Multipl Skleroz Tedavisinde Nanotaşıyıcı Sistemlerin Uygulanması

Year 2024, Volume: 44 Issue: 2, 182 - 197, 01.06.2024

Nihat Kurt , Sibel Bozdağ Pehlivan , Levent Öner

https://doi.org/10.52794/hujpharm.1397361

Abstract

Nörodejeneratif hastalıklar arasında kompleks bir immünopatolojiye sahip olan Multipl Skleroz (MS)’un tedavisinde birçok faktörün dikkate alınması gerekmektedir. Bu çok faktörlü hastalıktaki klinik bulgular miyelin kaybının ilerlemesine, enflamasyonun evresine, aksonların durumuna ve oligodendrosit öncü hücrelerinin aktivitesine bağlıdır. Uzun yıllardır süregelen yoğun çalışmalara rağmen hastalığın çok
faktörlü oluşu ve kan-beyin engeli (KBE) gibi ilaçların beyne ulaşmasını engelleyen yapılar nedeniyle henüz kesin bir tedavi bulunamamıştır. Bu durum, bilim insanlarını yeni yaklaşımlar aramaya yönlendirmiştir. Yapılan araştırmalarda genellikle nanotaşıyıcı olarak adlandırılan nano boyuttaki farmasötik taşıyıcıların MS’nin yalnızca teşhisinde değil aynı zamanda tedavisinde de rolüstlenebileceğini göstermiştir. MS’nin tedavisi için klinik öncesi in vitro ve in vivo çalışmalarla başarılı olduğu gösterilen bu sistemlerin klinik uygulamaya geçiş yapabilmesi için çalışmalar yoğun bir şekilde devam etmektedir. Bu derlemede MS tedavisine yönelik nanotaşıyıcılar konusunda literatürde yer alan en güncel gelişmeler değerlendirilmiştir.

Keywords

Multipl Skleroz, kan-beyin engeli, ilaç taşıyıcı sistem, nanotaşıyıcı, nanopartikül

Ethical Statement

Yok

Supporting Institution

Yok

Project Number

Yok

Thanks

Yok

Application of Nanocarrier Systems in the Treatment of Multiple Sclerosis

Abstract

Numerous factors need to be taken into consideration in the treatment of Multiple Sclerosis (MS), which has a complex immunopathology among neurodegenerative diseases. Clinical findings in this multifactorial disease depend on the progression of myelin loss, the stage of inflammation, the status of axons, and the activity of oligodendrocyte precursor cells. Despite intensive studies for many years, a definitive treatment has yet to be found due to the multifactorial nature of the disease and structures, such as the blood-brain barrier (BBB) that prevents drugs from reaching the brain. This situation has led scientists to search for new approaches. Studies have shown that nanosized pharmaceutical carriers, often called nanocarriers, might play a role not only in the diagnosis but also in the treatment of MS. Studies are continuing intensively to transition these systems, which have been shown to be successful in preclinical in vitro and in vivo studies for the treatment of MS, to clinical application. In this review, the most current developments in the literature on nanocarriers for MS treatment are evaluated.

Keywords

Multiple Sclerosis, blood-brain barrier, drug delivery system, nanocarrier, nanoparticle

Project Number

Yok

References

• 1. Pires PC, Santos AO. Nanosystems in nose-to-brain drug delivery: A review of non-clinical brain targeting studies. J Control Release 2018;270:89–100. https://doi.org/10.1016/j. jconrel.2017.11.047
• 2. Rayatpour A, Javan M. Targeting the brain lesions using pep- tides: A review focused on the possibility of targeted drug de- livery to multiple sclerosis lesions. Pharmacological Research 2021;167:105441. https://doi.org/10.1016/j.phrs.2021.105441
• 3. J. van der Star B, Y.S. Vogel D, Kipp M, Puentes F, Ba- ker D, Amor S. In Vitro and In Vivo Models of Multip- le Sclerosis. CNSNDDT 2012;11:570–88. https://doi. org/10.2174/187152712801661284
• 4. Martínez-Larrosa J, Matute-Blanch C, Montalban X, Comabel- la M. Modelling multiple sclerosis using induced pluripotent stem cells. Journal of Neuroimmunology 2020;349:577425. https://doi.org/10.1016/j.jneuroim.2020.577425
• 5. Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, et al. Rising prevalence of multiple sclerosis worldwi- de: Insights from the Atlas of MS, third edition. Mult Scler 2020;26:1816–21. https://doi.org/10.1177/1352458520970841
• 6. Bechtel MA, Wong HK. Neurologic adverse effects from der- matologic drugs. Comprehensive Dermatologic Drug Therapy, Elsevier; 2013, p. 711-717.e2. https://doi.org/10.1016/B978- 1-4377-2003-7.00063-7
• 7. Dolati S, Babaloo Z, Jadidi-Niaragh F, Ayromlou H, Sadreddi- ni S, Yousefi M. Multiple sclerosis: Therapeutic applications of advancing drug delivery systems. Biomedicine & Pharma- cotherapy 2017;86:343–53. https://doi.org/10.1016/j.biop- ha.2016.12.010
• 8. Gadhave DG, Sugandhi VV, Kokare CR. Potential bioma- terials and experimental animal models for inventing new drug delivery approaches in the neurodegenerative disorder: Multiple sclerosis. Brain Research 2023:148674. https://doi. org/10.1016/j.brainres.2023.148674
• 9. Tabansky I, Messina MD, Bangeranye C, Goldstein J, Blitz- Shabbir KM, Machado S, et al. Advancing drug delivery systems for the treatment of multiple sclerosis. Immunol Res 2015;63:58–69. https://doi.org/10.1007/s12026-015-8719-0
• 10. Wei W, Ma D, Li L, Zhang L. Progress in the Application of Drugs for the Treatment of Multiple Sclerosis. Front Pharmacol 2021;12:724718. https://doi.org/10.3389/fphar.2021.724718
• 11. Zadeh AR, Askari M, Azadani NN, Ataei A, Ghadimi K, Fala- hatian M. Mechanism and adverse effects of multiple sclerosis drugs: a review article. Part 1. Int J Physiol Pathophysiol Phar- macol 2019;11:95–104
• 12. Barbieri MA, Sorbara EE, Battaglia A, Cicala G, Rizzo V, Spina E, et al. Adverse Drug Reactions with Drugs Used in Multiple Sclerosis: An Analysis from the Italian Pharmacovi- gilance Database. Front Pharmacol 2022;13:808370. https:// doi.org/10.3389/fphar.2022.808370
• 13. Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, et al. Multiple sclerosis. Nat Rev Dis Primers 2018;4:43. https://doi.org/10.1038/s41572-018-0041-4
• 14. Correale J, Halfon MJ, Jack D, Rubstein A, Villa A. Ac- ting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis. Multiple Sclerosis and Rela- ted Disorders 2021;56:103264. https://doi.org/10.1016/j. msard.2021.103264
• 15. Mwema A, Muccioli GG, des Rieux A. Innovative drug de- livery strategies to the CNS for the treatment of multiple sclerosis. J Control Release 2023;364:435–57. https://doi. org/10.1016/j.jconrel.2023.10.052
• 16. Misra A, Ganesh S, Shahiwala A. Drug Delivery To The Central Nervous System: A Review. J Pharm Pharm Sci 2003;6:252–73
• 17. Furtado D, Björnmalm M, Ayton S, Bush AI, Kempe K, Ca- ruso F. Overcoming the Blood–Brain Barrier: The Role of Nanomaterials in Treating Neurological Diseases. Advan- ced Materials 2018;30:1801362. https://doi.org/10.1002/ adma.201801362
• 18. Pardridge WM. CSF, blood-brain barrier, and brain drug de- livery. Expert Opinion on Drug Delivery 2016;13:963–75. https://doi.org/10.1517/17425247.2016.1171315
• 19. Kadry H, Noorani B, Cucullo L. A blood–brain barrier over- view on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 2020;17:69. https://doi. org/10.1186/s12987-020-00230-3
• 20. Rahiman N, Mohammadi M, Alavizadeh SH, Arabi L, Badiee A, Jaafari MR. Recent advancements in nanoparticle-media- ted approaches for restoration of multiple sclerosis. J Control Release 2022;343:620–44. https://doi.org/10.1016/j.jcon- rel.2022.02.009
• 21. Quintana FJ. Nanoparticles for the induction of antigen- specific Tregs. Immunotherapy 2013;5:437–40. https://doi. org/10.2217/imt.13.25
• 22. Soica C, Coricovac D, Dehelean C, Pinzaru I, Mioc M, Danciu C, et al. Nanocarriers as Tools in Delivering Active Compo- unds for Immune System Related Pathologies. NANOTEC 2016;10:128–45. https://doi.org/10.2174/1872210510999160 427113345
• 23. Serra P, Santamaria P. Nanoparticle-based autoimmune dise- ase therapy. Clinical Immunology 2015;160:3–13. https://doi. org/10.1016/j.clim.2015.02.003
• 24. Wen MM, El-Salamouni NS, El-Refaie WM, Hazzah HA, Ali MM, Tosi G, et al. Nanotechnology-based drug delivery systems for Alzheimer’s disease management: Technical, industrial, and clinical challenges. J Control Release 2017;245:95–107. https://doi.org/10.1016/j.jcon- rel.2016.11.025
• 25. Naahidi S, Jafari M, Edalat F, Raymond K, Khademhosseini A, Chen P. Biocompatibility of engineered nanoparticles for drug delivery. J Control Release 2013;166:182–94. https://doi. org/10.1016/j.jconrel.2012.12.013
• 26. Andrieux K, Couvreur P. Polyalkylcyanoacrylate nanopartic- les for delivery of drugs across the blood–brain barrier. WI- REs Nanomed Nanobiotechnol 2009;1:463–74. https://doi. org/10.1002/wnan.5
• 27. Annu, Sartaj A, Qamar Z, Md S, Alhakamy NA, Baboota S, et al. An Insight to Brain Targeting Utilizing Polymeric Nanoparticles: Effective Treatment Modalities for Neurolo- gical Disorders and Brain Tumor. Front Bioeng Biotechnol 2022;10:788128. https://doi.org/10.3389/fbioe.2022.788128
• 28. Mittal P, Saharan A, Verma R, Altalbawy FMA, Alfaidi MA, Batiha GE-S, et al. Dendrimers: A New Race of Phar- maceutical Nanocarriers. BioMed Research International 2021;2021:1–11. https://doi.org/10.1155/2021/8844030
• 29. Chauhan A. Dendrimers for Drug Delivery. Molecules 2018;23:938. https://doi.org/10.3390/molecules23040938
• 30. Pérez-Carrión MD, Posadas I. Dendrimers in Neurodegenera- tive Diseases. Processes 2023;11:319. https://doi.org/10.3390/ pr11020319
• 31. Kaur A, Singh N, Kaur H, Kakoty V, Sharma DS, Khursheed R, et al. Neurodegenerative diseases and brain delivery of the- rapeutics: Bridging the gap using dendrimers. Journal of Drug Delivery Science and Technology 2023;87:104868. https://doi. org/10.1016/j.jddst.2023.104868
• 32. Sherje AP, Jadhav M, Dravyakar BR, Kadam D. Dendrimers: A versatile nanocarrier for drug delivery and targeting. Interna- tional Journal of Pharmaceutics 2018;548:707–20. https://doi. org/10.1016/j.ijpharm.2018.07.030
• 33. Wang Y, Ying X, Xu H, Yan H, Li X, Tang H. The functio- nal curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals. IJN 2017;Volume 12:1369–84. https://doi.org/10.2147/IJN. S124276
• 34. Ciani L, Ristori S, Salvati A, Calamai L, Martini G. DOTAP/ DOPE and DC-Chol/DOPE lipoplexes for gene delivery: zeta potential measurements and electron spin resonan- ce spectra. Biochimica et Biophysica Acta (BBA) - Bio- membranes 2004;1664:70–9. https://doi.org/10.1016/j.bba- mem.2004.04.003
• 35. Barbara R, Belletti D, Pederzoli F, Masoni M, Keller J, Bal- lestrazzi A, et al. Novel Curcumin loaded nanoparticles engineered for Blood-Brain Barrier crossing and able to disrupt Abeta aggregates. International Journal of Phar- maceutics 2017;526:413–24. https://doi.org/10.1016/j.ijp- harm.2017.05.015
• 36. Gajbhiye KR, Pawar A, Mahadik KR, Gajbhiye V. PEGylated nanocarriers: A promising tool for targeted delivery to the bra- in. Colloids and Surfaces B: Biointerfaces 2020;187:110770. https://doi.org/10.1016/j.colsurfb.2019.110770
• 37. Patel S, Chavhan S, Soni H, Babbar AK, Mathur R, Mish- ra AK, et al. Brain targeting of risperidone-loaded solid lipid nanoparticles by intranasal route. Journal of Drug Tar- geting 2011;19:468–74. https://doi.org/10.3109/106118 6X.2010.523787
• 38. Rostami E, Kashanian S, Azandaryani AH, Faramarzi H, Do- latabadi JEN, Omidfar K. Drug targeting using solid lipid na- noparticles. Chemistry and Physics of Lipids 2014;181:56–61. https://doi.org/10.1016/j.chemphyslip.2014.03.006
• 39. Kaur IP, Bhandari R, Bhandari S, Kakkar V. Potential of solid lipid nanoparticles in brain targeting. J Control Re- lease 2008;127:97–109. https://doi.org/10.1016/j.jcon- rel.2007.12.018
• 40. Duan Y, Dhar A, Patel C, Khimani M, Neogi S, Sharma P, et al. A brief review on solid lipid nanoparticles: part and parcel of contemporary drug delivery systems. RSC Adv 2020;10:26777–91. https://doi.org/10.1039/D0RA03491F
• 41. Ghasemiyeh P, Mohammadi-Samani S. Solid lipid nanopar- ticles and nanostructured lipid carriers as novel drug deli- very systems: applications, advantages and disadvantages. Res Pharma Sci 2018;13:288. https://doi.org/10.4103/1735- 5362.235156
• 42. Gokce EH, Korkmaz E, Dellera E, Sandri G, Bonferoni MC, Ozer O. Resveratrol-loaded solid lipid nanoparticles versus nanostructured lipid carriers: evaluation of antioxidant poten- tial for dermal applications. International Journal of Nanome- dicine 2012;7:1841–50
• 43. Hernández-Esquivel R-A, Navarro-Tovar G, Zárate- Hernández E, Aguirre-Bañuelos P. Solid Lipid Nanoparticles (SLN). In: Sharma A, editor. Nanocomposite Materials for Biomedical and Energy Storage Applications, Rijeka: Intec- hOpen; 2022. https://doi.org/10.5772/intechopen.102536
• 44. Gugleva V, Andonova V. Recent Progress of Solid Lipid Na- noparticles and Nanostructured Lipid Carriers as Ocular Drug Delivery Platforms. Pharmaceuticals 2023;16:474. https://doi. org/10.3390/ph16030474
• 45. Moraes AS, Paula RFO, Pradella F, Santos MPA, Oliveira EC, von Glehn F, et al. The Suppressive Effect of IL -27 on Encep- halitogenic Th17 Cells Induced by Multiwalled Carbon Nano- tubes Reduces the Severity of Experimental Autoimmune En- cephalomyelitis. CNS Neurosci Ther 2013;19:682–7. https:// doi.org/10.1111/cns.12121
• 46. Singh AV, Khare M, Gade WN, Zamboni P. Theranostic Imp- lications of Nanotechnology in Multiple Sclerosis: A Future Perspective. Autoimmune Diseases 2012;2012:1–12. https:// doi.org/10.1155/2012/160830
• 47. Bolskar R. Encyclopedia of Nanotechnology. Amsterdam, The Netherlands: Springer; 2012. https://doi.org/10.1007/978-94- 017-9780-1
• 48. Jain KK. The role of nanobiotechnology in drug disco- very. Drug Discovery Today 2005;10:1435–42. https://doi. org/10.1016/S1359-6446(05)03573-7
• 49. Bianco A, Kostarelos K, Prato M. Applications of carbon nano- tubes in drug delivery. Current Opinion in Chemical Biology 2005;9:674–9. https://doi.org/10.1016/j.cbpa.2005.10.005
• 50. Liu K, Zhang J-J, Cheng F-F, Zheng T-T, Wang C, Zhu J-J. Green and facile synthesis of highly biocompatible graphe- ne nanosheets and its application for cellular imaging and drug delivery. J Mater Chem 2011;21:12034. https://doi. org/10.1039/c1jm10749f
• 51. Zheng M, Liu S, Li J, Qu D, Zhao H, Guan X, et al. Integrating Oxaliplatin with Highly Luminescent Carbon Dots: An Unp- recedented Theranostic Agent for Personalized Medicine. Ad- vanced Materials 2014;26:3554–60. https://doi.org/10.1002/ adma.201306192
• 52. [Mishra A, Kumar R, Mishra J, Dutta K, Ahlawat P, Kumar A, et al. Strategies facilitating the permeation of nanoparticles through blood-brain barrier: An insight towards the develop- ment of brain-targeted drug delivery system. Journal of Drug Delivery Science and Technology 2023;86:104694. https://doi. org/10.1016/j.jddst.2023.104694
• 53. Fang J, Lai Y, Chiu T, Chen Y, Hu S, Chen S. Magnetic Core– Shell Nanocapsules with Dual-Targeting Capabilities and Co- Delivery of Multiple Drugs to Treat Brain Gliomas. Adv He- althcare Materials 2014;3:1250–60. https://doi.org/10.1002/ adhm.201300598
• 54. Pedram M, Shamloo A, Alasty A, Ghafar-Zadeh E. Toward Epileptic Brain Region Detection Based on Magnetic Nano- particle Patterning. Sensors 2015;15:24409–27. https://doi. org/10.3390/s150924409
• 55. Roet M, Hescham S-A, Jahanshahi A, Rutten BPF, Ani- keeva PO, Temel Y. Progress in neuromodulation of the brain: A role for magnetic nanoparticles? Progress in Neu- robiology 2019;177:1–14. https://doi.org/10.1016/j.pneuro- bio.2019.03.002
• 56. Yafout M, Ousaid A, Khayati Y, El Otmani IS. Gold nano- particles as a drug delivery system for standard chemothe- rapeutics: A new lead for targeted pharmacological cancer treatments. Scientific African 2021;11:e00685. https://doi. org/10.1016/j.sciaf.2020.e00685
• 57. Pan Y, Neuss S, Leifert A, Fischler M, Wen F, Simon U, et al. Size-Dependent Cytotoxicity of Gold Nanoparticles. Small 2007;3:1941–9. https://doi.org/10.1002/smll.200700378
• 58. Kong F-Y, Zhang J-W, Li R-F, Wang Z-X, Wang W-J, Wang W. Unique Roles of Gold Nanoparticles in Drug Delivery, Tar- geting and Imaging Applications. Molecules 2017;22:1445. https://doi.org/10.3390/molecules22091445
• 59. Khongkow M, Yata T, Boonrungsiman S, Ruktanonchai UR, Graham D, Namdee K. Surface modification of gold nano- particles with neuron-targeted exosome for enhanced blood– brain barrier penetration. Sci Rep 2019;9:8278. https://doi. org/10.1038/s41598-019-44569-6
• 60. Kalluri R. The biology and function of exosomes in cancer. Journal of Clinical Investigation 2016;126:1208–15. https:// doi.org/10.1172/JCI81135
• 61. Fais S, O’Driscoll L, Borras FE, Buzas E, Camussi G, Cappel- lo F, et al. Evidence-Based Clinical Use of Nanoscale Extra- cellular Vesicles in Nanomedicine. ACS Nano 2016;10:3886– 99. https://doi.org/10.1021/acsnano.5b08015
• 62. Wiklander OPB, Nordin JZ, O’Loughlin A, Gustafsson Y, Corso G, Mäger I, et al. Extracellular vesicle in vivo biodist- ribution is determined by cell source, route of administration and targeting. J of Extracellular Vesicle 2015;4:26316. https:// doi.org/10.3402/jev.v4.26316
• 63. Tian T, Zhang H-X, He C-P, Fan S, Zhu Y-L, Qi C, et al. Surfa- ce functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials 2018;150:137–49. https://doi.org/10.1016/j.biomaterials.2017.10.012
• 64. Sidoryk-Węgrzynowicz M, Dąbrowska-Bouta B, Sulkowski G, Strużyńska L. Nanosystems and exosomes as future app- roaches in treating multiple sclerosis. Eur J of Neuroscience 2021;54:7377–404. https://doi.org/10.1111/ejn.15478
• 65. Patel T, Zhou J, Piepmeier JM, Saltzman WM. Polymeric nanoparticles for drug delivery to the central nervous system. Advanced Drug Delivery Reviews 2012;64:701–5. https://doi. org/10.1016/j.addr.2011.12.006
• 66. Pearson RM, Casey LM, Hughes KR, Wang LZ, North MG, Getts DR, et al. Controlled Delivery of Single or Multiple An- tigens in Tolerogenic Nanoparticles Using Peptide-Polymer Bioconjugates. Molecular Therapy 2017;25:1655–64. https:// doi.org/10.1016/j.ymthe.2017.04.015
• 67. Cappellano G, Woldetsadik AD, Orilieri E, Shivakumar Y, Rizzi M, Carniato F, et al. Subcutaneous inverse vaccination with PLGA particles loaded with a MOG peptide and IL-10 decreases the severity of experimental autoimmune encepha- lomyelitis. Vaccine 2014;32:5681–9. https://doi.org/10.1016/j. vaccine.2014.08.016
• 68. Rittchen S, Boyd A, Burns A, Park J, Fahmy TM, Metcalfe S, et al. Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF). Biomaterials 2015;56:78– 85. https://doi.org/10.1016/j.biomaterials.2015.03.044
• 69. Li PY, Bearoff F, Zhu P, Fan Z, Zhu Y, Fan M, et al. PEGy- lation enables subcutaneously administered nanoparticles to induce antigen-specific immune tolerance. J Control Release 2021;331:164–75. https://doi.org/10.1016/j.jcon- rel.2021.01.013
• 70. Pei W, Wan X, Shahzad KA, Zhang L, Song S, Jin X, et al. Direct modulation of myelin-autoreactive CD4 + and CD8 + T cells in EAE mice by a tolerogenic nanoparticle co-carrying myelin peptide-loaded major histocompatibility complexes, CD47 and multiple regulatory molecules. IJN 2018;Volume 13:3731–50.https://doi.org/10.2147/IJN.S164500
• 71. McCarthy DP, Yap JW-T, Harp CT, Song WK, Chen J, Pearson RM, et al. An antigen-encapsulating nanoparticle platform for TH1/17 immune tolerance therapy. Nanomedicine: Nanotech- nology, Biology and Medicine 2017;13:191–200. https://doi. org/10.1016/j.nano.2016.09.007
• 72. Zhao X, Sun L, Wang J, Xu X, Ni S, Liu M, et al. Nose to brain delivery of Astragaloside IV by β-Asarone modified chitosan nanoparticles for multiple sclerosis therapy. Interna- tional Journal of Pharmaceutics 2023;644:123351. https://doi. org/10.1016/j.ijpharm.2023.123351
• 73. Hayder M, Varilh M, Turrin C-O, Saoudi A, Caminade A-M, Poupot R, et al. Phosphorus-Based Dendrimer ABP Treats Neuroinflammation by Promoting IL-10-Producing CD4 + T Cells. Biomacromolecules 2015;16:3425–33. https://doi. org/10.1021/acs.biomac.5b00643
• 74. Wegmann KW, Wagner CR, Whitham RH, Hinrichs DJ. Synthetic Peptide Dendrimers Block the Development and Expression of Experimental Allergic Encephalomyelitis. The Journal of Immunology 2008;181:3301–9. https://doi. org/10.4049/jimmunol.181.5.3301
• 75. Shimizu K, Agata K, Takasugi S, Goto S, Narita Y, Asai T, et al. New strategy for MS treatment with autoantigen- modified liposomes and their therapeutic effect. J Control Release 2021;335:389–97. https://doi.org/10.1016/j.jcon- rel.2021.05.027
• 76. Schmidt J, Metselaar JM, Wauben MHM, Toyka KV, Storm G, Gold R. Drug targeting by long-circulating liposomal glu- cocorticosteroids increases therapeutic efficacy in a model of multiple sclerosis. Brain 2003;126:1895–904. https://doi. org/10.1093/brain/awg176
• 77. Gaillard PJ, Appeldoorn CCM, Rip J, Dorland R, van der Pol SMA, Kooij G, et al. Enhanced brain delivery of liposomal methylprednisolone improved therapeutic efficacy in a mo- del of neuroinflammation. J Control Release 2012;164:364–9. https://doi.org/10.1016/j.jconrel.2012.06.022
• 78. Lee D-H, Rötger C, Appeldoorn CCM, Reijerkerk A, Glad- dines W, Gaillard PJ, et al. Glutathione PEGylated liposomal methylprednisolone (2B3-201) attenuates CNS inflammation and degeneration in murine myelin oligodendrocyte glycop- rotein induced experimental autoimmune encephalomyelitis. Journal of Neuroimmunology 2014;274:96–101. https://doi. org/10.1016/j.jneuroim.2014.06.025
• 79. Gandomi N, Varshochian R, Atyabi F, Ghahremani MH, Sha- rifzadeh M, Amini M, et al. Solid lipid nanoparticles surface modified with anti-Contactin-2 or anti-Neurofascin for brain- targeted delivery of medicines. Pharmaceutical Development and Technology 2017;22:426–35. https://doi.org/10.1080/108 37450.2016.1226901
• 80. Esposito E, Cortesi R, Drechsler M, Fan J, Fu BM, Calde- ran L, et al. Nanoformulations for dimethyl fumarate: Physi- cochemical characterization and in vitro / in vivo behavior. European Journal of Pharmaceutics and Biopharmaceutics 2017;115:285–96. https://doi.org/10.1016/j.ejpb.2017.04.011
• 81. Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Vitamin-Derived Nanolipoidal Carriers for Brain Deli- very of Dimethyl Fumarate: A Novel Approach with Preclini- cal Evidence. ACS Chem Neurosci 2017;8:1390–6. https://doi. org/10.1021/acschemneuro.7b00041
• 82. Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Stearic acid based, systematically designed oral lipid nanoparticles for enhanced brain delivery of dimethyl fumara- te. Nanomedicine 2017;12:2607–21. https://doi.org/10.2217/ nnm-2017-0082
• 83. Kumar P, Sharma G, Gupta V, Kaur R, Thakur K, Malik R, et al. Oral Delivery of Methylthioadenosine to the Brain Emp- loying Solid Lipid Nanoparticles: Pharmacokinetic, Behavi- oral, and Histopathological Evidences. AAPS PharmSciTech 2019;20:74. https://doi.org/10.1208/s12249-019-1296-0
• 84. Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Enhanced Brain Delivery of Dimethyl Fumarate Emp- loying Tocopherol-Acetate-Based Nanolipidic Carriers: Evi- dence from Pharmacokinetic, Biodistribution, and Cellular Uptake Studies. ACS Chem Neurosci 2017;8:860–5. https:// doi.org/10.1021/acschemneuro.6b00428
• 85. Kumar P, Sharma G, Gupta V, Kaur R, Thakur K, Malik R, et al. Preclinical Explorative Assessment of Dimethyl Fumarate-Ba- sed Biocompatible Nanolipoidal Carriers for the Management of Multiple Sclerosis. ACS Chem Neurosci 2018;9:1152–8. https://doi.org/10.1021/acschemneuro.7b00519
• 86. Gadhave DG, Kokare CR. Nanostructured lipid carriers en- gineered for intranasal delivery of teriflunomide in multiple sclerosis: optimization and in vivo studies. Drug Development and Industrial Pharmacy 2019;45:839–51.https://doi.org/10.1 080/03639045.2019.1576724
• 87. Chen Y-W, Hwang KC, Yen C-C, Lai Y-L. Fullerene deri- vatives protect against oxidative stress in RAW 264.7 cells and ischemia-reperfused lungs. American Journal of Physi- ology-Regulatory, Integrative and Comparative Physiology 2004;287:R21–6. https://doi.org/10.1152/ajpregu.00310.2003
• 88. Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petro- vic-Stojkovic S, Puckett L, et al. Reversal of axonal loss and disability in a mouse model of progressive multiple sclero- sis. J Clin Invest 2008;118:1532–43. https://doi.org/10.1172/ JCI33464.
• 89. Bonoiu A, Mahajan SD, Ye L, Kumar R, Ding H, Yong K-T, et al. MMP-9 gene silencing by a quantum dot–siRNA nanoplex delivery to maintain the integrity of the blood brain barrier. Brain Research 2009;1282:142–55. https://doi.org/10.1016/j. brainres.2009.05.047
• 90. Hess KL, Oh E, Tostanoski LH, Andorko JI, Susumu K, Deschamps JR, et al. Engineering Immunological Tolerance Using Quantum Dots to Tune the Density of Self-Antigen Display. Adv Funct Materials 2017;27:1700290. https://doi. org/10.1002/adfm.201700290
• 91. Millward JM, Schnorr J, Taupitz M, Wagner S, Wuerfel JT, Infante-Duarte C. Iron Oxide Magnetic Nanoparticles High- light Early Involvement of the Choroid Plexus in Central Ner- vous System Inflammation. ASN Neuro 2013;5:AN20120081. https://doi.org/10.1042/AN20120081
• 92. [Siegers GM, Krishnamoorthy S, Gonzalez-Lara LE, McFad- den C, Chen Y, Foster PJ. Pre-Labeling of Immune Cells in Normal Bone Marrow and Spleen for Subsequent Cell Tracking by MRI. Tomography 2016;2:26–34. https://doi. org/10.18383/j.tom.2016.00103
• 93. Kirschbaum K, Sonner JK, Zeller MW, Deumelandt K, Bode J, Sharma R, et al. In vivo nanoparticle imaging of innate immu- ne cells can serve as a marker of disease severity in a model of multiple sclerosis. Proc Natl Acad Sci USA 2016;113:13227– 32. https://doi.org/10.1073/pnas.1609397113
• 94. Yeste A, Nadeau M, Burns EJ, Weiner HL, Quintana FJ. Nano- particle-mediated codelivery of myelin antigen and a toleroge- nic small molecule suppresses experimental autoimmune en- cephalomyelitis. Proc Natl Acad Sci USA 2012;109:11270–5. https://doi.org/10.1073/pnas.1120611109
• 95. Aghaie T, Jazayeri MH, Avan A, Anissian A, Salari A. Gold nanoparticles and polyethylene glycol alleviate clinical symptoms and alter cytokine secretion in a mouse model of experimental autoimmune encephalomyelitis. IUBMB Life 2019;71:1313–21. https://doi.org/10.1002/iub.2045
• 96. Nosratabadi R, Rastin M, Sankian M, Haghmorad D, Mahmo- udi M. Hyperforin-loaded gold nanoparticle alleviates expe- rimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells and upregulating regulatory T cells. Nanomedi- cine: Nanotechnology, Biology and Medicine 2016;12:1961– 71. https://doi.org/10.1016/j.nano.2016.04.001
• 97. Hosseini Shamili F, Alibolandi M, Rafatpanah H, Abnous K, Mahmoudi M, Kalantari M, et al. Immunomodulatory pro- perties of MSC-derived exosomes armed with high affinity aptamer toward mylein as a platform for reducing multiple sclerosis clinical score. J Control Release 2019;299:149–64. https://doi.org/10.1016/j.jconrel.2019.02.032
• 98. Li Z, Liu F, He X, Yang X, Shan F, Feng J. Exosomes deri- ved from mesenchymal stem cells attenuate inflammation and demyelination of the central nervous system in EAE rats by regulating the polarization of microglia. International Immu- nopharmacology 2019;67:268–80. https://doi.org/10.1016/j. intimp.2018.12.001
• 99. Rajan TS, Giacoppo S, Diomede F, Ballerini P, Paolantonio M, Marchisio M, et al. The secretome of periodontal ligament stem cells from MS patients protects against EAE. Sci Rep 2016;6:38743. https://doi.org/10.1038/srep38743
• 100. Clark K, Zhang S, Barthe S, Kumar P, Pivetti C, Kreutzberg N, et al. Placental Mesenchymal Stem Cell-Derived Extra- cellular Vesicles Promote Myelin Regeneration in an Animal Model of Multiple Sclerosis. Cells 2019;8:1497. https://doi. org/10.3390/cells8121497