteins or peptides known to penetrate the BBB are introduced. It is hoped that this paper will provide some direction for the development of CNS drugs.
引文
[1]许锬,施霖,刘瑞璋.脑肿瘤的理化致病因素[J].中国公共卫生,2000,16(7):651-652.
[2]王维琼. 2016年中国恶性肿瘤发病和死亡分析[J].临床医药文献杂志:电子版,2017,4(19):3604-3604.
[3]陈万青,郑荣寿,曾红梅,等. 2011年中国恶性肿瘤发病和死亡分析[J].中国肿瘤,2017,25(1):1-10.
[4]王焱超,梁锐超,方芳.中枢神经系统药物穿透血脑屏障的研究进展[J].华西医学,2015,(7):1351-1356.
[5] Samii A,Bickel U,Stroth U,et al. Blood-brain barrier transport of neuropeptides:analysis with a metabolically stable dermorphin analogue[J]. Am J Physiol,1994,267(1):124-31.
[6] Kastin AJ, Akerstrom V, Pan W. Glial cell line-derived neurotrophic factor does not enter normal mouse brain[J].Neurosci Lett,2003,340(3):239-241.
[7] Pan W,Kastin AJ,Banks WA,et al. Effects of peptides:a cross-listing of peptides and their central actions published in the journal Peptides from 1994 through 1998[J]. Peptides,1999,20(9):1127-38.
[8] Pan W,Kastin AJ. Interactions of IGF-1 with the blood-brain barrier in vivo and in situ[J]. Neuroendocrinology,2000,72(3):171-178.
[9] Deguchi Y,Naito T,Yuge T. Blood-brain barrier transport of125I-labeled basic fibroblast growth factor[J].Pharm Res,2000,17(1):63-69.
[10] Brndli AW,Adamson ED,Simons K. Transcytosis of epidermal growth factor. The epidermal growth factor receptor mediates uptake but not transcytosis[J]. J Biol Chem, 1991, 266(13):8560.
[11] Pan W,Kastin AJ,Brennan JM. Saturable entry of leukemia inhibitory factor from blood to the central nervous system[J]. J Neuroimmunol,2000,106(1-2):172-180.
[12] Kurek JB,Radford AJ,Crump DE,et al. LIF(AM424),a promising growth factor for the treatment of ALS[J]. J Neurol Sci,1998,160(3):S106-S113.
[13] Kastin AJ,Akerstrom V. Differential interactions of urocortin/corticotropin-releasing hormone peptides with the blood-brain barrier[J]. Neuroendocrinol,2002,75(6):367-374.
[14] Banks WA,Kastin AJ,Jaspan JB. Regional variation in transport of pancreatic polypeptide across the blood-brain barrier of mice[J]. Pharmacol Biochem Be,1995,51(1):139-47.
[15] Kastin AJ,Akerstrom V,Hackler L. Food Deprivation Decreases Blood Galanin-Like Peptide and Its Rapid Entry into the Brain[J]. Neuroendocrinol,2001,74(6):423-432.
[16] Kastin AJ,Akerstrom V,Hackler L,et al. Adrenomedullin and the blood-brain barrier[J]. Horm Metab Res,2001,33(01):19-25.
[17] Kastin AJ,Fasold MB,Smith RR,et al. Saturable brain-toblood transport of endomorphins[J]. Exp Brain Res,2001,139(1):70-75.
[18] Calvo P,Gouritin B,Villarroya H,et al. Quantification and localization of PEGylated polycyanoacrylate nanoparticles in brain and spinal cord during experimental allergic encephalomyelitis in the rat[J]. Eur J Neurosci,2010,15(8):1317-1326.
[19] Martins JM,Banks WA,Kastin AJ. Transport of CRH from mouse brain directly affects peripheral production of betaendorphin by the spleen[J]. Am J Physiol,1997,273(1):1083-9.
[20] Neuwelt EA, Barnett PA, Hellstr9m I, et al. Delivery of melanoma-associated immunoglobulin monoclonal antibody and fab fragments to normal brain utilizing osmotic blood-brain barrier disruption[J]. Cancer Res,1988,48(17):4725-4729.
[21] Poduslo JF,Curran GL. Glycation increases the permeability of proteins across the blood-nerve and blood-brain barriers[J]. Mol Brain Res,1994,23(1-2):157-162.
[22] Chikhale EG,Ng KY,Burton PS,et al. Hydrogen bonding potential as a determinant of the in vitro and in situ blood-brain barrier permeability of peptides[J]. Pharm Res,1994,11(3):412-9.
[23] Banks WA,Kastin AJ. Peptide transport systems for opiates across the blood-brain barrier[J]. Am J Physiol,1990,259(1):1-10.
[24] Kastin AJ,Hahn K,Zadina JE. Regional differences in peptide degradation by rat cerebral microvessels:a potential novel regulatory mechanism for communication between blood and brain[J]. Life Sci,2001,69(11):1305-1312.
[25] Li Q,Sai Y,Kato Y,et al. Transporter-mediated renal handling of nafamostat mesilate[J]. J Pharm Sci,2004,93(2):262-272.
[26] Akta Y,Yemisci M,Andrieux K,et al. Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26[J]. Bioconjugate Chem,2005,16(6):1503-1511.
[27] Sakurada S, Hayashi T, Yuhki M, et al. Differential antinociceptive effects induced by intrathecally administered endomorphin-1 and endomorphin-2 in the mouse[J]. Eur J Pharmacol,2001,427(3):203-210.
[28]许金明,郑惠民.肽类物质的跨血脑屏障转运研究进展[J].中国药理学通报,1998,(s1):34-37.
[29] Chikhale EG,Burton PS,Borchardt RT. The effect of verapamil on the transport of peptides across the blood-brain barrier in rats:kinetic evidence for an apically polarized efflux mechanism[J]. J Pharmacol Exp Ther,1995,273(1):298-303.
[30] Dhanasekaran M,Polt R. New prospects for glycopeptide based analgesia:glycoside-induced penetration of the blood-brain barrier[J]. Curr Drug Deliv,2005,2(1):59-73.
[31] Poduslo JF,Curran GL. Polyamine modification increases the permeability of proteins at the blood-nerve and blood-brain barriers[J]. J Neurochem,2010,66(4):1599-1609.
[32] Lowenstein PR,Castro MG. Progress and challenges in viral vector-mediated gene transfer to the brain[J]. Curr Opin Mol Ther,2002,4(4):359-371.
[33] Muldoon LL, Nilaver G, Kroll RA, et al. Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus,herpesvirus,and iron oxide particles to normal rat brain[J]. Am J Pathol,1995,147(6):1840-1851.
[34] Dijkhuizen P,Zhang Y,Anderson P,et al. Regrowth of injured dorsal root axons into the spinal cord by adenoviral vectormediated NT-3 delivery[J]. J Neurosci Res,1998,54(4):554-562.
[35] Boado RJ,Zhang Y,Zhang Y,et al. GDNF fusion protein for targeted-drug delivery across the human blood– brain barrier[J]. Biotechnol Bioeng,2010,100(2):387-396.
[36] Kang YS,Pardridge WM. Brain delivery of biotin bound to a conjugate of neutral avidin and cationized human albumin[J].Pharm Res,1994,11(9):1257-1264.
[37] Wu D,Pardridge WM. Central nervous system pharmacologic effect in conscious rats after intravenous injection of a biotinylated vasoactive intestinal peptide analog coupled to a blood-brain barrier drug delivery system[J]. J Pharmacol Exp Ther,1996,279(1):77-83.
[38]黄秉仁.神经系统多肽(蛋白)药物研发现状与前景[J].生物产业技术,2009,(3):52-67.
[39]聂子涵,李俊发,赵丽.血脑屏障细胞体外培养模型研究进展[J].中国药学杂志,2018,53(3):165-168.
[40]黄丹,丛喆,徐珮,等. HIV/SIV入侵血脑屏障的分子机制探讨[J].中国比较医学杂志,2015,25(11):81-85.
[41] Bicker J,Alves G,Fortuna A,et al. Blood-brain barrier models and their relevance for a successful development of CNS drug delivery systems:a review[J].Eur J Pharm Biopharm,2014,87(3):409-432.
[42] Kikuchi R,De Morais SM,Kalvass JC. In vitro P-glycoprotein efflux ratio can predict the in vivo brain penetration regardless of biopharmaceutics drug disposition classification system class[J].Drug Metab Dispos,2013,41(12):2012-2017.
[43] Kamiichi A,Furihata T,Kishida S,et al. Establishment of a new conditionally immortalized cell line from human brain microvascular endothelial cells:A promising tool for human blood-brain barrier studies[J]. Brain Res,2012,1488(2):113-122.
[44] Tang T,Guan Z, Wenfeng YU, et al. Primary Culture of Cerebral Cortical Astrocytes from SD Rats in vitro[J]. Journal of Guiyang Medical College,2014,39(2):158-161.
[45] Gaillard PJ,Voorwinden LH,Vu D,et al. Astrocytes increase the functional expression of P-glycoprotein in an in vitro model of the blood-brain barrier[J]. Pharm Res,2000,17(10):1198.
[46]张靖华,樊怡,马健飞,等.小鼠腹膜透析模型的构建及腹膜转运关键蛋白的表达[J].中国比较医学杂志,2008,18(4):18-20.
[47] Abbott NJ. Astrocyte-endothelial interactions at the blood-brain barrier[J]. Nat Rev Neurosci,2006,7(1):41-53.
[48]王超,张会欣,邢邯英,等.通心络胶囊抑制p38 MAPK磷酸化抑制糖尿病周围神经病变小鼠氧化应激[J].中国药理学通报,2015,(5):726-730.
[49] Tarbell JM. Shear stress and the endothelial transport barrier[J].Cardiovas Res,2010,87(2):320.
[50] Cucullo L,Couraud PO,Weksler B,et al. Immortalized human brain endothelial cells and flow-based vascular modeling:a marriage of convenience for rational neurovascular studies[J]. J Cerebr Blood F Met,2008,28(2):312-328.
[51] Booth R,Kim H. Characterization of a microfluidic in vitro model of the blood-brain barrier(μBBB)[J]. Lab Chip,2012,12(10):1784-1792.
[52] He Y,Yao Y,Tsirka SE,et al. Cell-culture models of the blood-brain barrier[J]. Stroke,2014,45(8):2514-2526.
[53]沙保勇,刘洁,景晓红,等.血脑屏障体外模型研发[J].生命科学,2018,30(3):310-318.
[2]王维琼. 2016年中国恶性肿瘤发病和死亡分析[J].临床医药文献杂志:电子版,2017,4(19):3604-3604.
[3]陈万青,郑荣寿,曾红梅,等. 2011年中国恶性肿瘤发病和死亡分析[J].中国肿瘤,2017,25(1):1-10.
[4]王焱超,梁锐超,方芳.中枢神经系统药物穿透血脑屏障的研究进展[J].华西医学,2015,(7):1351-1356.
[5] Samii A,Bickel U,Stroth U,et al. Blood-brain barrier transport of neuropeptides:analysis with a metabolically stable dermorphin analogue[J]. Am J Physiol,1994,267(1):124-31.
[6] Kastin AJ, Akerstrom V, Pan W. Glial cell line-derived neurotrophic factor does not enter normal mouse brain[J].Neurosci Lett,2003,340(3):239-241.
[7] Pan W,Kastin AJ,Banks WA,et al. Effects of peptides:a cross-listing of peptides and their central actions published in the journal Peptides from 1994 through 1998[J]. Peptides,1999,20(9):1127-38.
[8] Pan W,Kastin AJ. Interactions of IGF-1 with the blood-brain barrier in vivo and in situ[J]. Neuroendocrinology,2000,72(3):171-178.
[9] Deguchi Y,Naito T,Yuge T. Blood-brain barrier transport of125I-labeled basic fibroblast growth factor[J].Pharm Res,2000,17(1):63-69.
[10] Brndli AW,Adamson ED,Simons K. Transcytosis of epidermal growth factor. The epidermal growth factor receptor mediates uptake but not transcytosis[J]. J Biol Chem, 1991, 266(13):8560.
[11] Pan W,Kastin AJ,Brennan JM. Saturable entry of leukemia inhibitory factor from blood to the central nervous system[J]. J Neuroimmunol,2000,106(1-2):172-180.
[12] Kurek JB,Radford AJ,Crump DE,et al. LIF(AM424),a promising growth factor for the treatment of ALS[J]. J Neurol Sci,1998,160(3):S106-S113.
[13] Kastin AJ,Akerstrom V. Differential interactions of urocortin/corticotropin-releasing hormone peptides with the blood-brain barrier[J]. Neuroendocrinol,2002,75(6):367-374.
[14] Banks WA,Kastin AJ,Jaspan JB. Regional variation in transport of pancreatic polypeptide across the blood-brain barrier of mice[J]. Pharmacol Biochem Be,1995,51(1):139-47.
[15] Kastin AJ,Akerstrom V,Hackler L. Food Deprivation Decreases Blood Galanin-Like Peptide and Its Rapid Entry into the Brain[J]. Neuroendocrinol,2001,74(6):423-432.
[16] Kastin AJ,Akerstrom V,Hackler L,et al. Adrenomedullin and the blood-brain barrier[J]. Horm Metab Res,2001,33(01):19-25.
[17] Kastin AJ,Fasold MB,Smith RR,et al. Saturable brain-toblood transport of endomorphins[J]. Exp Brain Res,2001,139(1):70-75.
[18] Calvo P,Gouritin B,Villarroya H,et al. Quantification and localization of PEGylated polycyanoacrylate nanoparticles in brain and spinal cord during experimental allergic encephalomyelitis in the rat[J]. Eur J Neurosci,2010,15(8):1317-1326.
[19] Martins JM,Banks WA,Kastin AJ. Transport of CRH from mouse brain directly affects peripheral production of betaendorphin by the spleen[J]. Am J Physiol,1997,273(1):1083-9.
[20] Neuwelt EA, Barnett PA, Hellstr9m I, et al. Delivery of melanoma-associated immunoglobulin monoclonal antibody and fab fragments to normal brain utilizing osmotic blood-brain barrier disruption[J]. Cancer Res,1988,48(17):4725-4729.
[21] Poduslo JF,Curran GL. Glycation increases the permeability of proteins across the blood-nerve and blood-brain barriers[J]. Mol Brain Res,1994,23(1-2):157-162.
[22] Chikhale EG,Ng KY,Burton PS,et al. Hydrogen bonding potential as a determinant of the in vitro and in situ blood-brain barrier permeability of peptides[J]. Pharm Res,1994,11(3):412-9.
[23] Banks WA,Kastin AJ. Peptide transport systems for opiates across the blood-brain barrier[J]. Am J Physiol,1990,259(1):1-10.
[24] Kastin AJ,Hahn K,Zadina JE. Regional differences in peptide degradation by rat cerebral microvessels:a potential novel regulatory mechanism for communication between blood and brain[J]. Life Sci,2001,69(11):1305-1312.
[25] Li Q,Sai Y,Kato Y,et al. Transporter-mediated renal handling of nafamostat mesilate[J]. J Pharm Sci,2004,93(2):262-272.
[26] Akta Y,Yemisci M,Andrieux K,et al. Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26[J]. Bioconjugate Chem,2005,16(6):1503-1511.
[27] Sakurada S, Hayashi T, Yuhki M, et al. Differential antinociceptive effects induced by intrathecally administered endomorphin-1 and endomorphin-2 in the mouse[J]. Eur J Pharmacol,2001,427(3):203-210.
[28]许金明,郑惠民.肽类物质的跨血脑屏障转运研究进展[J].中国药理学通报,1998,(s1):34-37.
[29] Chikhale EG,Burton PS,Borchardt RT. The effect of verapamil on the transport of peptides across the blood-brain barrier in rats:kinetic evidence for an apically polarized efflux mechanism[J]. J Pharmacol Exp Ther,1995,273(1):298-303.
[30] Dhanasekaran M,Polt R. New prospects for glycopeptide based analgesia:glycoside-induced penetration of the blood-brain barrier[J]. Curr Drug Deliv,2005,2(1):59-73.
[31] Poduslo JF,Curran GL. Polyamine modification increases the permeability of proteins at the blood-nerve and blood-brain barriers[J]. J Neurochem,2010,66(4):1599-1609.
[32] Lowenstein PR,Castro MG. Progress and challenges in viral vector-mediated gene transfer to the brain[J]. Curr Opin Mol Ther,2002,4(4):359-371.
[33] Muldoon LL, Nilaver G, Kroll RA, et al. Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus,herpesvirus,and iron oxide particles to normal rat brain[J]. Am J Pathol,1995,147(6):1840-1851.
[34] Dijkhuizen P,Zhang Y,Anderson P,et al. Regrowth of injured dorsal root axons into the spinal cord by adenoviral vectormediated NT-3 delivery[J]. J Neurosci Res,1998,54(4):554-562.
[35] Boado RJ,Zhang Y,Zhang Y,et al. GDNF fusion protein for targeted-drug delivery across the human blood– brain barrier[J]. Biotechnol Bioeng,2010,100(2):387-396.
[36] Kang YS,Pardridge WM. Brain delivery of biotin bound to a conjugate of neutral avidin and cationized human albumin[J].Pharm Res,1994,11(9):1257-1264.
[37] Wu D,Pardridge WM. Central nervous system pharmacologic effect in conscious rats after intravenous injection of a biotinylated vasoactive intestinal peptide analog coupled to a blood-brain barrier drug delivery system[J]. J Pharmacol Exp Ther,1996,279(1):77-83.
[38]黄秉仁.神经系统多肽(蛋白)药物研发现状与前景[J].生物产业技术,2009,(3):52-67.
[39]聂子涵,李俊发,赵丽.血脑屏障细胞体外培养模型研究进展[J].中国药学杂志,2018,53(3):165-168.
[40]黄丹,丛喆,徐珮,等. HIV/SIV入侵血脑屏障的分子机制探讨[J].中国比较医学杂志,2015,25(11):81-85.
[41] Bicker J,Alves G,Fortuna A,et al. Blood-brain barrier models and their relevance for a successful development of CNS drug delivery systems:a review[J].Eur J Pharm Biopharm,2014,87(3):409-432.
[42] Kikuchi R,De Morais SM,Kalvass JC. In vitro P-glycoprotein efflux ratio can predict the in vivo brain penetration regardless of biopharmaceutics drug disposition classification system class[J].Drug Metab Dispos,2013,41(12):2012-2017.
[43] Kamiichi A,Furihata T,Kishida S,et al. Establishment of a new conditionally immortalized cell line from human brain microvascular endothelial cells:A promising tool for human blood-brain barrier studies[J]. Brain Res,2012,1488(2):113-122.
[44] Tang T,Guan Z, Wenfeng YU, et al. Primary Culture of Cerebral Cortical Astrocytes from SD Rats in vitro[J]. Journal of Guiyang Medical College,2014,39(2):158-161.
[45] Gaillard PJ,Voorwinden LH,Vu D,et al. Astrocytes increase the functional expression of P-glycoprotein in an in vitro model of the blood-brain barrier[J]. Pharm Res,2000,17(10):1198.
[46]张靖华,樊怡,马健飞,等.小鼠腹膜透析模型的构建及腹膜转运关键蛋白的表达[J].中国比较医学杂志,2008,18(4):18-20.
[47] Abbott NJ. Astrocyte-endothelial interactions at the blood-brain barrier[J]. Nat Rev Neurosci,2006,7(1):41-53.
[48]王超,张会欣,邢邯英,等.通心络胶囊抑制p38 MAPK磷酸化抑制糖尿病周围神经病变小鼠氧化应激[J].中国药理学通报,2015,(5):726-730.
[49] Tarbell JM. Shear stress and the endothelial transport barrier[J].Cardiovas Res,2010,87(2):320.
[50] Cucullo L,Couraud PO,Weksler B,et al. Immortalized human brain endothelial cells and flow-based vascular modeling:a marriage of convenience for rational neurovascular studies[J]. J Cerebr Blood F Met,2008,28(2):312-328.
[51] Booth R,Kim H. Characterization of a microfluidic in vitro model of the blood-brain barrier(μBBB)[J]. Lab Chip,2012,12(10):1784-1792.
[52] He Y,Yao Y,Tsirka SE,et al. Cell-culture models of the blood-brain barrier[J]. Stroke,2014,45(8):2514-2526.
[53]沙保勇,刘洁,景晓红,等.血脑屏障体外模型研发[J].生命科学,2018,30(3):310-318.