j. res. pharm. Journal of Research in Pharmacy 2630-6344 Marmara University Pharmaceutical Sciences Pharmaceutical Delivery Technologies Eczacılık Bilimleri İlaç Dağıtım Teknolojileri Lipid nanocapsules: A Novel Strategy for Brain Targeting via Nasal Administration https://orcid.org/0000-0002-2069-5853 Ibrahim Mennatullah Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University https://orcid.org/0000-0002-0594-7119 Basalious Emad Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University https://orcid.org/0000-0003-0070-1969 El-nabarawi Mohamed Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University https://orcid.org/0000-0001-5953-5374 Makhlouf Amal Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University 06 28 2025 28 2 545 559 01 27 2024 03 02 2024 Copyright © 2010, Journal of Research in Pharmacy 2010 Journal of Research in Pharmacy

In spite of the great advance in drug delivery systems (DDSs) for the control of the neurological disorders like Alzheimer's disease, Parkinson's disease, epilepsy and seizures, yet there is a demand for innovative DDSs for brain targeting. The biggest hurdle for directing the drug to the brain is the presence of the blood-brain barrier (BBB) which hampers the passage of medicants to the brain. Many recent approaches to allow carriage of medicaments to the brain have come out during the last twenty years. Intranasal delivery of drugs is one of these approaches which can bypass the BBB in a noninvasive way. Lipid nanocapsules (LNCs) act as an appropriate platform and novel strategy for nose to brain drug delivery due to their several advantages. They can be produced in a quick, simple, solvent-free and scalable-up process. Therefore, this review depicts mechanisms of nose-to-brain drug delivery and the several approaches for improving nasal absorption of drugs with a special emphasis on lipid nanocapsules-based approaches. It discusses the composition and method of preparation of LNCs, their advantages and their application in nose to brain drug delivery. The upcoming prospect of nasal drug delivery to the brain is also discussed.

 Neurological disorders Blood–brain barrier Brain targeting Intranasal delivery Nanocapsules [1] Ballabh P, Braun A, Nedergaard M. The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004; 16(1): 1-13. https://doi.org/10.1016/j.nbd.2003.12.016 [2] Löscher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol. 2005; 76(1): 22–76. https://doi.org/10.1016/j.pneurobio.2005.04.006 [3] Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat med. 2013; 19(12): 1584-1596. https://doi.org/10.1038/nm.3407 [4] Harilal S, Jose J, Kumar R, Unnikrishnan MK, Uddin MS, Mathew GE, Pratap R, Marathakam A, Mathew B. Revisiting the blood-brain barrier: A hard nut to crack in the transportation of drug molecules. BRB. 2020; 160: 121-140. https://doi.org/10.1016/j.brainresbull.2020.03.018 [5] Heurtault B, Saulnier P, Pech B, Proust J-E, Benoit J-P. A novel phase inversion-based process for the preparation of lipid nanocarriers. Pharm res. 2002; 19: 875-880. https://doi.org/10.1023/a:1016121319668 [6] Hureaux J, Lagarce F, Gagnadoux F, Vecellio L, Clavreul A, Roger E, Kempf M, Racineux J-L, Diot P, Benoit, J-P. Lipid nanocapsules: ready-to-use nanovectors for the aerosol delivery of paclitaxel. Eur j pharm biopharm. 2009; 73(2): 239-246. https://doi.org/10.1016/j.ejpb.2009.06.013 [7] Thomas O, Lagarce F. Lipid nanocapsules: a nanocarrier suitable for scale-up process. J Drug Deliv Sci Technol. 2013; 23(6): 555-559. https://doi.org/10.1016/S1773-2247(13)50084-0 [8] Heurtault B, Saulnier P, Pech B, Venier-Julienne M-C, Proust J-E, Phan-Tan-Luu R, Benoı̂t, J-P. The influence of lipid nanocapsule composition on their size distribution. Eur J Pharm Sci. 2003; 18(1): 55-61. https://doi.org/10.1016/S0928-0987(02)00241-5 [9] Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life sci. 2018; 195: 44-52. https://doi.org/10.1016/j.lfs.2017.12.025 [10] Mygind N, Änggård A. Anatomy and physiology of the nose—pathophysiologic alterations in allergic rhinitis. Clin rev allergy. 1984; 2: 173-188. https://doi.org/10.1007/bf02991098 [11] Mygind N, Dahl R. Anatomy, physiology and function of the nasal cavities in health and disease. Adv drug deliv rev. 1998; 29(1-2): 3-12. https://doi.org/10.1016/S0169-409X(97)00058-6 [12] Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv drug deliv rev. 2012; 64(7): 614-628. https://doi.org/10.1016/j.addr.2011.11.002 [13] Pires A, Fortuna A, Alves G, Falcão A. Intranasal drug delivery: how, why and what for? JPPS. 2009; 12(3): 288-311. https://doi.org/10.18433/j3nc79 [14] Djupesland PG, Messina JC, Mahmoud RA. The nasal approach to delivering treatment for brain diseases: an anatomic, physiologic, and delivery technology overview. Ther deliv. 2014; 5(6): 709-733. https://doi.org/10.4155/tde.14.41 [15] Costa C, Moreira J, Amaral M, Lobo JS, Silva AC. Nose-to-brain delivery of lipid-based nanosystems for epileptic seizures and anxiety crisis. J Control Release. 2019; 295: 187-200. https://doi.org/10.1016/j.jconrel.2018.12.049 [16] Bahadur S, Pardhi DM, Rautio J, Rosenholm JM, Pathak K. Intranasal nanoemulsions for direct nose-to-brain delivery of actives for CNS disorders. Pharmaceutics. 2020; 12(12): 1230. https://doi.org/10.3390/pharmaceutics12121230 [17] Gizurarson S. Anatomical and histological factors affecting intranasal drug and vaccine delivery. Curr Drug Deliv. 2012; 9(6): 566–82. https://doi.org/10.2174/156720112803529828 [18] Tan MS, Parekh HS, Pandey P, Siskind DJ, Falconer JR. Nose-to-brain delivery of antipsychotics using nanotechnology: A review. Expert Opin Drug Deliv. 2020; 17(6): 839-853. https://doi.org/10.1080/17425247.2020.1762563 [19] Thorne RG, Emory CR, Ala TA, Frey II WH. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain res. 1995; 692(1-2): 278-282. https://doi.org/10.1016/0006-8993(95)00637-6 [20] Thorne RG, Frey WH. Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations. Clin pharmacokinet. 2001; 40: 907-946. https://doi.org/10.2165/00003088-200140120-00003 [21] Dhuria SV, Hanson LR, Frey II WH. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J pharm sci. 2010; 99(4): 1654-1673. https://doi.org/10.1002/jps.21924 [22] Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat neurosci. 2002; 5(6): 514-516. https://doi.org/10.1038/nn0602-849 [23] Banks WA, During MJ, Niehoff ML. Brain uptake of the glucagon-like peptide-1 antagonist exendin (9-39) after intranasal administration. J Pharmacol Exp Ther. 2004; 309(2): 469-475. https://doi.org/10.1124/jpet.103.063222 [24] Charlton ST, Whetstone J, Fayinka ST, Read KD, Illum L, Davis SS. Evaluation of direct transport pathways of glycine receptor antagonists and an angiotensin antagonist from the nasal cavity to the central nervous system in the rat model. Pharm res. 2008; 25: 1531-1543. https://doi.org/10.1007/s11095-008-9550-2 [25] Nonaka N, Farr SA, Kageyama H, Shioda S, Banks WA. Delivery of galanin-like peptide to the brain: targeting with intranasal delivery and cyclodextrins. J Pharmacol Exp Ther. 2008; 325(2): 513-519. https://doi.org/10.1124/jpet.107.132381 [26] Renner DB, Svitak AL, Gallus NJ, Ericson ME, Frey WH, Hanson LR. Intranasal delivery of insulin via the olfactory nerve pathway. J Pharm Pharmacol. 2012; 64(12): 1709-1714. https://doi.org/10.1111/j.2042-7158.2012.01555.x [27] Xu J, Tao J, Wang J. Design and application in delivery system of intranasal antidepressants. Front Bioeng Biotechnol. 2020; 8: 626882. https://doi.org/10.3389/fbioe.2020.626882 [28] Dhas NL, Kudarha RR, Mehta TA. Intranasal delivery of nanotherapeutics/nanobiotherapeutics for the treatment of Alzheimer's disease: A proficient approach. Crit Rev Ther Drug Carr Syst. 2019; 36(5). https://doi.org/10.1615/critrevtherdrugcarriersyst.2018026762 [29] Javia A, Kore G, Misra A. Polymers in nasal drug delivery: An overview. Applications of polymers in drug delivery. 2021: 305-332. https://doi.org/10.1016/B978-0-12-819659-5.00011-2 [30] Kumar A, Pandey AN, Jain SK. Nasal-nanotechnology: revolution for efficient therapeutics delivery. Drug Deliv. 2016; 23(3): 671–83. https://doi.org/10.3109/10717544.2014.920431 [31] Agrawal M, Saraf S, Saraf S, Dubey SK, Puri A, Gupta U, Kesharwani P, Ravichandiran V, Kumar P, Naidu V. Stimuli-responsive In situ gelling system for nose-to-brain drug delivery. J Control Release. 2020; 327: 235-265. https://doi.org/10.1016/j.jconrel.2020.07.044 [32] Chhajed S, Sangale S, Barhate S. Advantageous nasal drug delivery system: a review. Int J Pharm Sci Res. 2011; 2(6): 1322. http://dx.doi.org/10.3390/pharmaceutics14051073 [33] Erdő F, Bors LA, Farkas D, Bajza Á, Gizurarson S. Evaluation of intranasal delivery route of drug administration for brain targeting. B R B. 2018; 143: 155-170. https://doi.org/10.1016/j.brainresbull.2018.10.009 [34] Cho H-J, Termsarasab U, Kim J-S, Kim D-D. In vitro nasal cell culture systems for drug transport studies. J Pharm Investig. 2010; 40(6): 321-332. https://doi.org/10.4333/KPS.2010.40.6.321 [35] Westin U, Piras E, Jansson B, Bergström U, Dahlin M, Brittebo E, Björk E. Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents. Eur j pharm sci. 2005; 24(5): 565-573. https://doi.org/10.1016/j.ejps.2005.01.009 [36] Gizurarson S. Animal models for intranasal drug delivery studies. A review article. Acta pharm nord. 1990; 2(2): 105-122. https://doi.org/10.1002/bdd.2348 [37] Sarma A, Das MK. Nose to brain delivery of antiretroviral drugs in the treatment of neuroAIDS. Mol biomed. 2020; 1: 1-23. https://doi.org/10.1186/s43556-020-00019-8 [38] Hoang VD, Uchenna AR, Mark J, Renaat K, Norbert V. Characterization of human nasal primary culture systems to investigate peptide metabolism. Int j pharm. 2002; 238(1-2): 247-256. https://doi.org/10.1016/S0378-5173(02)00077-7 [39] Kreft ME, Jerman UD, Lasič E, Lanišnik Rižner T, Hevir-Kene N, Peternel L, Kristan K. The characterization of the human nasal epithelial cell line RPMI 2650 under different culture conditions and their optimization for an appropriate in vitro nasal model. Pharm res. 2015; 32: 665-679. https://doi.org/10.1007/s11095-014-1494-0 [40] Salade L, Wauthoz N, Goole J, Amighi K. How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods. Int j pharm. 2019; 561: 47-65. https://doi.org/10.1016/j.ijpharm.2019.02.026 [41] Sibinovska N, Žakelj S, Kristan K. Suitability of RPMI 2650 cell models for nasal drug permeability prediction. Eur J Pharm and Biopharm. 2019; 145: 85-95. https://doi.org/10.1016/j.ejpb.2019.10.008 [42] Furubayashi T, Inoue D, Nishiyama N, Tanaka A, Yutani R, Kimura S, Katsumi H, Yamamoto A, Sakane T. Comparison of various cell lines and three-dimensional mucociliary tissue model systems to estimate drug permeability using an in vitro transport study to predict nasal drug absorption in rats. Pharmaceutics. 2020; 12(1): 79. https://doi.org/10.3390%2Fpharmaceutics12010079 [43] Inoue D, Furubayashi T, Tanaka A, Sakane T, Sugano K. Quantitative estimation of drug permeation through nasal mucosa using in vitro membrane permeability across Calu-3 cell layers for predicting in vivo bioavailability after intranasal administration to rats. Eur J Pharm and Biopharm. 2020; 149: 145-153. https://doi.org/10.1016/j.ejpb.2020.02.004 [44] Kreft ME, Jerman UD, Lasič E, Lanišnik Rižner T, Hevir-Kene N, Peternel L, Kristan K. The characterization of the human cell line Calu-3 under different culture conditions and its use as an optimized in vitro model to investigate bronchial epithelial function. Eur J Pharm Sci. 2015; 69: 1-9. https://doi.org/10.1016/j.ejps.2014.12.017 [45] Wu C, Li B, Zhang Y, Chen T, Chen C, Jiang W, Wang Q, Chen T. Intranasal delivery of paeoniflorin nanocrystals for brain targeting. Asian J Pharm Sci. 2020; 15(3): 326-335. https://doi.org/10.1016/j.ajps.2019.11.002 [46] Sibinovska N, Žakelj S, Trontelj J, Kristan K. Applicability of RPMI 2650 and Calu-3 Cell Models for Evaluation of Nasal Formulations. Pharmaceutics. 2022; 14(2). https://doi.org/10.3390/pharmaceutics14020369 [47] Dolberg AM, Reichl S. Expression of P-glycoprotein in excised human nasal mucosa and optimized models of RPMI 2650 cells. Int J Pharm. 2016; 508(1-2): 22-33. https://doi.org/10.1016/j.ijpharm.2016.05.010 [48] Kim D, Kim YH, Kwon S. Enhanced nasal drug delivery efficiency by increasing mechanical loading using hypergravity. Sci Rep. 2018; 8(1): 168. https://doi.org/10.1038/s41598-017-18561-x [49] Qian S, He L, Wang Q, Wong YC, Mak M, Ho C-Y, Han Y, Zuo Z. Intranasal delivery of a novel acetylcholinesterase inhibitor HLS-3 for treatment of Alzheimer's disease. Life sci. 2018; 207: 428-435. https://doi.org/10.1016/j.lfs.2018.06.032 [50] Wengst A, Reichl S. RPMI 2650 epithelial model and three-dimensional reconstructed human nasal mucosa as in vitro models for nasal permeation studies. Eur J Pharm Biopharm. 2010; 74(2): 290-297. https://doi.org/10.1016/j.ejpb.2009.08.008 [51] Hanson LR, Frey WH. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci. 2008; 9(3): 1–4. https://doi.org/10.1186/1471-2202-9-s3-s5 [52] Yousfan A, Rubio N, Natouf AH, Daher A, Al-Kafry N, Venne K, Kafa H. Preparation and characterisation of PHT-loaded chitosan lecithin nanoparticles for intranasal drug delivery to the brain. RSC advances. 2020; 10(48): 28992-29009. https://doi.org/10.1039/D0RA04890A [53] Cunha S, Swedrowska M, Bellahnid Y, Xu Z, Lobo JS, Forbes B, Silva AC. Thermosensitive in situ hydrogels of rivastigmine-loaded lipid-based nanosystems for nose-to-brain delivery: Characterisation, biocompatibility, and drug deposition studies. Int J Pharm. 2022; 620: 121720. https://doi.org/10.1016/j.ijpharm.2022.121720 [54] Nigam K, Kaur A, Tyagi A, Nematullah M, Khan F, Gabrani R, Dang S. Nose-to-brain delivery of lamotrigine-loaded PLGA nanoparticles. Drug deliv transl res. 2019; 9: 879-890. https://doi.org/10.1007/s13346-019-00622-5 [55] Shamarekh KS, Gad HA, Soliman ME, Sammour OA. Development and evaluation of protamine-coated PLGA nanoparticles for nose-to-brain delivery of tacrine: In-vitro and in-vivo assessment. J Drug Deliv Sci Technol. 2020; 57: 101724. https://doi.org/10.1016/j.jddst.2020.101724 [56] Fatouh AM, Elshafeey AH, Abdelbary A. Intranasal agomelatine solid lipid nanoparticles to enhance brain delivery: formulation, optimization and in vivo pharmacokinetics. Drug Des Devel Ther. 2017: 1815-1825. https://doi.org/10.2147/DDDT.S102500 [57] Abdelbary GA. Tadros MI. Brain targeting of olanzapine via intranasal delivery of core–shell difunctional block copolymer mixed nanomicellar carriers: in vitro characterization, ex vivo estimation of nasal toxicity and in vivo biodistribution studies. Int j pharm. 2013; 452(1-2): 300-310. https://doi.org/10.1016/j.ijpharm.2013.04.084 [58] Upadhyay P, Trivedi J, Pundarikakshudu K, Sheth N. Direct and enhanced delivery of nanoliposomes of anti schizophrenic agent to the brain through nasal route. Saudi Pharm J. 2017; 25(3): 346-358. https://doi.org/10.1016/j.jsps.2016.07.003 [59] SA N, Abdelmalak N, Naguib M. Transferosomes for trans-nasal brain delivery of clonazepam: preparation, optimization, ex-vivo cytotoxicity and pharmacodynamic study. Pharm Res. 2017; 1(2): 000107. https://doi.org/10.23880/OAJPR-16000107 [60] El Taweel MM, Aboul-Einien MH, Kassem MA, Elkasabgy NA. Intranasal zolmitriptan-loaded bilosomes with extended nasal mucociliary transit time for direct nose to brain delivery. Pharmaceutics. 2021; 13(11): 1828. https://doi.org/10.3390/pharmaceutics13111828 [61] Salama HA, Mahmoud AA, Kamel AO, Hady MA, Awad GA. Phospholipid based colloidal poloxamer–nanocubic vesicles for brain targeting via the nasal route. Colloids surf B biointerfaces. 2012; 100: 146-154. https://doi.org/10.1016/j.colsurfb.2012.05.010 [62] Dholkawala F, Voshavar C, Dutta AK. Synthesis and characterization of brain penetrant prodrug of neuroprotective D-264: Potential therapeutic application in the treatment of Parkinson’s disease. Eur J Pharm Biopharm. 2016; 103: 62-70. https://doi.org/10.1016/j.ejpb.2016.03.017 [63] Dhuria SV, Hanson LR, Frey WH. Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system. J Pharmacol Exp Ther. 2009; 328(1): 312-320. https://doi.org/10.1124/jpet.108.145565 [64] Lu Y, Du, S, Bai J, Li P, Wen, R, Zhao X. Bioavailability and brain-targeting of geniposide in gardenia-borneol co-compound by different administration routes in mice. Int J Mol Sci. 2012; 13(11): 14127-14135. https://doi.org/10.3390/ijms131114127 [65] Tawfik MA, Eltaweel MM, Fatouh AM, Shamsel-Din HA, Ibrahim AB. Brain targeting of zolmitriptan via transdermal terpesomes: statistical optimization and in vivo biodistribution study by 99mTc radiolabeling technique. Drug Deliv Transl Res. 2023; 13(12): 3059-3076. https://doi.org/10.1007/s13346-023-01373-0 [66] Taha E, Nour SA, Mamdouh W, Selim AA, Swidan MM, Ibrahim AB, Naguib MJ. Cod liver oil nano-structured lipid carriers (Cod-NLCs) as a promising platform for nose to brain delivery: Preparation, in vitro optimization, ex vivo cytotoxicity & in vivo biodistribution utilizing radioiodinated zopiclone. Int J Pharm: X. 2023; 5: 100160. https://doi.org/10.1016/j.ijpx.2023.100160 [67] Sayyed ME, Abd el-Motaleb M, Ibrahim IT, Rashed HM, El-Nabarawi MA, Ahmed MA. Preparation, characterization, and in vivo biodistribution study of intranasal 131I-clonazepam-loaded phospholipid magnesome as a promising brain delivery system. Eur J Pharm Sci. 2022; 169: 106089. https://doi.org/10.1016/j.ejps.2021.106089 [68] Kublik H, Vidgren MT. Nasal delivery systems and their effect on deposition and absorption. Advanced Drug Deliv Rev. 1998; 29(1): 157-177. https://doi.org/10.1016/S0169-409X(97)00067-7 [69] Charlton S, Jones N, Davis S, Illum L. Distribution and clearance of bioadhesive formulations from the olfactory region in man: Effect of polymer type and nasal delivery device. Eur j pharm sci. 2007; 30(3-4): 295-302. https://doi.org/10.1016/j.ejps.2006.11.018 [70] Craft S, Claxton A, Baker LD, Hanson AJ, Cholerton B, Trittschuh EH, Dahl D, Caulder E, Neth B, Montine TJ. Effects of regular and long-acting insulin on cognition and Alzheimer’s disease biomarkers: a pilot clinical trial. J Alzheimer's Dis. 2017; 57(4): 1325-1334. https://doi.org/10.3233/jad-161256 [71] Shrewsbury S, Swardstrom M, Satterly K, Campbell J, Tugiono N, Gillies J, Hoekman J. Placebo/Active Controlled, Safety, Pharmaco-Kinetic/Dynamic Study of INP105 (POD® olanzapine) in Healthy Adults. Western Journal of Emergency Medicine: Integrating Emergency Care with Population Health. 2019; 20(2). https://doi.org/10.4088/jcp.19m13086 [72] Quintana D, Westlye LT, Hope S, Naerland T, Elvsåshagen T, Dørum E, Rustan Ø, Valstad M, Rezvaya L, Lishaugen H. Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial. Transl psychiatry. 2017; 7(5): e1136-e1136. https://doi.org/10.1038/tp.2017.103 [73] Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch neurol. 2012; 69(1): 29-38. https://doi.org/10.1001/archneurol.2011.233 [74] Djupesland PG. Looking to the future of nasal drug delivery–an interview with Per Gisle Djupesland. Ther Deliv. 2018; 9(3): 163-168. https://doi.org/10.4155/tde-2018-0005 [75] Graff CL, Pollack GM. Functional evidence for P-glycoprotein at the nose-brain barrier. Pharm res. 2005; 22: 86-93. https://doi.org/10.1007/s11095-004-9013-3 [76] Kou L, Bhutia YD, Yao Q, He Z, Sun J, Ganapathy V. Transporter-guided delivery of nanoparticles to improve drug permeation across cellular barriers and drug exposure to selective cell types. Front pharmacol. 2018; 9: 27. https://doi.org/10.3389/fphar.2018.00027 [77] Kou L, Yao Q, Sivaprakasam S, Luo Q, Sun Y, Fu Q, He Z, Sun J, Ganapath Vy. Dual targeting of l-carnitine-conjugated nanoparticles to OCTN2 and ATB0,+ to deliver chemotherapeutic agents for colon cancer therapy. Drug Deliv. 2017; 24(1): 1338-1349. https://doi.org/10.1080/10717544.2017.1377316 [78] Hada N, Netzer WJ, Belhassan F, Wennogle LP, Gizurarson S. Nose-to-brain transport of imatinib mesylate: A pharmacokinetic evaluation. Eur J Pharml Sci. 2017; 102: 46-54. https://doi.org/10.1016/j.ejps.2017.02.032 [79] Uchegbu I, Wang Z, Xiong G, Tsang A, Schatzlein A. Nose to brain delivery. J Pharmacol Exp Ther. 2019; 370(3): 593-601. https://doi.org/10.1124/jpet.119.258152 [80] Jain KK. An overview of drug delivery systems. drug deliv syst. 2020: 1-54. https://doi.org/10.1007/978-1-4939-9798-5_1 [81] Erdoğar N, Akkın S, Bilensoy E. Nanocapsules for drug delivery: an updated review of the last decade. Recent patents on drug delivery & formulation. 2018; 12(4): 252-266. https://doi.org/10.2174/1872211313666190123153711 [82] Moura RP, Pacheco C, Pêgo AP, des Rieux A, Sarmento B. Lipid nanocapsules to enhance drug bioavailability to the central nervous system. J Control Release. 2020; 322: 390-400. https://doi.org/10.1016/j.jconrel.2020.03.042 [83] Purohit D, Jalwal P, Manchanda D, Saini S, Verma R, Kaushik D, Mittal V, Kumar M,Bhattacharya T, Rahman MH. Nanocapsules: An Emerging Drug Delivery System. Recent Pat Nanotechnol. 2023; 17(3): 190-207. https://doi.org/10.2174/1872210516666220210113256 [84] Huynh NT, Passirani C, Saulnier P, Benoit JP. Lipid nanocapsules: A new platform for nanomedicine. Int J Pharm. 2009; 379(2): 201-209. https://doi.org/10.1016/j.ijpharm.2009.04.026 [85] Carradori D, Labrak Y, Miron VE, Saulnier P, Eyer J, Préat V, Des Rieux A. Retinoic acid-loaded NFL-lipid nanocapsules promote oligodendrogenesis in focal white matter lesion. Biomaterials. 2020; 230: 119653. https://doi.org/10.1016/j.biomaterials.2019.119653 [86] Lamprecht A, Benoit J-P. Etoposide nanocarriers suppress glioma cell growth by intracellular drug delivery and simultaneous P-glycoprotein inhibition. J Control Release. 2006; 112(2): 208-213. https://doi.org/10.1016/j.jconrel.2006.02.014 [87] Resnier P, David S, Lautram N, Delcroix GJ-R, Clavreul A, Benoit J-P, Passirani C. EGFR siRNA lipid nanocapsules efficiently transfect glioma cells in vitro. Int j pharm. 2013; 454(2): 748-755. https://doi.org/10.1016/j.ijpharm.2013.04.001 [88] Tsakiris N, Papavasileiou M, Bozzato E, Lopes A, Vigneron AM, Préat V. Combinational drug-loaded lipid nanocapsules for the treatment of cancer. Int j pharm. 2019; 569: 118588. https://doi.org/10.1016/j.ijpharm.2019.118588 [89] Giacomeli R, Izoton JC, Dos Santos RB, Boeira SP, Jesse CR, Haas SE. Neuroprotective effects of curcumin lipid-core nanocapsules in a model Alzheimer’s disease induced by β-amyloid 1-42 peptide in aged female mice. Brain res. 2019; 1721: 146325. https://doi.org/10.1016/j.brainres.2019.146325 [90] Dhanikula AB, Khalid NM,, Lee SD, Yeung R, Risovic V, Wasan KM, Leroux JC. Long circulating lipid nanocapsules for drug detoxification. Biomaterials. 2007; 28(6): 1248-1257. https://doi.org/10.1016/j.biomaterials.2006.10.036 [91] Vrignaud S, Anton N, Passirani C, Benoit JP, Saulnier P. Aqueous core nanocapsules: a new solution for encapsulating doxorubicin hydrochloride. Drug dev ind pharm. 2013; 39(11): 1706-1711. https://doi.org/10.3109/03639045.2012.730526 [92] Chouchou A, Aubert-Pouessel A, Dorandeu C, Zghaib Z, Cuq P, Devoisselle JM, Bonnet PA, Bégu S, Deleuze-Masquefa C. Lipid nanocapsules formulation and cellular activities evaluation of a promising anticancer agent: EAPB0503. Int j pharm investig. 2017; 7(4): 155. https://doi.org/10.4103%2Fjphi.JPHI_53_17 [93] Kapoor M, Cloyd JC, Siegel RA. A review of intranasal formulations for the treatment of seizure emergencies. J Control Release. 2016; 237: 147-159. https://doi.org/10.1016/j.jconrel.2016.07.001 [94] Keller LA, Merkel O, Popp A. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Deliv Transl Res. 2022; 12(4): 735–57. https://doi.org/10.1007/s13346-020-00891-5 [95] Wang H, Zhao Y, Wu Y, Hu YI, Nan K, Nie G, Chen H. Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles. Biomaterials. 2011; 32(32): 8281-8290. https://doi.org/10.1016/j.biomaterials.2011.07.032 [96] Wang F, Jiang X, Lu W. Profiles of methotrexate in blood and CSF following intranasal and intravenous administration to rats. Int j pharm. 2003; 263(1-2): 1-7. https://doi.org/10.1016/S0378-5173(03)00341-7 [97] Feng Y, He H, Li F, Lu Y, Qi J, Wu W. An update on the role of nanovehicles in nose-to-brain drug delivery. Drug discov today. 2018; 23(5): 1079-1088. https://doi.org/10.1016/j.drudis.2018.01.005 [98] Mohsen K, Azzazy HM, Allam NK, Basalious EB. Intranasal lipid nanocapsules for systemic delivery of nimodipine into the brain: In vitro optimization and in vivo pharmacokinetic study. Mater Sci Eng C. 2020; 116: 111236. https://doi.org/10.1016/j.msec.2020.111236 [99] Alsarra IA, Hamed AY, Alanazi FK, El Maghraby GM. Vesicular systems for intranasal drug delivery. Drug delivery to the central nervous system. 2010: 175-203. https://doi.org/10.1007/978-1-60761-529-3_8 [100] Soane R, Hinchcliffe M, Davis S, Illum L. Clearance characteristics of chitosan-based formulations in the sheep nasal cavity. Int j pharm. 2001; 217(1-2): 183-191. https://doi.org/10.1016/s0378-5173(01)00602-0 [101] Rejman J, Oberle V, Zuhorn IS, Hoekstra D. Size-dependent internalization of particles via the pathways of clathrin-and caveolae-mediated endocytosis. Biochem j. 2004; 377(1): 159-169. https://doi.org/10.1042/bj20031253 [102] Bourganis V, Kammona O, Alexopoulos A, Kiparissides C. Recent advances in carrier mediated nose-to-brain delivery of pharmaceutics. Eur j pharm biopharm. 2018; 128: 337-362. https://doi.org/10.1016/j.ejpb.2018.05.009 [103] Karavasili C, atouros DG. Smart materials: in situ gel-forming systems for nasal delivery. Drug discov today. 2016; 21(1): 157-166. https://doi.org/10.1016/j.drudis.2015.10.016 [104] Fraga Dias Ad, Dallemole DR, Bruinsmann FA, Lopes Silva LF, Cruz-Lopez O, Conejo-Garcia A, Oliveira Battastini AM, Campos JM, Guterres SS, Pohlmann AR. Development of bozepinib-loaded nanocapsules for nose-to-brain delivery: preclinical evaluation in glioblastoma. Nanomed. 2021; 16(23): 2095-2115. https://doi.org/10.2217/nnm-2021-0164 [105] Bseiso EA, AbdEl-Aal SA, Nasr M, Sammour OA, El Gawad NAA. Nose to brain delivery of melatonin lipidic nanocapsules as a promising post-ischemic neuroprotective therapeutic modality. Drug Deliv. 2022; 29(1): 2469-2480. https://doi.org/10.1080/10717544.2022.2104405 [106] Bruinsmann FA, Alves ADCS, de Fraga Dias A, Silva LFL, Visioli F, Pohlmann AR, Figueiró F, Sonvico F, Guterres SS. Nose-to-brain delivery of simvastatin mediated by chitosan-coated lipid-core nanocapsules allows for the treatment of glioblastoma in vivo. Int J Pharm. 2022; 616: 121563. https://doi.org/10.1016/j.ijpharm.2022.121563 [107] de Cristo Soares Alves A, Lavayen V, de Fraga Dias A, Bruinsmann FA, Scholl JN, Ce R, Visioli F, Oliveira Battastini AM, Staniscuaski Guterres S, Figueiro F. EGFRvIII peptide nanocapsules and bevacizumab nanocapsules: a nose-to-brain multitarget approach against glioblastoma. Nanomed. 2021; 16(20): 1775-1790. https://doi.org/10.2217/nnm-2021-0169 [108] Clementino A, Batger M, Garrastazu G, Pozzoli M, Del Favero E, Rondelli V, Gutfilen B, Barboza T, Sukkar MB, Souza SA, Cantù L, Sonvico F. The nasal delivery of nanoencapsulated statins - an approach for brain delivery. Int J Nanomed. 2016; 11: 6575-6590. https://doi.org/10.2147/IJN.S119033 [109] Mwema A, Bottemanne P, Paquot A, Ucakar B, Vanvarenberg K, Alhouayek M, Muccioli GG, des Rieux A. Lipid nanocapsules for the nose-to-brain delivery of the anti-inflammatory bioactive lipid PGD2-G. Nanomed: NBM. 2023; 48: 102633. https://doi.org/10.1016/j.nano.2022.102633 [110] Ibrahim MM, Basalious EB, El-Nabarawi MA, Makhlouf AIA, Sayyed ME, Ibrahim IT. Nose to brain delivery of mirtazapine via lipid nanocapsules: Preparation, statistical optimization, radiolabeling, in vivo biodistribution and pharmacokinetic study. Drug Deliv Transl Res. 2024. https://doi.org/10.1007/s13346-024-01528-7 [111] Gad SR, El-Gogary RI, George MY, Hathout RM. Nose-to-brain delivery of 18β-Glycyrrhetinic acid using optimized lipid nanocapsules: A novel alternative treatment for Alzheimer’s disease. Int J Pharm. 2023; 645: 123387. https://doi.org/10.1016/j.ijpharm.2023.123387 [112] Chapman CD, Frey II WH, Craft S, Danielyan L, Hallschmid M, Schiöth HB, Benedict C. Intranasal treatment of central nervous system dysfunction in humans. Pharm Res. 2013; 30(10): 2475-84. https://doi.org/10.1007/s11095-012-0915-1