中樞神經系統藥物穿透血腦屏障的研究進展_West China Medical Journal

Authors：

 王焱超 , 梁銳超 ,  方芳

四川大學華西醫院神經外科（成都 610041）;

Corresponding?author：

方芳, Email: merrisn@hotmail.com

Keywords：

血腦屏障; 藥物治療; 轉運

DOI：

10.7507/1002-0179.20150391

Video：

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血腦屏障通過限制化合物進入中樞神經系統而維持神經系統內環境的相對穩定，并保護神經細胞免受有害物質侵害。但同時血腦屏障也限制了血液所運載的化合物與正常新陳代謝所必需的營養物質到達中樞神經系統所需的通路。這種嚴格限制的存在導致藥物難以進入中樞神經系統，這成為當前中樞神經系統疾病藥物治療的關鍵瓶頸。因此，人們研發出了許多提升中樞神經系統內藥物濃度的新方法。現就用于提高血液中藥物穿透血腦屏障效率的物理方法、藥理學方法以及生理學方法研究進展作一綜述。

Citation： 王焱超, 梁銳超, 方芳. 中樞神經系統藥物穿透血腦屏障的研究進展. West China Medical Journal, 2015, 30(7): 1351-1356. doi: 10.7507/1002-0179.20150391 Copy

1.	Ehrlich P. Das sauerstoff-Bedürfnis des organismus:eine farbanalytische studie[M]. Berlin:Hirschwald, 1885:3-16.
2.	Pardridge WM. Blood-brain barrier delivery[J]. Drug Discov Today, 2007, 12(1/2):54-61.
3.	Blasberg RG, Patlak C, Fenstermacker JD. Intrathecal chemotherapy:brain tissue profiles after verntriculocisternal perfusion[J]. J Pharmacol Exp Ther, 1975, 195(1):73-83.
4.	Pardridge WM. The blood-brain barrier:bottleneck in brain drug development[J]. NeuroRx, 2005, 2(1):3-14.
5.	Pardridge WM. Drug targeting to the brain[J]. Pharm Res, 2007, 24(9):1733-1744.
6.	Bobo RH, Laske DW, Akbasak A, et al. Convection-enhanced delivery of macromolecules in the brain[J]. Proc Natl Acad Sci USA, 1994, 91(6):2076-2080.
7.	Vandergrift WA, Patel SJ, Nicholas JS, et al. Convection-enhanced delivery of immunotoxins and radioisotopes for treatment of malignant gliomas[J]. Neurosurg Focus, 2006, 20(4):E13.
8.	Fung LK, Ewend MG, Sills A, et al. Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain[J]. Cancer Res, 1998, 58(4):672-684.
9.	Fortin D, Desjardins A, Benko A, et al. Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors:the Sherbrooke experience[J]. Cancer, 2005, 103(12):2606-2615.
10.	Hynynen K, Mcdannold N, Vykhodtseva N, et al. Noninvasive Mr imaging-guided focal opening of the blood-brain barrier in rabbits[J]. Radiology, 2001, 220(3):640-646.
11.	Gabathuler R. Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases[J]. Neurobiol Dis, 2010, 37(1):48-57.
12.	Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings[J]. Adv Drug Deliv Rev, 2001, 46(1/2/3):3-26.
13.	Bradley MO, Webb NL, Anthony FH, et al. Tumor targeting by covalent conjugation of a natural fatty acid to paclitaxel[J]. Clin Cancer Res, 2001, 7(10):3229-3238.
14.	Batra kova EV, Kabanov AV. Pluronic block copolymers:evolution of drug delivery concept from inert nanocarriers to biological response modifiers[J]. J Control Release, 2008, 130(2):98-106.
15.	Qu X, Khutoryanskiy VV, Stewart A, et al. Carbohydrate-based micelle clusters which enhance hydrophobic drug bioavailability by up to 1 order of magnitude[J]. Biomacromolecules, 2006, 7(12):3452-3459.
16.	Allen DD, Lockman PR, Roder KE, et al. Active transport of highaffinity choline and nicotine analogs into the central nervous system by the blood-brain barrier choline transporter[J]. J Pharmacol Exp Ther, 2003, 304(3):1268-1274.
17.	Pardridge WM. Blood-brain barrier drug targeting:the future of brain drug development[J]. Mol Interv, 2003, 3(2):90-105, 51.
18.	Zhang Y, Pardridge WM. Delivery of beta-galactosidase to mouse brain via the blood-brain barrier transferrin receptor[J]. J Pharmacol Exp Ther, 2005, 313(3):1075-1081.
19.	Zhang Y, Pardridge WM. Blood-brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion[J]. Brain Res, 2006, 1111(1):227-229.
20.	Ulbrich K, Hekmatara T, Herbert E, et al. Transferrin-and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (BBB)[J]. Eur J Pharm Biopharm, 2009, 71(2):251-256.
21.	Coloma MJ, Lee HJ, Kurihara A, et al. Transport across the Primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor[J]. Pharm Res, 2000, 17(3):266-274.
22.	Jones AR, Shusta EV. Blood-brain barrie r transport of therapeutics via receptor-mediation[J]. Pharm Res, 2007, 24(9):1759-1771.
23.	Boado RJ, Zhang Y, Zhang Y, et al. GDNF fusion protein for targeted-drug delivery across the human blood-brain barrier[J]. Biotechnol Bioeng, 2008, 100(2):387-396.
24.	Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems[J]. Cell Mol Neurobiol, 2000, 20(1):77-95.
25.	Gosk S, Vermehren C, Storm G, et al. Targeting anti-transferrin receptor antibody (OX26) and OX26-conjugated liposomes to brain capillary endothelial cells using in situ perfusion[J]. J Cereb Blood Flow Metab, 2004, 24(11):1193-1204.
26.	Pardridge WM. shRNA and siRNA delivery to the brain[J]. Adv Drug Deliv Rev, 2007, 59(2/3):141-152.
27.	Herz J, Strickland DK. LRP:a multifunctional scavenger and signaling receptor[J]. J Clin Invest, 2001, 108(6):779-784.
28.	Bu G, Maksymovitch EA, Nerbonne JM, et al. Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons[J]. J Biol Chem, 1994, 269(28):18521-18528.
29.	Yamamoto M, Ikeda K, Ohshima K, et al. Increased expression of low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor in human malignant astrocytomas[J]. Cancer Res, 1997, 57(13):2799-2805.
30.	Olivier JC. Drug transport to brain with targeted nanoparticles[J]. NeuroRx, 2005, 2(1):108-119.
31.	Kreuter J, Shamenkov D, Petrov V, et al. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier[J]. J Drug Target, 2002, 10(4):317-325.
32.	Pan W, Kastin AJ, Zankel TC, et al. Efficient transfer of receptorassociated protein (RAP) across the blood-brain barrier[J]. J Cell Sci, 2004, 117(Pt 21):5071-5078.
33.	Migliorini MM, Behre EH, Brew S, et al. Allosteric modulation of ligand binding to low density lipoprotein receptor-related protein by the receptor-associated protein requires critical lysine residues within its carboxyl-terminal domain[J]. J Biol Chem, 2003, 278(20):17986-17992.
34.	Prince WS, McCormick LM, Wendt DJ, et al. Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the receptor-associated protein (RAP) and alpha-L-iduronidase or acid alpha-glucosidase[J]. J Biol Chem, 2004, 279(33):35037-35046.
35.	Demeule M, Régina A, Ché C, et al. Identification and design of peptides as a new drug delivery system for the brain[J]. J Pharmacol Exp Ther, 2008, 324(3):1064-1072.
36.	Demeule M, Currie JC, Bertrand Y, et al. Involvement of the lowdensity lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2[J]. J Neurochem, 2008, 106(4):1534-1544.
37.	Donahue JE, Flaherty SL, Johanson CE, et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease[J]. Acta neuropathologica, 2006, 112(4):405-415.
38.	Thomas FC, Taskar K, Rudraraju V, et al. Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer[J]. Pharm Res, 2009, 26(11):2486-2494.
39.	Temsamani J, Rousselle C, Rees AR, et al. Vector-mediated drug delivery to the brain[J]. Expert Opin Biol Ther, 2001, 1(5):773-782.
40.	Rousselle C, Clair P, Smirnova M, et al. Improved brain uptake and pharmacological activity of dalargin using a peptide-vectormediated strategy[J]. J Pharmacol Exp Ther, 2003, 306(1):371-376.
41.	Liu L, Guo K, Lu J, et al. Biologically active core/shell nanoparticles self-assembled from cholesterol-terminated PEG-TAT for drug delivery across the blood-brain barrier[J]. Biomaterials, 2008, 29(10):1509-1517.
42.	Agyare EK, Curran GL, Ramakrishnan M, et al. Development of a smart nano-vehicle to target cerebrovascular amyloid deposits and brain parenchymal plaques observed in Alzheimer's disease and cerebral amyloid angiopathy[J]. Pharm Res, 2008, 25(11):2674-2684.
43.	Kumar P, Wu H, Mcbride JL, et al. Transvascular delivery of small interfering RNA to the central nervous system[J]. Nature, 2007, 448(7149):39-43.
44.	Lockman PR, Koziara JM, Mumper RJ, et al. Nanoparticle surface charges alter blood-brain barrier integrity and permeability[J]. J Drug Target, 2004, 12(9/10):635-641.

1. Ehrlich P. Das sauerstoff-Bedürfnis des organismus:eine farbanalytische studie[M]. Berlin:Hirschwald, 1885:3-16.
2. Pardridge WM. Blood-brain barrier delivery[J]. Drug Discov Today, 2007, 12(1/2):54-61.
3. Blasberg RG, Patlak C, Fenstermacker JD. Intrathecal chemotherapy:brain tissue profiles after verntriculocisternal perfusion[J]. J Pharmacol Exp Ther, 1975, 195(1):73-83.
4. Pardridge WM. The blood-brain barrier:bottleneck in brain drug development[J]. NeuroRx, 2005, 2(1):3-14.
5. Pardridge WM. Drug targeting to the brain[J]. Pharm Res, 2007, 24(9):1733-1744.
6. Bobo RH, Laske DW, Akbasak A, et al. Convection-enhanced delivery of macromolecules in the brain[J]. Proc Natl Acad Sci USA, 1994, 91(6):2076-2080.
7. Vandergrift WA, Patel SJ, Nicholas JS, et al. Convection-enhanced delivery of immunotoxins and radioisotopes for treatment of malignant gliomas[J]. Neurosurg Focus, 2006, 20(4):E13.
8. Fung LK, Ewend MG, Sills A, et al. Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain[J]. Cancer Res, 1998, 58(4):672-684.
9. Fortin D, Desjardins A, Benko A, et al. Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors:the Sherbrooke experience[J]. Cancer, 2005, 103(12):2606-2615.
10. Hynynen K, Mcdannold N, Vykhodtseva N, et al. Noninvasive Mr imaging-guided focal opening of the blood-brain barrier in rabbits[J]. Radiology, 2001, 220(3):640-646.
11. Gabathuler R. Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases[J]. Neurobiol Dis, 2010, 37(1):48-57.
12. Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings[J]. Adv Drug Deliv Rev, 2001, 46(1/2/3):3-26.
13. Bradley MO, Webb NL, Anthony FH, et al. Tumor targeting by covalent conjugation of a natural fatty acid to paclitaxel[J]. Clin Cancer Res, 2001, 7(10):3229-3238.
14. Batra kova EV, Kabanov AV. Pluronic block copolymers:evolution of drug delivery concept from inert nanocarriers to biological response modifiers[J]. J Control Release, 2008, 130(2):98-106.
15. Qu X, Khutoryanskiy VV, Stewart A, et al. Carbohydrate-based micelle clusters which enhance hydrophobic drug bioavailability by up to 1 order of magnitude[J]. Biomacromolecules, 2006, 7(12):3452-3459.
16. Allen DD, Lockman PR, Roder KE, et al. Active transport of highaffinity choline and nicotine analogs into the central nervous system by the blood-brain barrier choline transporter[J]. J Pharmacol Exp Ther, 2003, 304(3):1268-1274.
17. Pardridge WM. Blood-brain barrier drug targeting:the future of brain drug development[J]. Mol Interv, 2003, 3(2):90-105, 51.
18. Zhang Y, Pardridge WM. Delivery of beta-galactosidase to mouse brain via the blood-brain barrier transferrin receptor[J]. J Pharmacol Exp Ther, 2005, 313(3):1075-1081.
19. Zhang Y, Pardridge WM. Blood-brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion[J]. Brain Res, 2006, 1111(1):227-229.
20. Ulbrich K, Hekmatara T, Herbert E, et al. Transferrin-and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (BBB)[J]. Eur J Pharm Biopharm, 2009, 71(2):251-256.
21. Coloma MJ, Lee HJ, Kurihara A, et al. Transport across the Primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor[J]. Pharm Res, 2000, 17(3):266-274.
22. Jones AR, Shusta EV. Blood-brain barrie r transport of therapeutics via receptor-mediation[J]. Pharm Res, 2007, 24(9):1759-1771.
23. Boado RJ, Zhang Y, Zhang Y, et al. GDNF fusion protein for targeted-drug delivery across the human blood-brain barrier[J]. Biotechnol Bioeng, 2008, 100(2):387-396.
24. Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems[J]. Cell Mol Neurobiol, 2000, 20(1):77-95.
25. Gosk S, Vermehren C, Storm G, et al. Targeting anti-transferrin receptor antibody (OX26) and OX26-conjugated liposomes to brain capillary endothelial cells using in situ perfusion[J]. J Cereb Blood Flow Metab, 2004, 24(11):1193-1204.
26. Pardridge WM. shRNA and siRNA delivery to the brain[J]. Adv Drug Deliv Rev, 2007, 59(2/3):141-152.
27. Herz J, Strickland DK. LRP:a multifunctional scavenger and signaling receptor[J]. J Clin Invest, 2001, 108(6):779-784.
28. Bu G, Maksymovitch EA, Nerbonne JM, et al. Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons[J]. J Biol Chem, 1994, 269(28):18521-18528.
29. Yamamoto M, Ikeda K, Ohshima K, et al. Increased expression of low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor in human malignant astrocytomas[J]. Cancer Res, 1997, 57(13):2799-2805.
30. Olivier JC. Drug transport to brain with targeted nanoparticles[J]. NeuroRx, 2005, 2(1):108-119.
31. Kreuter J, Shamenkov D, Petrov V, et al. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier[J]. J Drug Target, 2002, 10(4):317-325.
32. Pan W, Kastin AJ, Zankel TC, et al. Efficient transfer of receptorassociated protein (RAP) across the blood-brain barrier[J]. J Cell Sci, 2004, 117(Pt 21):5071-5078.
33. Migliorini MM, Behre EH, Brew S, et al. Allosteric modulation of ligand binding to low density lipoprotein receptor-related protein by the receptor-associated protein requires critical lysine residues within its carboxyl-terminal domain[J]. J Biol Chem, 2003, 278(20):17986-17992.
34. Prince WS, McCormick LM, Wendt DJ, et al. Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the receptor-associated protein (RAP) and alpha-L-iduronidase or acid alpha-glucosidase[J]. J Biol Chem, 2004, 279(33):35037-35046.
35. Demeule M, Régina A, Ché C, et al. Identification and design of peptides as a new drug delivery system for the brain[J]. J Pharmacol Exp Ther, 2008, 324(3):1064-1072.
36. Demeule M, Currie JC, Bertrand Y, et al. Involvement of the lowdensity lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2[J]. J Neurochem, 2008, 106(4):1534-1544.
37. Donahue JE, Flaherty SL, Johanson CE, et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease[J]. Acta neuropathologica, 2006, 112(4):405-415.
38. Thomas FC, Taskar K, Rudraraju V, et al. Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer[J]. Pharm Res, 2009, 26(11):2486-2494.
39. Temsamani J, Rousselle C, Rees AR, et al. Vector-mediated drug delivery to the brain[J]. Expert Opin Biol Ther, 2001, 1(5):773-782.
40. Rousselle C, Clair P, Smirnova M, et al. Improved brain uptake and pharmacological activity of dalargin using a peptide-vectormediated strategy[J]. J Pharmacol Exp Ther, 2003, 306(1):371-376.
41. Liu L, Guo K, Lu J, et al. Biologically active core/shell nanoparticles self-assembled from cholesterol-terminated PEG-TAT for drug delivery across the blood-brain barrier[J]. Biomaterials, 2008, 29(10):1509-1517.
42. Agyare EK, Curran GL, Ramakrishnan M, et al. Development of a smart nano-vehicle to target cerebrovascular amyloid deposits and brain parenchymal plaques observed in Alzheimer's disease and cerebral amyloid angiopathy[J]. Pharm Res, 2008, 25(11):2674-2684.
43. Kumar P, Wu H, Mcbride JL, et al. Transvascular delivery of small interfering RNA to the central nervous system[J]. Nature, 2007, 448(7149):39-43.
44. Lockman PR, Koziara JM, Mumper RJ, et al. Nanoparticle surface charges alter blood-brain barrier integrity and permeability[J]. J Drug Target, 2004, 12(9/10):635-641.

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中樞神經系統藥物穿透血腦屏障的研究進展

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