Fullerene nanoparticle as new therapeutic agent for the nervous system disorders

Document Type : Review Paper

Authors

1 Biology Education Department, Tishk International University, Erbil, Iraq

2 Department of pharmaceutics, College of pharmacy, University of Al-Ameed, Karbala, Iraq

3 College of Nursing, University of Al-Ameed, Karbala, Iraq

4 Department of Clinical Laboratories, College of Applied Medical Sciences, University of Kerbala, Karbala, Iraq

5 Department of Biophysics, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran

10.22038/nmj.2024.78043.1903

Abstract

Neurodegenerative diseases and brain tumors are significant medical ailments that impact the brain. Administering therapeutic drugs to the brain is more challenging compared to other organs or systems. The existence of the blood-brain barrier (BBB) poses significant complexities and challenges in delivering drugs to the brain. This study explores the potential of Fullerene nanoparticles as a novel therapeutic agent for delivering drugs to the brain and their neuroprotective roles within the central nervous system. Novel drug delivery methods have been devised to surmount obstacles posed by BBB and accomplish targeted drug delivery to the brain. Carbon nanostructures are an excellent option for delivering drugs into the brain because they have favorable biocompatibility and can easily penetrate BBB. Furthermore, these nanocarriers has the potential to serve as a therapeutic agent inside the central nervous system, exhibiting neurogenerative properties in some cases. Additionally, their impact on the proliferation of neurons and their ability to counteract the formation of amyloid plaques is particularly remarkable. Carbon-based nanomaterials, including zero-dimensional fullerene (C60), one-dimensional carbon nanotubes (CNTs), and two-dimensional graphene, have shown significant potential in the area of nanomedicine. This is attributed to their unique blend of chemical and physical characteristics, as well as their hydrophobic surfaces. Fullerene nanoparticles have the potential to greatly improve the treatment of brain illnesses by serving as both carriers and therapeutic agents. 

Keywords


1.    Alajangi HK, Kaur M, Sharma A, Rana S, Thakur S, Chatterjee M, et al. Blood–brain barrier: emerging trends on transport models and new-age strategies for therapeutics intervention against neurological disorders. Mol Brain. 2022;15(1):1-28. 
2.    Kroto HW, Heath JR, O’Brien SC, Curl RF, Smalley RE. C60: Buckminsterfullerene. Nature. 1985;318(6042):162-163.
3.    Ma H, Liang X-J. Fullerenes as unique nanopharmaceuticals for disease treatment. Sci China Chem. 2010;53:2233-2240.
4.    Adiseshaiah P, Dellinger A, MacFarland D, Stern S, Dobrovolskaia M, Ileva L, et al. A novel gadolinium-based trimetasphere metallofullerene for application as a magnetic resonance imaging contrast agent. Invest Radiol. 2013;48(11):745-754.   
5.    Kneale L, Smy M, Malek M. Coincidence-based reconstruction for reactor antineutrino detection in gadolinium-doped Cherenkov detectors. Nucl Instrum Methods Phys Res Sect A Accel Spectrometers Detect Assoc Equip. 2023;1053:168375.
6.    Chen A, Sun Y, Lei Y, Li C, Liao S, Meng J, et al. Single-cell spatial transcriptome reveals cell-type organization in the macaque cortex. Cell. 2023;186(17):3726-3743.
7.    Raina M, Sharma S, Koul S. Fanatical Clout of Porous Carbon Materials—A Peek in Therapeutics.  Handbook of Porous Carbon Materials: Springer; 2023. p. 841-883.
8.    Li F, Ouyang J, Chen Z, Zhou Z, Milon Essola J, Ali B, et al. Nanomedicine for T‐Cell Mediated Immunotherapy. Adv Mater. 2023:2301770.
9.    Sosnowska M, Kutwin M, Zawadzka K, Pruchniewski M, Strojny B, Bujalska Z, et al. Influence of C60 Nanofilm on the Expression of Selected Markers of Mesenchymal–Epithelial Transition in Hepatocellular Carcinoma. Cancers. 2023;15(23):5553.
10.    MASCHIO A. Biomateriali per il trattamento di disturbi neurodegenerativi.
11.    Gaur M, Misra C, Yadav AB, Swaroop S, Maolmhuaidh FÓ, Bechelany M, et al. Biomedical applications of carbon nanomaterials: fullerenes, quantum dots, nanotubes, nanofibers, and graphene. Materials. 2021;14(20):5978.
12.    Henna T, Raphey V, Sankar R, Shirin VA, Gangadharappa H, Pramod K. Carbon nanostructures: The drug and the delivery system for brain disorders. Int J Pharm. 2020;587:119701.
13.    Bhakta P, Barthunia B. Fullerene and its applications: A review. JIAOMR. 2020;32(2):159-163.
14.    Masoudi Asil S, Guerrero ED, Bugarini G, Cayme J, De Avila N, Garcia J, et al. Theranostic applications of multifunctional carbon nanomaterials. View. 2023;4(2):20220056.
15.    Harish V, Tewari D, Gaur M, Yadav AB, Swaroop S, Bechelany M, et al. Review on nanoparticles and nanostructured materials: Bioimaging, biosensing, drug delivery, tissue engineering, antimicrobial, and agro-food applications. Nanomaterials. 2022;12(3):457.
16.    Prylutskyy Y, Nozdrenko D, Gonchar O, Prylutska S, Bogutska K, Franskevych D, et al. C60 fullerene attenuates muscle force reduction in a rat during fatigue development. Heliyon. 2022;8(12).
17.    Dellinger A, Zhou Z, Connor J, Madhankumar A, Pamujula S, Sayes CM, et al. Application of fullerenes in nanomedicine: an update. Nanomedicine. 2013;8(7):1191-1208.
18.    Fernandes NB, Shenoy RUK, Kajampady MK, DCruz CE, Shirodkar RK, Kumar L, et al. Fullerenes for the treatment of cancer: an emerging tool. Environ Sci Pollut Res. 2022;29(39):58607-58627.
19.    Hamblin MR. Fullerenes as photosensitizers in photodynamic therapy: pros and cons. Photochem Photobiol Sci. 2018;17(11):1515-1533.
20.    Baskar AV, Benzigar MR, Talapaneni SN, Singh G, Karakoti AS, Yi J, et al. Self‐Assembled Fullerene Nanostructures: Synthesis and Applications. Adv Funct Mater. 2022;32(6):2106924.
21.    Jiang G, Yang Y. Preparation and tribology properties of water-soluble fullerene derivative nanoball. Arab J Chem. 2017;10:S870-S876.
22.    Dong X, Liu X, Cheng M, Huang D, Zhang G, Wang W, et al. Prussian blue and its analogues: Reborn as emerging catalysts for a Fenton-like process in water purification. Coord Chem Rev. 2023;482:215067.
23.    Beyaz S, Aslan A, Gok O, Ozercan IH, Agca CA. Fullerene C60 protects against 7, 12-dimethylbenz [a] anthracene (DMBA) induced-pancreatic damage via NF-κB and Nrf-2/HO-1 axis in rats. Toxicol Res. 2023;12(5):954-963.
24.    Demir E, Aslan A. Protective effect of pristine C60 fullerene nanoparticle in combination with curcumin against hyperglycemia‐induced kidney damage in diabetes caused by streptozotocin. J Food Biochem. 2020;44(11):e13470.
25.    Bağlayan Ö, Parlak C, Dikmen G, Alver Ö. The quest of the most stable structure of a carboxyfullerene and its drug delivery limits: A DFT and QTAIM approach. Comput Theor Chem. 2023;1221:114036.
26.    Xu P-Y, Li X-Q, Chen W-G, Deng L-L, Tan Y-Z, Zhang Q, et al. Progress in antiviral fullerene research. Nanomaterials. 2022;12(15):2547.
27.    Dhiman S, Kaur A, Sharma M. Fullerenes for anticancer drug targeting: teaching an old dog a new trick. Mini-Rev Med Chem. 2022;22(22):2864-2880.
28.    Gudkov SV, Guryev EL, Gapeyev AB, Sharapov MG, Bunkin NF, Shkirin AV, et al. Unmodified hydrated С60 fullerene molecules exhibit antioxidant properties, prevent damage to DNA and proteins induced by reactive oxygen species and protect mice against injuries caused by radiation-induced oxidative stress. NBM. 2019;15(1):37-46. 
29.    Demir E. Therapeutic effect of curcumin and C60 fullerene against hyperglycemia-mediated tissue damage in diabetic rat lungs. J Bioenerg Biomembr. 2021;53(1):25-38.
30.    Gao X, Li L, Cai X, Huang Q, Xiao J, Cheng Y. Targeting nanoparticles for diagnosis and therapy of bone tumors: Opportunities and challenges. Biomaterials. 2021;265:120404.
31.    Shershakova N, Andreev S, Tomchuk A, Makarova E, Nikonova A, Turetskiy E, et al. Wound healing activity of aqueous dispersion of fullerene C60 produced by “green technology”. NBM. 2023;47:102619.
32.    Tomchuk AA, Shershakova NN, Andreev SM, Turetskiy EA, Ivankov OI, Kyzyma OA, et al. C60 and C60-arginine aqueous solutions: In vitro toxicity and structural study. Fuller Nanotub Carbon Nanostruct. 2020;28(4):245-249.
33.    Uludag K, Wang DM, Zhang XY. Tardive Dyskinesia Development, Superoxide Dismutase Levels, and Relevant Genetic Polymorphisms. Oxid Med Cell Longev. 2022;2022.
34.    Shytikov D, Shytikova I, Rohila D, Kulaga A, Dubiley T, Pishel I. Effect of long-term treatment with C60 fullerenes on the lifespan and health status of CBA/Ca mice. Rejuvenation Res. 2021;24(5):345-353.
35.    Arslan J, Jamshed H, Qureshi H. Early detection and prevention of Alzheimer’s disease: role of oxidative markers and natural antioxidants. Front Aging Neurosci. 2020;12:231.
36.    Koutsaliaris IK, Moschonas IC, Pechlivani LM, Tsouka AN, Tselepis AD. Inflammation, oxidative stress, vascular aging and atherosclerotic ischemic stroke. Curr Med Chem. 2022;29(34):5496-5509.
37.    Kung H-C, Lin K-J, Kung C-T, Lin T-K. Oxidative stress, mitochondrial dysfunction, and neuroprotection of polyphenols with respect to resveratrol in Parkinson’s disease. Biomedicines. 2021;9(8):918.
38.    Liaquat Z, Xu X, Zilundu PLM, Fu R, Zhou L. The current role of dexmedetomidine as neuroprotective agent: an updated review. Brain Sci. 2021;11(7):846.
39.    Fisher M, Manwani B, VanNostrand M. Prevention and Treatment of Stroke. Vascular Medicine: A Companion to Braunwald’s Heart Disease E-Book. 2019:391.
40.    Gonchar OO, Maznychenko AV, Klyuchko OM, Mankovska IM, Butowska K, Borowik A, et al. C60 fullerene reduces 3-nitropropionic acid-induced oxidative stress disorders and mitochondrial dysfunction in rats by modulation of p53, Bcl-2 and Nrf2 targeted proteins. Int J Mol Sci. 2021;22(11):5444.
41.    Dugan L, Lovett E, Quick K, Lotharius J, Lin T, O’malley K. Fullerene-based antioxidants and neurodegenerative disorders. Parkinsonism Relat Disord. 2001;7(3):243-246.
42.    Dugan LL, Turetsky DM, Du C, Lobner D, Wheeler M, Almli CR, et al. Carboxyfullerenes as neuroprotective agents. PNAS. 1997;94(17):9434-9439.
43.    Makarova E, Gordon RY, Podolski IY. Fullerene C60 prevents neurotoxicity induced by intrahippocampal microinjection of amyloid-β peptide. J Nanosci Nanotechnol. 2012;12(1):119-126.
44.    Rakhit S, Nordness MF, Lombardo SR, Cook M, Smith L, Patel MB, editors. Management and challenges of severe traumatic brain injury. Seminars in Respiratory and Critical Care Medicine; 2020: Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York.
45.    Xu G, Guo J, Sun C. Eucalyptol ameliorates early brain injury after subarachnoid haemorrhage via antioxidant and anti-inflammatory effects in a rat model. Pharm Biol. 2021;59(1):112-118.
46.    Huang SS, Tsai SK, Chih CL, Chiang L-Y, Hsieh HM, Teng CM, et al. Neuroprotective effect of hexasulfobutylated C60 on rats subjected to focal cerebral ischemia. Free Radic Biol Med. 2001;30(6):643-649.
47.    Lin AM-Y, Fang S-F, Lin S-Z, Chou C-K, Luh T-Y, Ho L-T. Local carboxyfullerene protects cortical infarction in rat brain. Neurosci Res. 2002;43(4):317-321.
48.    Zha Y-y, Yang B, Tang M-l, Guo Q-c, Chen J-t, Wen L-p, et al. Concentration-dependent effects of fullerenol on cultured hippocampal neuron viability. Int J Nanomedicine. 2012:3099-3109.
49.    Lin AM, Chyi B, Wang S, Yu HH, Kanakamma P, Luh TY, et al. Carboxyfullerene prevents iron‐induced oxidative stress in rat brain. J Neurochem. 1999;72(4):1634-1640.
50.    Lao F, Li W, Han D, Qu Y, Liu Y, Zhao Y, et al. Fullerene derivatives protect endothelial cells against NO-induced damage. Nanotechnology. 2009;20(22):225103.
51.    Shafiq F, Iqbal M, Raza SH, Akram NA, Ashraf M. Fullerenol [60] Nano-cages for protection of crops against oxidative stress: a critical review. J Plant Growth Regul. 2023;42(3):1267-1290.
52.    Ali SS, Hardt JI, Quick KL, Kim-Han JS, Erlanger BF, Huang T-t, et al. A biologically effective fullerene (C60) derivative with superoxide dismutase mimetic properties. Free Radic Biol Med. 2004;37(8):1191-1202.
53.    Cai X, Jia H, Liu Z, Hou B, Luo C, Feng Z, et al. Polyhydroxylated fullerene derivative C60 (OH) 24 prevents mitochondrial dysfunction and oxidative damage in an MPP+‐induced cellular model of Parkinson’s disease. J Neurosci Res. 2008;86(16):3622-3634.
54.    Wu R-M, Mohanakumar KP, Murphy DL, Chiueh CC. Antioxidant mechanism and protection of nigral neurons against MPP+ toxicity by deprenyl (selegiline). Ann N Y Acad Sci. 1994;738:214-221.
55.    Malekzadeh D, Asadi A, Abdolmaleki A, Dehghan G. Neuroprotection of fullerene in improving cognitive–behavioral disruptions and neurobiochemical enzymes activities. Nanomedicine. 2023;18(6):525-539.
56.    Agraharam G, Saravanan N, Girigoswami A, Girigoswami K. Future of Alzheimer’s disease: nanotechnology-based diagnostics and therapeutic approach. BioNanoScience. 2022;12(3):1002-1017.
57.    Shi E, Kyung A, editors. Study on the Biochemical Nanoparticles for Bio-imaging and Molecular Diagnostics of Alzheimer’s Disease. 2020 IEEE International IOT, Electronics and Mechatronics Conference (IEMTRONICS); 2020: IEEE.
58.    Kepinska M, Kizek R, Milnerowicz H. Fullerene as a doxorubicin nanotransporter for targeted breast cancer therapy: Capillary electrophoresis analysis. Electrophoresis. 2018;39(18):2370-2379.
59.    Xie L, Luo Y, Lin D, Xi W, Yang X, Wei G. The molecular mechanism of fullerene-inhibited aggregation of Alzheimer’s β-amyloid peptide fragment. Nanoscale. 2014;6(16):9752-9762.
60.    Vorobyov V, Kaptsov V, Gordon R, Makarova E, Podolski I, Sengpiel F. Neuroprotective Effects of Hydrated Fullerene C 60: Cortical and Hippocampal EEG Interplay in an Amyloid-Infused Rat Model of Alzheimer’s Disease. J Alzheimers Dis. 2015;45(1):217-233.
61.    da Silva Gonçalves A, França TCC, Vital de Oliveira O. Computational studies of acetylcholinesterase complexed with fullerene derivatives: A new insight for Alzheimer disease treatment. J Biomol Struct Dyn. 2016;34(6):1307-1316.
62.    Tanzi L, Terreni M, Zhang Y. Synthesis and biological application of glyco-and peptide derivatives of fullerene C60. Eur J Med Chem. 2022;230:114104.
63.    Ghosh D, Dutta G, Sugumaran A, Chakrabarti G, Debnath B. Fullerenes: Bucky Balls in the Therapeutic Application.  Carbon Nanostructures in Biomedical Applications: Springer; 2023. p. 1-25.
64.    Al Fawaz YF. Antibacterial efficacy of NanoCare, Fullerene (C60) activated by UV light, and Morinda Oleifera against S. Mutans and bond integrity of composite resin to Caries affected dentin. Photodiagnosis Photodyn Ther. 2023:103926.
65.    Du Z, Gao N, Wang X, Ren J, Qu X. Near‐Infrared Switchable Fullerene‐Based Synergy Therapy for Alzheimer’s Disease. Small. 2018;14(33):1801852.
66.    Li M, Xu C, Wu L, Ren J, Wang E, Qu X. Self‐Assembled Peptide–Polyoxometalate Hybrid Nanospheres: Two in One Enhances Targeted Inhibition of Amyloid β‐Peptide Aggregation Associated with Alzheimer’s Disease. Small. 2013;9(20):3455-3461.
67.    Li Z, Wang C, Cheng L, Gong H, Yin S, Gong Q, et al. PEG-functionalized iron oxide nanoclusters loaded with chlorin e6 for targeted, NIR light induced, photodynamic therapy. Biomaterials. 2013;34(36):9160-9170.
68.    Alexander AG, Marfil V, Li C. Use of Caenorhabditis elegans as a model to study Alzheimer’s disease and other neurodegenerative diseases. Front Genet. 2014;5:279.
69.    Alvarez J, Alvarez-Illera P, Santo-Domingo J, Fonteriz RI, Montero M. Modeling Alzheimer’s disease in caenorhabditis elegans. Biomedicines. 2022;10(2):288.
70.    Ferreira JP, Albuquerque HM, Cardoso SM, Silva AM, Silva VL. Dual-target compounds for Alzheimer’s disease: natural and synthetic AChE and BACE-1 dual-inhibitors and their structure-activity relationship (SAR). Eur J Med Chem. 2021;221:113492. 
71.    Shityakov S, Förster C. Multidrug resistance protein P-gp interaction with nanoparticles (fullerenes and carbon nanotube) to assess their drug delivery potential: A theoretical molecular docking study. Int J Comput Biol Drug Des. 2013;6(4):343-357.
72.    Önmez A, Alpay M, Torun S, Şahin İE, Öneç K, Değirmenci Y. Serum seladin-1 levels in diabetes mellitus and Alzheimer’s disease patients. Acta Neurol Belg. 2020;120:1399-1404.
73.    Sliz E, Shin J, Syme C, Patel Y, Parker N, Richer L, et al. A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents. Mol Psychiatry. 2021;26(8):3795-3805.
74.    Nørregaard R, Mutsaers HA, Frøkiær J, Kwon T-H. Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis. Physiol Rev. 2023;103(4):2847-2892.
75.    Frisoni P, Diani L, De Simone S, Bosco MA, Cipolloni L, Neri M. Forensic Diagnosis of Freshwater or Saltwater Drowning Using the Marker Aquaporin 5: An Immunohistochemical Study. Medicina. 2022;58(10):1458.
76.    Mayor E. Neurotrophic effects of intermittent fasting, calorie restriction and exercise: a review and annotated bibliography. Front Aging. 2023;4:1161814.
77.    Sechi GP, Bardanzellu F, Pintus MC, Sechi MM, Marcialis MA, Fanos V. Thiamine as a possible neuroprotective strategy in neonatal hypoxic-ischemic encephalopathy. Antioxidants. 2021;11(1):42.
78.    Asil SM, Ahlawat J, Barroso GG, Narayan M. Nanomaterial based drug delivery systems for the treatment of neurodegenerative diseases. Biomater Sci. 2020;8(15):4109-4128.
79.    Parlak C, Alver Ö. A density functional theory investigation of the surface interaction of Propofol drug with silicon decorated C60 fullerene. Eskişehir Tek Üniv Bilim Tek Derg B Teorik Bilimler. 2021;9(1):15-19.
80.    Tashiro R, Bautista-Garrido J, Ozaki D, Sun G, Obertas L, Mobley AS, et al. Transplantation of astrocytic mitochondria modulates neuronal antioxidant defense and neuroplasticity and promotes functional recovery after intracerebral hemorrhage. J Neurosci. 2022;42(36):7001-14.
81.    Timoshen K, Khrebina A, Lebedev V, Loglio G, Miller R, Sedov V, et al. Dynamic surface properties of carboxyfullerene solutions. J Mol Liq. 2023;372:121174.
82.    Liu J, Shi L, Wang Y, Li M, Zhou C, Zhang L, et al. Ruthenium-based metal-organic framework with reactive oxygen and nitrogen species scavenging activities for alleviating inflammation diseases. Nano Today. 2022;47:101627.
83.    Alabrahim OAA, Azzazy HME-S. Polymeric nanoparticles for dopamine and levodopa replacement in Parkinson’s disease. Nanoscale Adv. 2022;4(24):5233-5244.
84.    Bhosale A, Paul G, Mazahir F, Yadav A. Theoretical and applied concepts of nanocarriers for the treatment of Parkinson’s diseases. OpenNano. 2023;9:100111.
85.    Uprety A, Kang Y, Kim SY. Blood-brain barrier dysfunction as a potential therapeutic target for neurodegenerative disorders. Arch Pharmacal Res. 2021;44(5):487-498.
86.    Li X, Deng R, Li J, Li H, Xu Z, Zhang L, et al. Oral [60] fullerene reduces neuroinflammation to alleviate Parkinson’s disease via regulating gut microbiome. Theranostics. 2023;13(14):4936.
87.    Reina M, Celaya CA, Muñiz J. C36 and C35E (E= N and B) fullerenes as potential nanovehicles for neuroprotective drugs: A comparative DFT study. ChemistrySelect. 2021;6(19):4844-4858.
88.    Frazao NF, Albuquerque EL, Fulco UL, Azevedo DL, Mendonça GL, Lima-Neto P, et al. Four-level levodopa adsorption on C 60 fullerene for transdermal and oral administration: A computational study. RSC Adv. 2012;2(22):8306-8322. 
89.    Stetska V, Dovbynchuk T, Makedon Y, Dziubenko N. The effect of water-soluble pristine C60 fullerene on 6-OHDA-induced Parkinson’s disease in rats. Regul Mech Biosyst. 2021;12(4):599-607.
90.    Teixeira MI, Lopes C, Amaral MH, Costa P. Current insights on lipid nanocarrier-assisted drug delivery in the treatment of neurodegenerative diseases. Eur J Pharm Biopharm. 2020;149:192-217.
91.    Guo Z-H, Khattak S, Rauf MA, Ansari MA, Alomary MN, Razak S, et al. Role of Nanomedicine-Based Therapeutics in the Treatment of CNS Disorders. Molecules. 2023;28(3):1283.
92.    Bao Q, Hu P, Xu Y, Cheng T, Wei C, Pan L, et al. Simultaneous blood–brain barrier crossing and protection for stroke treatment based on edaravone-loaded ceria nanoparticles. ACS Nano. 2018; 12: 6794–805. J Build Eng. 2021;43.
93.    Heckman KL, Estevez AY, DeCoteau W, Vangellow S, Ribeiro S, Chiarenzelli J, et al. Variable in vivo and in vitro biological effects of cerium oxide nanoparticle formulations. Front Pharmacol. 2020;10:1599.
94.    Maeda Y, Nagase S, Akasaka T. Radical reaction and Photoreaction.  Handbook of Fullerene Science and Technology: Springer; 2022. p. 1-46.
95.    Polo Arroyabe Y. Controlling the fate of stem cells through two-and three-dimensional scaffolds based on bioresorbable polymers and graphenen derivatives: a study towards nerve tissue regeneration. 2022.
96.    Sun Y, Xu B, Pan X, Wang H, Wu Q, Li S, et al. Carbon-based nanozymes: Design, catalytic mechanism, and bioapplication. Coord Chem Rev. 2023;475:214896.
97.    Tu Nguyen K, Nguyet Pham M, Van Vo T, Duan W, Ha-Lien Tran P, Truong-Dinh Tran T. Strategies of engineering nanoparticles for treating neurodegenerative disorders. Curr Drug Metab. 2017;18(9):786-797.
98.    Krishnan Nair C, Menon A, Chandrasekharan D. The importance of nanoparticles for development of radioprotective agents. Int J Radiol Radiat Ther. 2023;10(5):112-117.
99.    Ali SS, Hardt JI, Dugan LL. SOD activity of carboxyfullerenes predicts their neuroprotective efficacy: a structure-activity study. NBM. 2008;4(4):283-294.
100. de Alcantara Lemos J, Soares DCF, Pereira NC, Gomides LS, de Oliveira Silva J, Bruch GE, et al. Preclinical evaluation of PEG-Multiwalled carbon nanotubes: Radiolabeling, biodistribution and toxicity in mice. J Drug Deliv Sci Technol. 2023:104607.
101. Shabani M, Erfani S, Abdolmaleki A, Afzali FE, Khoshnazar SM. Alpha-pinene modulates inflammatory response and protects against brain ischemia via inducible nitric oxide synthase-nuclear factor–kappa B-cyclooxygenase-2 pathway. Mol Biol Rep. 2023:1-12.
102. Mondal J, An JM, Surwase SS, Chakraborty K, Sutradhar SC, Hwang J, et al. Carbon nanotube and its derived nanomaterials based high performance biosensing platform. Biosensors. 2022;12(9):731.
103. Zhang B, Jiang X. Magnetic Nanoparticles Mediated Thrombolysis–a Review. IEEE Open J Nanotechnol. 2023;5(42):6457-6470.
104. Naz F, Siddique YH. Nanotechnology: Its application in treating neurodegenerative diseases. CNS Neurol Disord Drug Targets. 2021;20(1):34-53.
105. Monti D, Moretti L, Salvioli S, Straface E, Malorni W, Pellicciari R, et al. C60 carboxyfullerene exerts a protective activity against oxidative stress-induced apoptosis in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2000;277(3):711-717.
106. Liu H, Zhang L, Yan M, Yu J. Carbon nanostructures in biology and medicine. J Mater Chem B. 2017;5(32):6437-6450.
107. Parvez S, Kaushik M, Ali M, Alam MM, Ali J, Tabassum H, et al. Dodging blood brain barrier with “nano” warriors: Novel strategy against ischemic stroke. Theranostics. 2022;12(2):689.
108. MATSUSHIMA Y, HOSHINO Y. Cell viability of C60 fullerene with three-dimensional culture using glass fiber and two-dimensional culture. Nanobiomedicine. 2020;12(2):110-114.
109. Kazemzadeh H, Mozafari M. Fullerene-based delivery systems. Drug Discov Today. 2019;24(3):898-905.
110. Salatin S, Farhoudi M, Farjami A, Maleki Dizaj S, Sharifi S, Shahi S. Nanoparticle Formulations of Antioxidants for the Management of Oxidative Stress in Stroke: A Review. Biomedicines. 2023;11(11):3010.
111. Ren H, Li J, Peng A, Liu T, Chen M, Li H, et al. Water-soluble, alanine-modified fullerene C60 promotes the proliferation and neuronal differentiation of neural stem cells. Int J Mol Sci. 2022;23(10):5714.
112. Vani JR, Mohammadi MT, Foroshani MS, Jafari M. Polyhydroxylated fullerene nanoparticles attenuate brain infarction and oxidative stress in rat model of ischemic stroke. EXCLI journal. 2016;15:378.
113. Fluri F, Grünstein D, Cam E, Ungethuem U, Hatz F, Schäfer J, et al. Fullerenols and glucosamine fullerenes reduce infarct volume and cerebral inflammation after ischemic stroke in normotensive and hypertensive rats. Exp Neurol. 2015;265:142-151.
114. Docampo MJ, Lutterotti A, Sospedra M, Martin R. Mechanistic and biomarker studies to demonstrate immune tolerance in multiple sclerosis. Front Immunol. 2022;12:787498.
115. Chrabąszcz K, Kołodziej M, Roman M, Pięta E, Piergies N, Rudnicka-Czerwiec J, et al. Carotenoids contribution in rapid diagnosis of multiple sclerosis by Raman spectroscopy. BBA. 2023:130395.
116. Escribano BM, Muñoz-Jurado A, Luque E, Galván A, LaTorre M, Caballero-Villarraso J, et al. Effect of the combination of different therapies on oxidative stress in the experimental model of multiple sclerosis. Neuroscience. 2023;529:116-128.
117. Fakhri S, Abdian S, Zarneshan SN, Moradi SZ, Farzaei MH, Abdollahi M. Nanoparticles in combating neuronal dysregulated signaling pathways: recent approaches to the nanoformulations of phytochemicals and synthetic drugs against neurodegenerative diseases. Int J Nanomedicine. 2022:299-331.
118. Flor Rdl, Robertson J, Shevchenko RV, Alavijeh M, Bickerton S, Fahmy T, et al. Multiple sclerosis: LIFNano-CD4 for trojan horse delivery of the neuro-protective biologic “LIF” into the brain: Preclinical proof of concept. Front Med Technol. 2021;3:640569.
119. Marcos-Contreras OA, Greineder CF, Kiseleva RY, Parhiz H, Walsh LR, Zuluaga-Ramirez V, et al. Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood–brain barrier. PNAS. 2020;117(7):3405-3414.
120. Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petrovic-Stojkovic S, Puckett L, et al. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J Clin Invest. 2008;118(4):1532-1543.
121. Mittal KR, Pharasi N, Sarna B, Singh M, Rachana, Haider S, et al. Nanotechnology-based drug delivery for the treatment of CNS disorders. Transl Neurosci. 2022;13(1):527-546.
122. Cifuentes-Rius A, Desai A, Yuen D, Johnston AP, Voelcker NH. Inducing immune tolerance with dendritic cell-targeting nanomedicines. Nat Nanotechnol. 2021;16(1):37-46.
123. Hlavaty KA, Luo X, Shea LD, Miller SD. Cellular and molecular targeting for nanotherapeutics in transplantation tolerance. Clin Immunol. 2015;160(1):14-23.
124. Sodhi RK, Madan J, Babu MA, Singh Y. Nanoformulations for neurodegenerative disorders.  Multifunctional Nanocarriers: Elsevier; 2022. p. 419-439.
125. Thorp EB, Boada C, Jarbath C, Luo X. Nanoparticle platforms for antigen-specific immune tolerance. Front Immunol. 2020;11:945.
126. Gurumukhi VC, Bari SB. Quality by design (QbD)–based fabrication of atazanavir-loaded nanostructured lipid carriers for lymph targeting: bioavailability enhancement using chylomicron flow block model and toxicity studies. Drug Deliv Transl Res. 2022;12(5):1230-1252.
127. Pal K. Nanovaccinology: Clinical Application of Nanostructured Materials Research to Translational Medicine: Springer Nature; 2023.
128. Babu NS. Neuroprotective Micro RNAs as a Potential Therapeutic for Hiv-Associated Neurocognitive Disorders: University of Pittsburgh; 2020.
129. Medzhidova M, Abdullaeva M, Fedorova N, Romanova V, Kushch A. In vitro antiviral activity of fullerene amino acid derivatives in cytomegalovirus infection. Antibiotiki i Khimioterapiia= Antibiot Chemother. 2004;49(8-9):13-20.
130. Lin C-M, Lu T-Y. C60 fullerene derivatized nanoparticles and their application to therapeutics. Recent Pat Nanotechnol. 2012;6(2):105-113.
131. Suresh Babu N. Neuroprotective micro RNAs as a potential therapeutic for HIV-associated neurocognitive disorders: University of Pittsburgh; 2021.
132. Schinazi R, Sijbesma R, Srdanov G, Hill C, Wudl F. Synthesis and virucidal activity of a water-soluble, configurationally stable, derivatized C60 fullerene. Antimicrob Agents Chemother. 1993;37(8):1707-1710.
133. Shoji M, Takahashi E, Hatakeyama D, Iwai Y, Morita Y, Shirayama R, et al. Anti-influenza activity of c60 fullerene derivatives. PloS one. 2013;8(6):e66337.
134. Bosi S, Da Ros T, Spalluto G, Prato M. Fullerene derivatives: an attractive tool for biological applications. Eur J Med Chem. 2003;38(11-12):913-923.
135. Friedman SH, DeCamp DL, Sijbesma RP, Srdanov G, Wudl F, Kenyon GL. Inhibition of the HIV-1 protease by fullerene derivatives: model building studies and experimental verification. J Am Chem Soc. 1993;115(15):6506-6509.
136. Pantarotto D, Tagmatarchis N, Bianco A, Prato M. Synthesis and biological properties of fullerene-containing amino acids and peptides. Mini Rev Med Chem. 2004;4(7):805-814.
137. Deftu AT, Amuzescu B. Protective Effects of Nanosof® Suspension on Cultured Cells Exposed to H2O2. 2021;12: 2548-2559.
138. Sharma N, Zahoor I, Singh S, Behl T, Antil A. Expatiating the pivotal role of Dendrimers as emerging nanocarrier for management of Liver Disorders. J Integr Sci Technol. 2023;11(2):489-494.
139. Solassol J, Crozet C, Lehmann S. Prion propagation in cultured cells. Br Med Bull. 2003;66(1):87-97.
140. Ye S, Zhou T, Pan D, Lai Y, Yang P, Chen M, et al. Fullerene C60 derivatives attenuated microglia-mediated prion peptide neurotoxicity. J Biomed Nanotechnol. 2016;12(9):1820-1833.
141. Singh S, Barik D, Lawrie K, Mohapatra I, Prasad S, Naqvi AR, et al. Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment. Int J Mol Sci. 2023;24(19):14960.
142. Paul D, Barhoi D. Glioblastoma: Physiopathology and Complications.  Physiology and Function of Glial Cells in Health and Disease: IGI Global; 2024. p. 261-279.
143. Kumar M, Sharma G, Kumar R, Singh B, Katare OP, Raza K. Lysine-based C60-fullerene nanoconjugates for monomethyl fumarate delivery: a novel nanomedicine for brain cancer cells. ACS Biomater Sci Eng. 2018;4(6):2134-2142.
144. Kumar A, Kumar V, Singh K, Kumar S, Kim Y-S, Lee Y-M, et al. Therapeutic advances for Huntington’s disease. Brain Sci. 2020;10(1):43.
145. Hickman RA, Faust PL, Marder K, Yamamoto A, Vonsattel J-P. The distribution and density of Huntingtin inclusions across the Huntington disease neocortex: regional correlations with Huntingtin repeat expansion independent of pathologic grade. cta Neuropathol. Commun. 2022;10(1):1-12.
146. Seillier C, Lesept F, Toutirais O, Potzeha F, Blanc M, Vivien D. Targeting NMDA receptors at the neurovascular unit: Past and future treatments for central nervous system diseases. Int J Mol Sci. 2022;23(18):10336.
147. Temitayo GI, Olaiya OG. Corticohippocampal Neuroenergetics and histomorphology in aluminium-induced neurotoxicity: Putative therapeutic roles of ascorbic acid and nicotine. BioRxiv. 2020:2020.07. 09.195495.
148. Fão L, Rego AC. Mitochondrial and redox-based therapeutic strategies in Huntington’s disease. Antioxid Redox Signal. 2021;34(8):650-673.
149. Gupta S, Khan A, Vishwas S, Gulati M, Singh TG, Dua K, et al. Demethyleneberberine: A possible treatment for Huntington’s disease. Med Hypotheses. 2021;153:110639.
150. Ji T, Kohane DS. Nanoscale systems for local drug delivery. Nano today. 2019;28:100765.
151. Bolshakova OI, Borisenkova AA, Golomidov IM, Komissarov AE, Slobodina AD, Ryabova EV, et al. Fullerenols Prevent Neuron Death and Reduce Oxidative Stress in Drosophila Huntington’s Disease Model. Cells. 2022;12(1):170.
152. Baumgartner T, Pitsch J, Olaciregui‐Dague K, Hoppe C, Racz A, Rüber T, et al. Seizure underreporting in LGI1 and CASPR2 antibody encephalitis. Epilepsia. 2022;63(9):e100-e5.
153. Asadi A, Abdolmaleki A. New Drugs and their Mechanism in the Treatment of Epilepsy. Neurosci. J. Shefaye Khatam. 2022;10(2):104-110.
154. Matias M, Santos AO, Silvestre S, Alves G. Fighting Epilepsy with Nanomedicines—Is This the Right Weapon? Pharmaceutics. 2023;15(2):306.
155. Mojarrad F, Asadi A, Abdolmaleki A, Mirzaee S, Zahri S. Preparation of cinnamon-coated cerium oxide nanoparticles and evaluation of their anticonvulsant effect in rats. Pharm Chem J. 2023;57(5):648-655.
156. Pedrero SG, Staedler D, Gerber-Lemaire S. Recent Developments on the Use of Nanomaterials for the Treatment of Epilepsy. Mini-Rev Med Chem. 2022;22(11):1460-1475.
157. He Z, Yin G, Li QQ, Zeng Q, Duan J. Diabetes mellitus causes male reproductive dysfunction: a review of the evidence and mechanisms. In vivo. 2021;35(5):2503-2511.
158. Bal R, Türk G, Tuzcu M, Yilmaz O, Ozercan I, Kuloglu T, et al. Protective effects of nanostructures of hydrated C60 fullerene on reproductive function in streptozotocin-diabetic male rats. Toxicology. 2011;282(3):69-81.
159. Furman BL. Streptozotocin‐induced diabetic models in mice and rats. Curr Protoc. 2021;1(4):e78.
160. Li X, Zhen M, Zhou C, Deng R, Yu T, Wu Y, et al. Gadofullerene nanoparticles reverse dysfunctions of pancreas and improve hepatic insulin resistance for type 2 diabetes mellitus treatment. ACS nano. 2019;13(8):8597-8608.
161. Namdar F, Bahrami F, Bahari Z, Ghanbari B, Shahyad S, Mohammadi MT. Fullerene C60 nanoparticle attenuates pain and tumor necrosis factor-α protein expression in the hippocampus following diabetic neuropathy in rats. Physiol Pharmacol. 2022;26(4):451-458.
162. Ruiz‐Santaquiteria M, Illescas BM, Abdelnabi R, Boonen A, Mills A, Martí‐Marí O, et al. Multivalent Tryptophan‐and Tyrosine‐Containing [60] Fullerene Hexa‐Adducts as Dual HIV and Enterovirus A71 Entry Inhibitors. Chem Eur J. 2021;27(41):10700-10710.
163. Malik R, Patil S. Nanotechnology: Regulatory outlook on nanomaterials and nanomedicines in United States, Europe and India. Appl Clin Res. 2020;7(3):225-236.
164. Ramachandran G, Wolf SM, Paradise J, Kuzma J, Hall R, Kokkoli E, et al. Recommendations for oversight of nanobiotechnology: dynamic oversight for complex and convergent technology.  Emerg Technol Routledge. 2020. p. 379-405.
165. Oberdörster E. Manufactured nanomaterials (fullerenes, C60) induce oxidative stress in the brain of juvenile largemouth bass. Environ Health Perspect. 2004;112(10):1058-1062.
166. Mason TJ, Vinatoru M. Sonochemistry: Fundamentals and Evolution: Walter de Gruyter GmbH & Co KG; 2023.
167. Heidari SM, Anctil A. Identifying alternative solvents for C60 manufacturing using singular and combined toxicity assessments. J Hazard Mater. 2020;393:122337.
168. Quick KL, Ali SS, Arch R, Xiong C, Wozniak D, Dugan LL. A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice. Neurobiol Aging. 2008;29(1):117-128.
169. Baati T, Bourasset F, Gharbi N, Njim L, Abderrabba M, Kerkeni A, et al. The prolongation of the lifespan of rats by repeated oral administration of [60] fullerene. Biomaterials. 2012;33(19):4936-4946.
170. Malhotra N, Audira G, Castillo AL, Siregar P, Ruallo JMS, Roldan MJ, et al. An update report on the biosafety and potential toxicity of fullerene-based nanomaterials toward aquatic animals. Oxid Med Cell Longev. 2021;2021:191-6.
171. Zhu S, Oberdörster E, Haasch ML. Toxicity of an engineered nanoparticle (fullerene, C60) in two aquatic species, Daphnia and fathead minnow. Mar Environ Res. 2006;62:S5-S9.
172. Pesado-Gómez C, Serrano-García JS, Amaya-Flórez A, Pesado-Gómez G, Soto-Contreras A, Morales-Morales D, et al. Fullerenes: Historical background, novel biological activities versus possible health risks. Coord Chem Rev. 2024;501:215550.
173. Rananaware P, Brahmkhatri VP. Fullerene Derivatives for Drug Delivery applications.  Advanced Porous Biomaterials for Drug Delivery Applications: CRC Press; 2022. p. 373-393.
174. Bratovcic A, editor Biomedical Application of Nanocomposites Based on Fullerenes-C60. International Conference “New Technologies, Development and Applications”; 2023: Springer.
175. Benhouria Y, Essaoudi I, Ainane A, Ahuja R. Dynamic magneto-caloric effect of a C70 fullerene: Dynamic Monte Carlo. Physica E Low Dimens Syst Nanostruct. 2019;108:191-196.
176. Dastjerdi S, Akgöz B. On the statics of fullerene structures. Int J Eng Sci. 2019;142:125-144.