BRAIN-TARGETED NANO-DRUG DELIVERY FOR THE TREATMENT OF PARKINSON'S DISEASE

Abstract

Parkinson’s Disease affects 2% to 3% of overall individuals aged 65 years or older worldwide and is considered to be the second most common age-related neurodegenerative disease. Neuropathologic features of Parkinson’s Disease attributes to a loss of pigmented dopaminergic neurons in the substantia nigra and the formation of Lewy Bodies, as a result of intracellular accumulation of α-synuclein proteins. To our current day, only a few therapeutic approaches are considered promising, one of which is the Nanoscale approach. It gives an advantage over conventional approaches by offering solutions to complications that occur in the current treatment methods used for Parkinson’s Disease, namely by encapsulating and protecting the drug from extracellular degradations, allowing for a more sustained, efficient, and targeted drug release profile, thus reducing the risk of adverse effects of the drug used. In this study, we review, discuss, and briefly explain the nanoscale approaches, alternative administration routes, and studies conducted in vivo and in vitro for an efficient treatment and an alternative approach to Parkinson’s Disease.

Keywords

• Blood–Brain Barrier
• Nano-drug Delivery
• Nanoparticles
• Parkinson's Disease

References

1. Abedi-Gaballu, F., Dehghan, G., Ghaffari, M., Yekta, R., Abbaspour-Ravasjani, S., Baradaran, B., Ezzati Nazhad Dolatabadi, J., & Hamblin, M. R. (2018). PAMAM dendrimers as efficient drug and gene delivery nanosystems for cancer therapy. In Applied Materials Today (Vol. 12, pp. 177–190). Elsevier Ltd. https://doi.org/10.1016/j.apmt.2018.05.002
2. Agrawal, M., Ajazuddin, Tripathi, D. K., Saraf, S., Saraf, S., Antimisiaris, S. G., Mourtas, S., Hammarlund-Udenaes, M., & Alexander, A. (2017). Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer’s disease. In Journal of Controlled Release (Vol. 260, pp. 61–77). Elsevier B.V. https://doi.org/10.1016/j.jconrel.2017.05.019
3. Alexander, K. (2018). Biomedical Applications of Nano-Sized Polymeric Micelles and Polyion Complexes. Journal of Siberian Federal University. Biology, 11(2), 110–118. https://doi.org/10.17516/1997-1389-0053
4. Arango, D., Bittar, A., Esmeral, N. P., Ocasión, C., Muñoz-Camargo, C., Cruz, J. C., Reyes, L. H., & Bloch, N. I. (2021). Understanding the Potential of Genome Editing in Parkinson’s Disease. International Journal of Molecular Sciences 2021, Vol. 22, Page 9241, 22(17), 9241. https://doi.org/10.3390/IJMS22179241
5. Azeem, A., Talegaonkar, S., Negi, L. M., Ahmad, F. J., Khar, R. K., & Iqbal, Z. (2012). Oil based nanocarrier system for transdermal delivery of ropinirole: A mechanistic, pharmacokinetic and biochemical investigation. International Journal of Pharmaceutics, 422(1–2), 436–444. https://doi.org/10.1016/j.ijpharm.2011.10.039
6. Balestrino, R., & Schapira, A. H. V. (2020). Parkinson disease. European Journal of Neurology, 27(1), 27–42. https://doi.org/10.1111/ENE.14108
7. Banerjee, D., Das, P. K., & Mukherjee, J. (2023). Nervous System. Textbook of Veterinary Physiology, 265–293. https://doi.org/10.1007/978-981-19-9410-4_11
8. Batrakova, E. v., & Kim, M. S. (2015). Using exosomes, naturally-equipped nanocarriers, for drug delivery. Journal of Controlled Release, 219, 396–405. https://doi.org/10.1016/j.jconrel.2015.07.030

9. Bolger, G. T. (2018). Routes of Drug Administration ☆. In Reference Module in Biomedical Sciences. Elsevier. https://doi.org/10.1016/B978-0-12-801238-3.11099-2
10. Braak, H., del Tredici, K., Rüb, U., de Vos, R. A. I., Jansen Steur, E. N. H., & Braak, E. (2003). Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging, 24(2), 197–211. https://doi.org/10.1016/S0197-4580(02)00065-9
11. Castro, K. C. de, Costa, J. M., & Campos, M. G. N. (2022). Drug-loaded polymeric nanoparticles: a review. International Journal of Polymeric Materials and Polymeric Biomaterials, 71(1), 1–13. https://doi.org/10.1080/00914037.2020.1798436
12. Chen, M., Quan, G., Sun, Y., Yang, D., Pan, X., & Wu, C. (2020). Nanoparticles-encapsulated polymeric microneedles for transdermal drug delivery. Journal of Controlled Release, 325, 163–175. https://doi.org/10.1016/j.jconrel.2020.06.039
13. Chillag-Talmor, O., Giladi, N., Linn, S., Gurevich, T., El-Ad, B., Silverman, B., Friedman, N., & Peretz, C. (2011). Use of a refined drug tracer algorithm to estimate prevalence and incidence of Parkinson’s disease in a large israeli population. Journal of Parkinson’s Disease, 1(1), 35–47. https://doi.org/10.3233/JPD-2011-11024
14. da Silva Córneo, E., de Bem Silveira, G., Scussel, R., Correa, M. E. A. B., da Silva Abel, J., Luiz, G. P., Feuser, P. E., Silveira, P. C. L., & Machado-de-Ávila, R. A. (2020). Effects of gold nanoparticles administration through behavioral and oxidative parameters in animal model of Parkinson’s disease. Colloids and Surfaces B: Biointerfaces, 196, 111302. https://doi.org/10.1016/j.colsurfb.2020.111302
15. Date, A. A., Hanes, J., & Ensign, L. M. (2016). Nanoparticles for oral delivery: Design, evaluation and state-of-the-art. Journal of Controlled Release, 240, 504–526. https://doi.org/10.1016/j.jconrel.2016.06.016 de Bem Silveira, G., Muller, A. P., Machado-De-Ávila, R. A., & Silveira, P. C. L. (2021). Advance in the use of gold nanoparticles in the treatment of neurodegenerative diseases: New perspectives. In Neural Regeneration Research (Vol. 16, Issue 12, pp. 2425–2426). Wolters Kluwer Medknow Publications. https://doi.org/10.4103/1673-5374.313040
16. Ding, S., Khan, A. I., Cai, X., Song, Y., Lyu, Z., Du, D., Dutta, P., & Lin, Y. (2020). Overcoming blood-brain barrier transport: Advances in nanoparticle-based drug delivery strategies. Materials Today (Kidlington, England), 37, 112. https://doi.org/10.1016/J.MATTOD.2020.02.001
17. Duan, Y., Dhar, A., Patel, C., Khimani, M., … S. N.-R., & 2020, undefined. (n.d.). A brief review on solid lipid nanoparticles: Part and parcel of contemporary drug delivery systems. Pubs.Rsc.Org. Retrieved July 13, 2022, from https://pubs.rsc.org/en/content/articlehtml/2020/ra/d0ra03491f
18. Dudhipala, N., & Gorre, T. (2020). Neuroprotective Effect of Ropinirole Lipid Nanoparticles Enriched Hydrogel for Parkinson’s Disease: İn vitro, Ex Vivo, Pharmacokinetic and Pharmacodynamic Evaluation. Pharmaceutics, 12(5), 448. https://doi.org/10.3390/pharmaceutics12050448
19. Dykman, L. A., & Khlebtsov, N. G. (2011). Gold Nanoparticles in Biology and Medicine: Recent Advances and Prospects. Acta Naturae, 3(2), 34–55. https://doi.org/10.32607/20758251-2011-3-2-34-56
20. Enriquez-Traba, J., Yarur-Castillo, H. E., Flores, R. J., Weil, T., Roy, S., Usdin, T. B., LaGamma, C. T., Arenivar, M., Wang, H., Tsai, V. S., Moritz, A. E., Sibley, D. R., Moratalla, R., Freyberg, Z. Z., & Tejeda, H. A. (2023). Dissociable control of motivation and reinforcement by distinct ventral striatal dopamine receptors. BioRxiv, 2023.06.27.546539. https://doi.org/10.1101/2023.06.27.546539
21. Esposito, E., Fantin, M., Marti, M., Drechsler, M., Paccamiccio, L., Mariani, P., Sivieri, E., Lain, F., Menegatti, E., Morari, M., & Cortesi, R. (2008). Solid lipid nanoparticles as delivery systems for bromocriptine. Pharmaceutical
22. Research, 25(7), 1521–1530. https://doi.org/10.1007/s11095-007-9514-y Fang, J. Y., Hung, C. F., Chi, C. H., & Chen, C. C. (2009). Transdermal permeation of selegiline from hydrogel-membrane drug delivery systems. International Journal of Pharmaceutics, 380(1–2), 33–39. https://doi.org/10.1016/j.ijpharm.2009.06.025
23. Ferrer-Lorente, R., Lozano-Cruz, T., Fernández-Carasa, I., Miłowska, K., de La Mata, F. J., Bryszewska, M., Consiglio, A., Ortega, P., Gómez, R., & Raya, A. (2021). Cationic Carbosilane Dendrimers Prevent Abnormal α-Synuclein Accumulation in Parkinson’s Disease Patient-Specific Dopamine Neurons. Biomacromolecules, 22(11), 4582–4591. https://doi.org/10.1021/acs.biomac.1c00884
24. Fields, C. R., Bengoa-Vergniory, N., & Wade-Martins, R. (2019). Targeting Alpha-Synuclein as a Therapy for Parkinson’s Disease. Frontiers in Molecular Neuroscience, 12, 496177. https://doi.org/10.3389/FNMOL.2019.00299/BIBTEX
25. Gaba, B., Khan, T., Haider, M. F., Alam, T., Baboota, S., Parvez, S., & Ali, J. (2019). Vitamin E Loaded Naringenin Nanoemulsion via Intranasal Delivery for the Management of Oxidative Stress in a 6-OHDA Parkinson’s Disease Model. BioMed Research International, 2019. https://doi.org/10.1155/2019/2382563
26. Gambaryan, P. Y., Kondrasheva, I. G., Severin, E. S., Guseva, A. A., & Kamensky, A. A. (2014). Increasing the Effciency of Parkinson’s Disease Treatment Using a poly(lactic-co-glycolic acid) (PLGA) Based L-DOPA Delivery System. Experimental Neurobiology, 23(3), 246–252. https://doi.org/10.5607/en.2014.23.3.246
27. Gartziandia, O., Herran, E., Pedraz, J. L., Carro, E., Igartua, M., & Hernandez, R. M. (2015). Chitosan coated nanostructured lipid carriers for brain delivery of proteins by intranasal administration. Colloids and Surfaces B: Biointerfaces, 134, 304–313. https://doi.org/10.1016/j.colsurfb.2015.06.054
28. Gonzalez-Carter, D. A., Leo, B. F., Ruenraroengsak, P., Chen, S., Goode, A. E., Theodorou, I. G., Chung, K. F., Carzaniga, R., Shaffer, M. S. P., Dexter, D. T., Ryan, M. P., & Porter, A. E. (2017). Silver nanoparticles reduce brain inflammation and related neurotoxicity through induction of H 2 S-synthesizing enzymes. Scientific Reports, 7. https://doi.org/10.1038/srep42871
29. Guimarães, D., Cavaco-Paulo, A., & Nogueira, E. (2021). Design of liposomes as drug delivery system for therapeutic applications. In International Journal of Pharmaceutics (Vol. 601, p. 120571). Elsevier B.V. https://doi.org/10.1016/j.ijpharm.2021.120571
30. Haider, M., Abdin, S. M., Kamal, L., & Orive, G. (2020). Nanostructured Lipid Carriers for Delivery of Chemotherapeutics: A Review. Pharmaceutics, 12(3), 288. https://doi.org/10.3390/pharmaceutics12030288
31. Haney, M. J., Klyachko, N. L., Zhao, Y., Gupta, R., Plotnikova, E. G., He, Z., Patel, T., Piroyan, A., Sokolsky, M., Kabanov, A. v., & Batrakova, E. v. (2015). Exosomes as drug delivery vehicles for Parkinson’s disease therapy. Journal of Controlled Release, 207, 18–30. https://doi.org/10.1016/j.jconrel.2015.03.033
32. Herholz, K. (2008). Acetylcholine esterase activity in mild cognitive impairment and Alzheimer’s disease. In European Journal of Nuclear Medicine and Molecular Imaging (Vol. 35, Issue SUPPL. 1, pp. 25–29). Springer. https://doi.org/10.1007/s00259-007-0699-4
33. Hernando, S., Herran, E., Figueiro-Silva, J., Pedraz, J. L., Igartua, M., Carro, E., & Hernandez, R. M. (2018). Intranasal administration of TAT-conjugated lipid nanocarriers loading GDNF for Parkinson’s disease. Molecular Neurobiology, 55(1), 145–155. https://doi.org/10.1007/s12035-017-0728-7
34. Hu, K., Shi, Y., Jiang, W., Han, J., Huang, S., & Jiang, X. (2011). Lactoferrin conjugated PEG-PLGA nanoparticles for brain delivery: Preparation, characterization and efficacy in Parkinsons disease. International Journal of Pharmaceutics, 415(1–2), 273–283. https://doi.org/10.1016/j.ijpharm.2011.05.062
35. Huang, R., Ke, W., Liu, Y., Wu, D., Feng, L., Jiang, C., & Pei, Y. (2010). Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model. Journal of the Neurological Sciences, 290(1–2), 123–130. https://doi.org/10.1016/j.jns.2009.09.032 Iacono, D., Geraci-Erck, M., Rabin, M. L., Adler, C. H., Serrano, G., Beach, T. G., & Kurlan, R. (2015). Parkinson disease and incidental Lewy body disease: Just a question of time? Neurology, 85(19), 1670–1679. https://doi.org/10.1212/WNL.0000000000002102
36. Kabanov, A., & Batrakova, E. (2005). New Technologies for Drug Delivery Across the Blood Brain Barrier. Current Pharmaceutical Design, 10(12), 1355–1363. https://doi.org/10.2174/1381612043384826
37. Kabanov, A. V., & Gendelman, H. E. (2007). Nanomedicine in the diagnosis and therapy of neurodegenerative disorders. In Progress in Polymer Science (Oxford) (Vol. 32, Issues 8–9, pp. 1054–1082). Pergamon. https://doi.org/10.1016/j.progpolymsci.2007.05.014
38. Kane, R. S., & Stroock, A. D. (2007). Nanobiotechnology: Protein-Nanomaterial Interactions. Biotechnology Progress, 23(2), 316–319. https://doi.org/10.1021/bp060388n Kikuchi, T., Morizane, A., Doi, D., Magotani, H., Onoe, H., Hayashi, T., Mizuma, H., Takara, S., Takahashi, R., Inoue, H.,
39. Morita, S., Yamamoto, M., Okita, K., Nakagawa, M., Parmar, M., & Takahashi, J. (2017). Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature, 548(7669), 592–596. https://doi.org/10.1038/NATURE23664
40. Kizelsztein, P., Ovadia, H., Garbuzenko, O., Sigal, A., & Barenholz, Y. (2009). Pegylated nanoliposomes remote-loaded with the antioxidant tempamine ameliorate experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 213(1–2), 20–25. https://doi.org/10.1016/j.jneuroim.2009.05.019
41. Leonardi, A., Crascí, L., Panico, A., & Pignatello, R. (2015). Antioxidant activity of idebenone-loaded neutral and cationic solid-lipid nanoparticles. Pharmaceutical Development and Technology, 20(6), 716–723. https://doi.org/10.3109/10837450.2014.915572
42. Li, Y., Zhu, Z., Huang, T., Zhou, Y., Wang, X., Yang, L., Chen, Z., Yu, W., & Li, P. (2018). The peripheral immune response after stroke—A double edge sword for blood‐brain barrier integrity. CNS Neuroscience & Therapeutics, 24(12), 1115–1128. https://doi.org/10.1111/cns.13081
43. Linhardt, R., Murugesan, S., & Xie, J. (2008). Immobilization of Heparin: Approaches and Applications. Current Topics in Medicinal Chemistry, 8(2), 80–100. https://doi.org/10.2174/156802608783378891
44. Łukasiewicz, S., Mikołajczyk, A., Błasiak, E., Fic, E., & Dziedzicka-Wasylewska, M. (2021). Polycaprolactone Nanoparticles as Promising Candidates for Nanocarriers in Novel Nanomedicines. Pharmaceutics, 13(2), 191. https://doi.org/10.3390/pharmaceutics13020191
45. Majoral, J. P., Zablocka, M., Ciepluch, K., Milowska, K., Bryszewska, M., Shcharbin, D., Katir, N., el Kadib, A., Caminade, A. M., & Mignani, S. (2021). Hybrid phosphorus-viologen dendrimers as new soft nanoparticles: Design and properties. In Organic Chemistry Frontiers (Vol. 8, Issue 16, pp. 4607–4622). Royal Society of Chemistry. https://doi.org/10.1039/d1qo00511a
46. Manatunga, D. C., Godakanda, V. U., Herath, H. M. L. P. B., de Silva, R. M., Yeh, C.-Y., Chen, J.-Y., Akshitha de Silva, A. A., Rajapaksha, S., Nilmini, R., & Nalin de Silva, K. M. (2020). Nanofibrous cosmetic face mask for transdermal delivery of nano gold: synthesis, characterization, release and zebra fish employed toxicity studies. Royal Society Open Science, 7(9), 201266. https://doi.org/10.1098/rsos.201266
47. Mao, B. H., Chen, Z. Y., Wang, Y. J., & Yan, S. J. (2018). Silver nanoparticles have lethal and sublethal adverse effects on development and longevity by inducing ROS-mediated stress responses. Scientific Reports, 8(1), 1–16. https://doi.org/10.1038/s41598-018-20728-z
48. Marsili, L., Rizzo, G., & Colosimo, C. (2018). Diagnostic criteria for Parkinson’s disease: From James Parkinson to the concept of prodromal disease. In Frontiers in Neurology (Vol. 9, Issue MAR). Frontiers Media S.A. https://doi.org/10.3389/fneur.2018.00156
49. McClements, D. J. (2021). Advances in edible nanoemulsions: Digestion, bioavailability, and potential toxicity. In Progress in Lipid Research (Vol. 81, p. 101081). Elsevier Ltd. https://doi.org/10.1016/j.plipres.2020.101081 Md, S., Haque, S., Fazil, M., Kumar, M., Baboota, S., Sahni, J. K., & Ali, J. (2014). Optimised nanoformulation of bromocriptine for direct nose-to-brain delivery: Biodistribution, pharmacokinetic and dopamine estimation by ultra-HPLC/mass spectrometry method. Expert Opinion on Drug Delivery, 11(6), 827–842. https://doi.org/10.1517/17425247.2014.894504
50. Mota, J. P. B., & Esteves, I. A. A. C. (2007). Simplified gauge-cell method and its application to the study of capillary phase transition of propane in carbon nanotubes. Adsorption, 13(1), 21–32. https://doi.org/10.1007/s10450-007-9006-8
51. Mukhtoraliyeva, S., Tukhtamurodova, Z., & Djuraeva, B. (2024). NERVOUS SYSTEM AND ITS MAIN FUNCTIONS. Евразийский Журнал Медицинских и Естественных Наук, 4(1), 61–67. https://doi.org/10.5281/ZENODO.5884973
52. Mustafa, G., Baboota, S., Ahuja, A., & Ali, J. (2012). Formulation Development of Chitosan Coated Intra Nasal Ropinirole Nanoemulsion for Better Management Option of Parkinson: An İn vitro Ex Vivo Evaluation. Current Nanoscience, 8(3), 348–360. https://doi.org/10.2174/157341312800620331
53. Nagatsu, T. (2023). Catecholamines and Parkinson’s disease: tyrosine hydroxylase (TH) over tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GCH1) to cytokines, neuromelanin, and gene therapy: a historical overview. Journal of Neural Transmission (Vienna, Austria : 1996). https://doi.org/10.1007/S00702-023-02673-Y
54. Nalls, M. A., Pankratz, N., Lill, C. M., Do, C. B., Hernandez, D. G., Saad, M., Destefano, A. L., Kara, E., Bras, J., Sharma, M., Schulte, C., Keller, M. F., Arepalli, S., Letson, C., Edsall, C., Stefansson, H., Liu, X., Pliner, H., Lee, J. H., … Ansorge, O. (2014). Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nature Genetics, 46(9), 989–993. https://doi.org/10.1038/ng.3043
55. Nirale, P., Paul, A., & Yadav, K. S. (2020). Nanoemulsions for targeting the neurodegenerative diseases: Alzheimer’s, Parkinson’s and Prion’s. In Life Sciences (Vol. 245, p. 117394). Elsevier Inc. https://doi.org/10.1016/j.lfs.2020.117394
56. Onodera, A., Nishiumi, F., Kakiguchi, K., Tanaka, A., Tanabe, N., Honma, A., Yayama, K., Yoshioka, Y., Nakahira, K., Yonemura, S., Yanagihara, I., Tsutsumi, Y., & Kawai, Y. (2015). Short-term changes in intracellular ROS localisation after the silver nanoparticles exposure depending on particle size. Toxicology Reports, 2, 574–579. https://doi.org/10.1016/j.toxrep.2015.03.004
57. Pardeshi, C. v, Rajput, P. v, Belgamwar, V. S., Tekade, A. R., & Surana, S. J. (2013a). Drug Delivery Novel surface modified solid lipid nanoparticles as intranasal carriers for ropinirole hydrochloride: application of factorial design approach Novel surface modified solid lipid nanoparticles as intranasal carriers for ropinirole hydrochloride: application of factorial design approach. Drug Deliv, 20(1), 47–56. https://doi.org/10.3109/10717544.2012.752421
58. Pardeshi, C. v., Rajput, P. v., Belgamwar, V. S., Tekade, A. R., & Surana, S. J. (2013b). Novel surface modified solid lipid nanoparticles as intranasal carriers for ropinirole hydrochloride: application of factorial design approach. Drug Delivery, 20(1), 47–56. https://doi.org/10.3109/10717544.2012.752421
59. Pardridge, W. M. (2005). The blood-brain barrier: Bottleneck in brain drug development. NeuroRx, 2(1), 3–14. https://doi.org/10.1602/neurorx.2.1.3
60. Patil, S. M., Sawant, S. S., & Kunda, N. K. (2020). Exosomes as drug delivery systems: A brief overview and progress update. European Journal of Pharmaceutics and Biopharmaceutics, 154, 259–269. https://doi.org/10.1016/j.ejpb.2020.07.026
61. Pissuwan, D. (2017). Monitoring and tracking metallic nanobiomaterials in vivo. In Monitoring and Evaluation of Biomaterials and their Performance İn vivo (pp. 135–149). Elsevier Inc. https://doi.org/10.1016/B978-0-08-100603-0.00007-9
62. Poewe, W., Seppi, K., Tanner, C. M., Halliday, G. M., Brundin, P., Volkmann, J., Schrag, A. E., & Lang, A. E. (2017). Parkinson disease. Nature Reviews Disease Primers, 3(1), 1–21. https://doi.org/10.1038/nrdp.2017.13
63. Przedborski, S., Vila, M., & Jackson-Lewis, V. (2003). Series Introduction: Neurodegeneration: What is it and where are we? Journal of Clinical Investigation, 111(1), 3. https://doi.org/10.1172/JCI17522
64. Pulgar, V. M. (2019). Transcytosis to cross the blood brain barrier, new advancements and challenges. Frontiers in Neuroscience, 13(JAN), 1019. https://doi.org/10.3389/fnins.2018.01019
65. Rabiei, M., Kashanian, S., Samavati, S. S., Jamasb, S., & McInnes, S. J. P. (2020). Nanomaterial and advanced technologies in transdermal drug delivery. In Journal of Drug Targeting (Vol. 28, Issue 4, pp. 356–367). Taylor and Francis Ltd. https://doi.org/10.1080/1061186X.2019.1693579
66. Rekas, A., Lo, V., Gadd, G. E., Cappai, R., & Yun, S. I. (2009). PAMAM Dendrimers as Potential Agents against Fibrillation of α -Synuclein, a Parkinson’s Disease-Related Protein. Macromolecular Bioscience, 9(3), 230–238. https://doi.org/10.1002/mabi.200800242
67. Rhea, E. M., & Banks, W. A. (2021). Interactions of Lipids, Lipoproteins, and Apolipoproteins with the Blood-Brain Barrier. In Pharmaceutical Research (Vol. 38, Issue 9, pp. 1469–1475). Springer. https://doi.org/10.1007/s11095-021-03098-6
68. Saeedi, M., Eslamifar, M., Khezri, K., & Dizaj, S. M. (2019). Applications of nanotechnology in drug delivery to the central nervous system. In Biomedicine and Pharmacotherapy (Vol. 111, pp. 666–675). Elsevier Masson SAS. https://doi.org/10.1016/j.biopha.2018.12.133
69. Sahin, A., Yoyen-Ermis, D., Caban-Toktas, S., Horzum, U., Aktas, Y., Couvreur, P., Esendagli, G., & Capan, Y. (2017). Evaluation of brain-targeted chitosan nanoparticles through blood–brain barrier cerebral microvessel endothelial cells. Journal of Microencapsulation, 34(7), 659–666. https://doi.org/10.1080/02652048.2017.1375039
70. Shahnawaz, M., Mukherjee, A., Pritzkow, S., Mendez, N., Rabadia, P., Liu, X., Hu, B., Schmeichel, A., Singer, W., Wu, G., Tsai, A. L., Shirani, H., Nilsson, K. P. R., Low, P. A., & Soto, C. (2020). Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature, 578(7794), 273–277. https://doi.org/10.1038/S41586-020-1984-7
71. Sharma, G., Sharma, A. R., Lee, S. S., Bhattacharya, M., Nam, J. S., & Chakraborty, C. (2019). Advances in nanocarriers enabled brain targeted drug delivery across blood brain barrier. In International Journal of Pharmaceutics (Vol. 559, pp. 360–372). Elsevier B.V. https://doi.org/10.1016/j.ijpharm.2019.01.056
72. Silva, S., Almeida, A. J., & Vale, N. (2021). Importance of nanoparticles for the delivery of antiparkinsonian drugs. Pharmaceutics, 13(4). https://doi.org/10.3390/pharmaceutics13040508
73. Souto, E. B., Baldim, I., Oliveira, W. P., Rao, R., Yadav, N., Gama, F. M., & Mahant, S. (2020). SLN and NLC for topical, dermal, and transdermal drug delivery. In Expert Opinion on Drug Delivery (Vol. 17, Issue 3, pp. 357–377). Taylor and Francis Ltd. https://doi.org/10.1080/17425247.2020.1727883
74. Spector, R. (2000). Drug transport in the mammalian central nervous system: Multiple complex systems. A critical analysis and commentary. In Pharmacology (Vol. 60, Issue 2, pp. 58–73). S. Karger AG. https://doi.org/10.1159/000028349
75. Stoker, T. B., Torsney, K. M., & Barker, R. A. (2018). Emerging treatment approaches for Parkinson’s disease. Frontiers in Neuroscience, 12(OCT), 419092. https://doi.org/10.3389/FNINS.2018.00693/BIBTEX
76. Su, Y., Sun, B., Gao, X., Dong, X., Fu, L., Zhang, Y., Li, Z., Wang, Y., Jiang, H., & Han, B. (2020). Intranasal Delivery of Targeted Nanoparticles Loaded With miR-132 to Brain for the Treatment of Neurodegenerative Diseases. Frontiers in Pharmacology, 11, 1165. https://doi.org/10.3389/fphar.2020.01165
77. Sultatos, L. (2007). First-pass effect. In xPharm: The Comprehensive Pharmacology Reference (pp. 1–2). Elsevier Inc. https://doi.org/10.1016/B978-008055232-3.60022-4
78. Sun, M., Cheng, R., Xu, X., & Chen, Y. (2006). Studies on adsorption of phenol and substituted phenols on carbon nanotubes. EDITORIAL BOARD OF CHEMICAL ….
79. Galatage, S. T., Hebalkar, A. S., Dhobale, S. V., Mali, O. R., Kumbhar, P. S., Nikade, S. V., & Killedar, S. G. (2021). Silver nanoparticles: properties, synthesis, characterization, applications and future trends. Silver micro-nanoparticles—Properties, synthesis, characterization, and applications.
80. Teleanu, D., Chircov, C., Grumezescu, A., Volceanov, A., & Teleanu, R. (2018). Blood-Brain Delivery Methods Using Nanotechnology. Pharmaceutics, 10(4), 269. https://doi.org/10.3390/pharmaceutics10040269
81. Tsai, M. J., Huang, Y. bin, Wu, P. C., Fu, Y. S., Kao, Y. R., Fang, J. Y., & Tsai, Y. H. (2011). Oral apomorphine delivery from solid lipid nanoparticleswith different monostearate emulsifiers: Pharmacokinetic and behavioral evaluations. Journal of Pharmaceutical Sciences, 100(2), 547–557. https://doi.org/10.1002/jps.22285
82. Üner, M. (2015). Characterization and imaging of solid lipid nanoparticles and nanostructured lipid carriers. In Handbook of Nanoparticles (pp. 117–141). Springer International Publishing. https://doi.org/10.1007/978-3-319-15338-4_3
83. Vekrellis, K., Xilouri, M., Emmanouilidou, E., Rideout, H. J., & Stefanis, L. (2011). Pathological roles of α-synuclein in neurological disorders. In The Lancet Neurology (Vol. 10, Issue 11, pp. 1015–1025). Elsevier. https://doi.org/10.1016/S1474-4422(11)70213-7
84. Venkatas, J., & Singh, M. (2021). Nanomedicine-mediated optimization of immunotherapeutic approaches in cervical cancer. Nanomedicine, 16(15), 1311–1328. https://doi.org/10.2217/nnm-2021-0044
85. von Roemeling, C., Jiang, W., Chan, C. K., Weissman, I. L., & Kim, B. Y. S. (2017). Breaking Down the Barriers to Precision Cancer Nanomedicine. In Trends in Biotechnology (Vol. 35, Issue 2, pp. 159–171). Elsevier Ltd. https://doi.org/10.1016/j.tibtech.2016.07.006
86. Wang, F., Yang, Z., Liu, M., Tao, Y., Li, Z., Wu, Z., & Gui, S. (2020). Facile nose-to-brain delivery of rotigotine-loaded polymer micelles thermosensitive hydrogels: İn vitro characterization and in vivo behavior study. International Journal of Pharmaceutics, 577, 119046. https://doi.org/10.1016/j.ijpharm.2020.119046
87. Wang, Y., Xu, H., Fu, Q., Ma, R., & Xiang, J. (2011). Protective effect of resveratrol derived from Polygonum cuspidatum and its liposomal form on nigral cells in Parkinsonian rats. Journal of the Neurological Sciences, 304(1–2), 29–34. https://doi.org/10.1016/j.jns.2011.02.025
88. Xue, J., Liu, T., Liu, Y., Jiang, Y., Seshadri, V. D. D., Mohan, S. K., & Ling, L. (2019). Neuroprotective effect of biosynthesised gold nanoparticles synthesised from root extract of Paeonia moutan against Parkinson disease – İn vitro & İn vivo model. Journal of Photochemistry and Photobiology B: Biology, 200, 111635. https://doi.org/10.1016/j.jphotobiol.2019.111635
89. Yang, D., Chen, M., Sun, Y., Jin, Y., Lu, C., Pan, X., Quan, G., & Wu, C. (2021). Microneedle-mediated transdermal drug delivery for treating diverse skin diseases. In Acta Biomaterialia (Vol. 121, pp. 119–133). Acta Materialia Inc. https://doi.org/10.1016/j.actbio.2020.12.004
90. Yang, Z., Zhang, Y., Yang, Y., Sun, L., Han, D., Li, H., & Wang, C. (2010). Pharmacological and toxicological target organelles and safe use of single-walled carbon nanotubes as drug carriers in treating Alzheimer disease. Nanomedicine: Nanotechnology, Biology, and Medicine, 6(3), 427–441. https://doi.org/10.1016/j.nano.2009.11.007
91. Zhao, M., Brunk, U. T., & Eaton, J. W. (2001). Delayed oxidant-induced cell death involves activation of phospholipase A2. FEBS Letters, 509(3), 399–404. https://doi.org/10.1016/S0014-5793(01)03184-2
92. Zhao, Y., Haney, M. J., Gupta, R., Bohnsack, J. P., He, Z., Kabanov, A. v., & Batrakova, E. v. (2014). GDNF-Transfected Macrophages Produce Potent Neuroprotective Effects in Parkinson’s Disease Mouse Model. PLoS ONE, 9(9), e106867. https://doi.org/10.1371/journal.pone.0106867
93. Zhao, Y., Xiong, S., Liu, P., Liu, W., Wang, Q., Liu, Y., Tan, H., Chen, X., Shi, X., Wang, Q., & Chen, T. (2020). Polymeric nanoparticles-based brain delivery with improved therapeutic efficacy of ginkgolide b in parkinson’s disease. International Journal of Nanomedicine, 15, 10453–10467. https://doi.org/10.2147/IJN.S272831
94. Zhou, Y., Peng, Z., Seven, E. S., & Leblanc, R. M. (2018). Crossing the blood-brain barrier with nanoparticles. Journal of Controlled Release, 270, 290–303. https://doi.org/10.1016/J.JCONREL.2017.12.015
95. Zhu, Y., Liu, C., & Pang, Z. (2019). Dendrimer-Based Drug Delivery Systems for Brain Targeting. Biomolecules, 9(12), 790. https://doi.org/10.3390/biom9120790