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Drug Delivery Letters

Author(s): Tosha Pandya and Abhay Dharamsi*

DOI: 10.2174/2210303113666230120124831

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Intranasal Delivery of Leuprolide Acetate Chitosan Nanoparticles for Treatment of Alzheimer’s Disease

Page: [120 - 132] Pages: 13

  • * (Excluding Mailing and Handling)

Abstract

Background: Alzheimer’s is one of the primary causes and the most prevalent form of age-related dementia worldwide. There is an urgent surge to find an effective treatment for AD due to its social implications on society.

Aim: Present research work aims to develop Chitosan nanoparticles of leuprolide acetate for the treatment of Alzheimer’s disease by delivery through the intranasal route.

Methods: Chitosan nanoparticles encapsulating leuprolide acetate were prepared using the ionic gelation method and optimized using a central composite design. The optimized nanoparticles were evaluated by DSC study, TEM analysis, release study of the drug in vitro and ex vivo, histopathology study, and accelerated stability study, In vivo kinetic and dynamic study.

Results: The optimized formulation exhibited particle size of 254.3 ± 10.7 nm, % EE of 85.6 ± 0.8 %, and zeta potential of +18.0 ± 0.2 mv. The release of drug from optimized nanoparticles in vitro was in a sustained manner, with only 75.7 % drug released at 48 hours. Higher permeation of the drug from nanoparticles (Papp =5.44 ± 0.34 x 104) was observed in the diffusion study ex vivo. Sheep nasal toxicity and accelerated stability study proved the intranasal safety and stability of the developed formulation. The in vivo drug uptake study indicated a greater brain drug concentration from chitosan nanoparticles than from plain drug solution. The anti-Alzheimer potential was also evident from behavioural studies and histopathology study of rat brain.

Conclusion: Thus, the chitosan nanoparticulate formulation of leuprolide acetate was found to have great potential for Alzheimer’s disease management.

Graphical Abstract

[1]
Shunan, D.; Yu, M.; Guan, H.; Zhou, Y. Neuroprotective effect of Betalain against AlCl3-induced Alzheimer’s disease in Sprague Dawley Rats via putative modulation of oxidative stress and nuclear factor kappa B (NF-κB) signaling pathway. Biomed. Pharmacother., 2021, 137, 111369.
[http://dx.doi.org/10.1016/j.biopha.2021.111369] [PMID: 33582452]
[2]
Thenmozhi, A.J.; Raja, T.R.W.; Janakiraman, U.; Manivasagam, T. Neuroprotective effect of hesperidin on aluminium chloride induced Alzheimer’s disease in Wistar rats. Neurochem. Res., 2015, 40(4), 767-776.
[http://dx.doi.org/10.1007/s11064-015-1525-1] [PMID: 25630717]
[3]
Burnham, V.L.; Thornton, J.E. Luteinizing hormone as a key player in the cognitive decline of Alzheimer’s disease. Horm. Behav., 2015, 76, 48-56.
[http://dx.doi.org/10.1016/j.yhbeh.2015.05.010] [PMID: 26031357]
[4]
Meethal, S.V.; Smith, M.A.; Bowen, R.L.; Atwood, C.S. The gonadotropin connection in Alzheimer’s disease. Endocr. J., 2005, 26(3), 317-326.
[http://dx.doi.org/10.1385/ENDO:26:3:317] [PMID: 16034187]
[5]
Wilson, A.C.; Vadakkadath Meethal, S.; Bowen, R.L.; Atwood, C.S. Leuprolide acetate: A drug of diverse clinical applications. Expert Opin. Investig. Drugs, 2007, 16(11), 1851-1863.
[http://dx.doi.org/10.1517/13543784.16.11.1851] [PMID: 17970643]
[6]
Casadesus, G.; Webber, K.M.; Atwood, C.S.; Pappolla, M.A.; Perry, G.; Bowen, R.L.; Smith, M.A. Luteinizing hormone modulates cognition and amyloid-β deposition in Alzheimer APP transgenic mice. Biochim. Biophys. Acta Mol. Basis Dis., 2006, 1762(4), 447-452.
[http://dx.doi.org/10.1016/j.bbadis.2006.01.008] [PMID: 16503402]
[7]
Wilson, A.C.; Salamat, M.S.; Haasl, R.J.; Roche, K.M.; Karande, A.; Meethal, S.V.; Terasawa, E.; Bowen, R.L.; Atwood, C.S. Human neurons express type I GnRH receptor and respond to GnRH I by increasing luteinizing hormone expression. J. Endocrinol., 2006, 191(3), 651-663.
[http://dx.doi.org/10.1677/joe.1.07047] [PMID: 17170222]
[8]
Naqvi, S.; Panghal, A.; Flora, S.J.S. Nanotechnology: A promising approach for delivery of neuroprotective drugs. Front. Neurosci., 2020, 14, 494.
[http://dx.doi.org/10.3389/fnins.2020.00494] [PMID: 32581676]
[9]
Zeb, A.; Rana, I.; Choi, H.I. Potential and applications of nanocarriers for efficient delivery of biopharmaceuticals. Pharmaceutics, 2020, 12(12), 1184.
[http://dx.doi.org/10.3390/pharmaceutics12121184]
[10]
Chenthamara, D.; Subramaniam, S.; Ramakrishnan, S.G.; Krishnaswamy, S.; Essa, M.M.; Lin, F.H.; Qoronfleh, M.W. Therapeutic efficacy of nanoparticles and routes of administration. Biomater. Res., 2019, 23(1), 20.
[http://dx.doi.org/10.1186/s40824-019-0166-x] [PMID: 31832232]
[11]
Su, Y.; Sun, B.; Gao, X.; Dong, X.; Fu, L.; Zhang, Y.; Li, Z.; Wang, Y.; Jiang, H.; Han, B. Intranasal delivery of targeted nanoparticles loaded with miR-132 to brain for the treatment of neurodegenerative diseases. Front. Pharmacol., 2020, 11, 1165.
[http://dx.doi.org/10.3389/fphar.2020.01165] [PMID: 32848773]
[12]
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.
[http://dx.doi.org/10.1016/j.ejpb.2018.05.009] [PMID: 29733950]
[13]
Pudlarz, A.; Szemraj, J. Nanoparticles as carriers of proteins, peptides and other therapeutic molecules. Open Life Sci., 2018, 13(1), 285-298.
[http://dx.doi.org/10.1515/biol-2018-0035] [PMID: 33817095]
[14]
Mitchell, M.J.; Billingsley, M.M.; Haley, R.M.; Wechsler, M.E.; Peppas, N.A.; Langer, R. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov., 2021, 20(2), 101-124.
[http://dx.doi.org/10.1038/s41573-020-0090-8] [PMID: 33277608]
[15]
Peptide-nanoparticle conjugates: A next generation of diagnostic and therapeutic platforms? Nano Converg., 2018, 5(1), 38.
[http://dx.doi.org/10.1186/s40580-018-0170-1]
[16]
Kamei, N.; Suwabe, S.; Arime, K.; Bando, H.; Murata, K.; Yamaguchi, M.; Yokoyama, N.; Tanaka, E.; Hashimoto, A.; Kanazawa, T.; Ago, Y.; Takeda-Morishita, M. Investigation of the transport pathways associated with enhanced brain delivery of peptide drugs by intranasal coadministration with penetratin. Pharmaceutics, 2021, 13(11), 1745.
[http://dx.doi.org/10.3390/pharmaceutics13111745] [PMID: 34834159]
[17]
Illum, L. Nasal drug delivery: New developments and strategies. Drug Discov. Today, 2002, 7(23), 1184-1189.
[http://dx.doi.org/10.1016/S1359-6446(02)02529-1] [PMID: 12547019]
[18]
Xu, J.; Tao, J.; Wang, J. Design and application in delivery system of intranasal antidepressants. Front. Bioeng. Biotechnol., 2020, 8, 626882.
[http://dx.doi.org/10.3389/fbioe.2020.626882] [PMID: 33409272]
[19]
Piazza, J.; Hoare, T.; Molinaro, L.; Terpstra, K.; Bhandari, J.; Selvaganapathy, P.R.; Gupta, B.; Mishra, R.K. Haloperidol-loaded intranasally administered lectin functionalized poly(ethylene glycol)-block-poly(d,l)-lactic-co-glycolic acid (PEG-PLGA) nanoparticles for the treatment of schizophrenia. Eur. J. Pharm. Biopharm., 2014, 87(1), 30-39.
[http://dx.doi.org/10.1016/j.ejpb.2014.02.007] [PMID: 24560967]
[20]
Keller, L.A.; Merkel, O.; Popp, A. Intranasal drug delivery: Opportunities and toxicologic challenges during drug development. Drug Deliv. Transl. Res., 2022, 12(4), 735-757.
[http://dx.doi.org/10.1007/s13346-020-00891-5] [PMID: 33491126]
[21]
Shang, Y.; Inthavong, K.; Qiu, D.; Singh, N.; He, F.; Tu, J. Prediction of nasal spray drug absorption influenced by mucociliary clearance. PLoS One, 2021, 16(1), e0246007.
[http://dx.doi.org/10.1371/journal.pone.0246007] [PMID: 33507973]
[22]
Elnaggar, Y.S.R.; Etman, S.M.; Abdelmonsif, D.A.; Abdallah, O.Y. Intranasal piperine-loaded chitosan nanoparticles as brain-targeted therapy in Alzheimer’s disease: Optimization, biological efficacy, and potential toxicity. J. Pharm. Sci., 2015, 104(10), 3544-3556.
[http://dx.doi.org/10.1002/jps.24557]
[23]
Wang, X.; Chi, N.; Tang, X. Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting. Eur. J. Pharm. Biopharm., 2008, 70(3), 735-740.
[http://dx.doi.org/10.1016/j.ejpb.2008.07.005] [PMID: 18684400]
[24]
Hoang, N.H.; Le Thanh, T.; Sangpueak, R.; Treekoon, J.; Saengchan, C.; Thepbandit, W.; Papathoti, N.K.; Kamkaew, A.; Buensanteai, N. Chitosan nanoparticles-based ionic gelation method: A promising candidate for plant disease management. Polymers, 2022, 14(4), 662.
[http://dx.doi.org/10.3390/polym14040662] [PMID: 35215574]
[25]
Silvestro, I.; Francolini, I.; Di Lisio, V.; Martinelli, A.; Pietrelli, L.; Scotto d’Abusco, A.; Scoppio, A.; Piozzi, A. Preparation and characterization of TPP-chitosan crosslinked scaffolds for tissue engineering. Materials, 2020, 13(16), 3577.
[http://dx.doi.org/10.3390/ma13163577] [PMID: 32823636]
[26]
Rajewski, J.; Dobrzyńska-Inger, A. Application of Response Surface Methodology (RSM) for the optimization of chromium(III) synergistic extraction by supported liquid membrane. Membranes, 2021, 11(11), 854.
[http://dx.doi.org/10.3390/membranes11110854] [PMID: 34832083]
[27]
Hassan, H.; Adam, S.K.; Alias, E.; Meor Mohd Affandi, M.M.R.; Shamsuddin, A.F.; Basir, R. Central composite design for formulation and optimization of solid lipid nanoparticles to enhance oral bioavailability of acyclovir. Molecules, 2021, 26(18), 5432.
[http://dx.doi.org/10.3390/molecules26185432] [PMID: 34576904]
[28]
Al-nemrawi, N.K.; Alkhatib, R.Q.; Ayyad, H.; Alshraiedeh, N.A. Formulation and characterization of tobramycin-chitosan nanoparticles coated with zinc oxide nanoparticles. Saudi Pharm. J., 2022, 30(4), 454-461.
[http://dx.doi.org/10.1016/j.jsps.2022.01.016] [PMID: 35527830]
[29]
Nanaki, S.G.; Andrianidou, S.; Barmpalexis, P.; Christodoulou, E.; Bikiaris, D.N. Leflunomide loaded chitosan nanoparticles for the preparation of aliphatic polyester based skin patches. Polymers, 2021, 13(10), 1539.
[http://dx.doi.org/10.3390/polym13101539] [PMID: 34064952]
[30]
Huang, T.; Wang, Y.; Shen, Y.; Ao, H.; Guo, Y.; Han, M.; Wang, X. Preparation of high drug-loading celastrol nanosuspensions and their anti-breast cancer activities in vitro and in vivo. Sci. Rep., 2020, 10(1), 8851.
[http://dx.doi.org/10.1038/s41598-020-65773-9] [PMID: 32483248]
[31]
Lee, B.; Yoon, S.; Lee, J.W.; Kim, Y.; Chang, J.; Yun, J.; Ro, J.C.; Lee, J.S.; Lee, J.H. Statistical characterization of the morphologies of nanoparticles through machine learning based electron microscopy image analysis. ACS Nano, 2020, 14(12), 17125-17133.
[http://dx.doi.org/10.1021/acsnano.0c06809] [PMID: 33231065]
[32]
Weng, J.; Tong, H.H.Y.; Chow, S.F. In vitro release study of the polymeric drug nanoparticles: Development and validation of a novel method. Pharmaceutics, 2020, 12(8), 732.
[http://dx.doi.org/10.3390/pharmaceutics12080732] [PMID: 32759786]
[33]
Kukudkar, P.; Rahate, S.; Trivedi, R.; Umekar, M.; Taksande, J. Intranasal topiramate polymeric nanoparticles for epilepsy: In vitro and ex vivo investigation. Int. J. Appl. Pharm, 2020, 12, 258-264.
[http://dx.doi.org/10.22159/ijap.2020v12i5.37385]
[34]
Bhanderi, M.; Shah, J.; Gorain, B.; Nair, A.B.; Jacob, S.; Asdaq, S.M.B.; Fattepur, S.; Alamri, A.S.; Alsanie, W.F.; Alhomrani, M.; Nagaraja, S.; Anwer, M.K. Optimized rivastigmine nanoparticles coated with eudragit for intranasal application to brain delivery: Evaluation and nasal ciliotoxicity studies. Materials, 2021, 14(21), 6291.
[http://dx.doi.org/10.3390/ma14216291] [PMID: 34771817]
[35]
Sawant, K.; Pandey, A.; Patel, S. Aripiprazole loaded poly(capro-lactone) nanoparticles: Optimization and in vivo pharmacokinetics. Mater. Sci. Eng. C, 2016, 66, 230-243.
[http://dx.doi.org/10.1016/j.msec.2016.04.089] [PMID: 27207059]
[36]
Shah, B.; Khunt, D.; Misra, M.; Padh, H. Application of Box-Behnken design for optimization and development of quetiapine fumarate loaded chitosan nanoparticles for brain delivery via intranasal route. Int. J. Biol. Macromol., 2016, 89, 206-218.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.04.076] [PMID: 27130654]
[37]
Barron, A.M.; Verdile, G.; Taddei, K.; Bates, K.A.; Martins, R.N. Effect of chronic hCG administration on Alzheimer’s-related cognition and A β accumulation in PS1KI mice. Endocrinology, 2010, 151(11), 5380-5388.
[http://dx.doi.org/10.1210/en.2009-1168] [PMID: 20844010]
[38]
Chauhdary, Z.; Saleem, U.; Ahmad, B.; Shah, S.; Shah, M.A. Neuroprotective evaluation of Tribulus terrestris L. in aluminum chloride induced Alzheimer’s disease. Pak. J. Pharm. Sci., 2019, 32(S2), 805-816.
[PMID: 31103976]
[39]
Prieur, E.; Jadavji, N. Assessing spatial working memory using the spontaneous alternation Y-maze test in aged male mice. Bio Protoc., 2019, 9(3), e3162.
[http://dx.doi.org/10.21769/BioProtoc.3162] [PMID: 33654968]
[40]
Abdallah, H.M.; El Sayed, N.S.; Sirwi, A.; Ibrahim, S.R.M.; Mohamed, G.A.; Abdel Rasheed, N.O. Mangostanaxanthone IV ameliorates streptozotocin-induced neuro-inflammation, amyloid deposition, and tau hyperphosphorylation via modulating PI3K/Akt/GSK-3β pathway. Biology, 2021, 10(12), 1298.
[http://dx.doi.org/10.3390/biology10121298] [PMID: 34943213]