Phytocompounds and lipid-based drug delivery system for neurodegenerative diseases

Abstract

Across the annals of time, organic molecules sourced from nature have found innumerable uses within the realms of healthcare, pharmaceuticals, and the study of living organisms. This abundant source of natural compounds has exhibited immense promise in the cure of diverse ailments, mainly neurodegenerative diseases owing to their minimum toxic and adverse effects. However, different challenges exist with phytocompounds from plants such as poor permeation, poor solubility (water/lipid), unsteadiness under extremely acidic pH conditions, and lack of targeting specificity. Furthermore, as a result of the existence of blood-brain barrier membrane and inconvenient pharmacokinetics characteristics of phytocompounds, their passage into the brain is constrained. In order to address this issue and augment the transportation of medications into the brain at a therapeutically effective level, it is imperative to formulate an innovative and pragmatic strategy. Many papers have shown that nanoformulations containing phytocompounds (resveratrol, quercetin, ferulic acid, curcumin, berberine, etc.) effectively improved many neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s diseases. This study provides an overview of phytocompounds that are used in nanosized lipid drug delivery systems. These systems are categorized according to lipid types and preparation techniques used in the formulation. Some studies regarding these systems and phytocompounds are also summarized.

Keywords

Neurodegenerative diseases / Phytocompounds / Lipid-based drug delivery systems / Phytosomes / Liposomes / Solid-lipid nanoparticles / Emulsions

Conflict of interest statement

The authors declare that they have no conflict of interest.

Funding

The study received no extramural funding.

Data availability statement

The data supporting the findings of this study are available from the corresponding authors upon request.

Authors’ contributions

CO and MK were involved in the conceptualization, design, definition of intellectual content, literature search, manuscript preparation, editing, and review of the manuscript. The authors have approved the final version of the manuscript.

References

[1] Dugger BN, Dickson DW. Pathology of neurodegenerative diseases. Cold Spring Harb Perspect Biol 2017; 9(7). doi: 10.1101/cshperspect.a028035.

[2] Marsh AP. Molecular mechanisms of proteinopathies across neurodegenerative disease: A review. Neurol Res Pract 2019; 1: 35. doi: 10.1186/s42466-019-0039-8.

[3] Sharifi-Rad J, Sharifi-Rad M, Salehi B, Iriti M, Roointan A, Mnayer D, et al. In vitro and in vivo assessment of free radical scavenging and antioxidant activities of Veronica persica Poir. Cell Mol Biol 2018; 64(8): 57-64.

[4] Lanctôt KL, Hahn-Pedersen JH, Eichinger CS, Freeman C, Clark A, Tarazona LRS, et al. Burden of illness in people with Alzheimer’s disease: A systematic review of epidemiology, comorbidities and mortality. J Prev Alzheimers Dis 2024; 11: 97-107.

[5] Salehi B, Albayrak S, Antolak H, Kregiel D, Pawlikowska E, Sharifi-Rad M, et al. Aloe genus plants: From farm to food applications and phytopharmacotherapy. Int J Mol Sci 2018; 19(9). doi: 10.3390/ijms19092843.

[6] Sahebnasagh A, Eghbali S, Saghafi F, Sureda A, Avan R. Neurohormetic phytochemicals in the pathogenesis of neurodegenerative diseases. Immun Ageing 2022; 19(1): 36. doi: 10.1186/s12979-022-00292-x.

[7] Ozay C, Kılıncarslan O, Mammadov R. Interactions between heavy metals and glucosinolates as defense mechanisms in Brassicaceae. Turk J Sci Rev 2016; 9(1): 12-22.

[8] Verma N, Shukla S. Impact of various factors responsible for fluctuation in plant secondary metabolites. J Appl Res Med Aromat Plants 2015; 2(4): 105-113.

[9] Howes MJ, Simmonds MS. The role of phytochemicals as micronutrients in health and disease. Curr Opin Clin Nutr Metab Care 2014; 17(6): 558-566.

[10] Ozay C, Mammadov R. Phenolic profile, antioxidant, and antiproliferative activities of Convolvulus aucheri Choisy. Vojnosanit Pregl 2022; 79: 488-495.

[11] Kaushik B, Sharma J, Kumar P, Shourie A. Phytochemical properties and pharmacological role of plants: Secondary metabolites. Biosci Biotech Res Asia 2021; 18(1): 23-35.

[12] Yadav DK. Potential therapeutic strategies of phytochemicals in neurodegenerative disorders. Curr Top Med Chem 2021; 21(31): 2814-2838.

[13] Khan A, Jahan S, Alshahrani S, Alshehri BM, Sameer AS, Arafah A, et al. Phytotherapeutic agents for neurodegenerative disorders: A neuropharmacological review. In: Bhat RA, Hakeem KR, Dervash MA (eds.) Phytomedicine. USA: Academic Press; 2021, p. 581-620.

[14] Twaij BM, Hasan MN. Bioactive secondary metabolites from plant sources: Types, synthesis, and their therapeutic uses. Int J Plant Biol 2022; 13(1): 4-14.

[15] Sharifi-Rad M, Lankatillake C, Dias DA, Docea AO, Mahomoodally MF, Lobine D, et al. Impact of natural compounds on neurodegenerative disorders: From preclinical to pharmacotherapeutics. J Clin Med 2020; 9(4). doi: 10.3390/jcm9041061.

[16] Mutha RE, Tatiya AU, Surana SJ. Flavonoids as natural phenolic compounds and their role in therapeutics: An overview. Futur J Pharm Sci 2021; 7(1): 25. doi: 10.1186/s43094-020-00161-8.

[17] Mammadov R, Kaska A, Ozay C. Phenolic composition, antioxidant and cytotoxic activities of Prospero autumnale. Indian J Pharm Sci 2017; 79(4): 585-590.

[18] Sun W, Shahrajabian MH. Therapeutic potential of phenolic compounds in medicinal plants-natural health products for human health. Molecules 2023; 28(4). doi: 10.3390/molecules28041845.

[19] Tiwari SC, Husain N. Biological activities and role of flavonoids in human health-A review. Indian J Sci Res 2017; 12(2): 193-196.

[20] Del Rio D, Rodriguez-Mateos A, Spencer JP, Tognolini M, Borges G, Crozier A. Dietary (poly)phenolics in human health: Structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid Redox Signal 2013; 18(14): 1818-1892.

[21] de Lima DP, Dos Santos Pinto Júnior E, de Menezes AV, de Souza DA, de São José VPB, da Silva BP, et al. Chemical composition, minerals concentration, total phenolic compounds, flavonoids content and antioxidant capacity in organic and conventional vegetables. Food Res Int 2024; 175. doi: 10.1016/j.foodres.2023.113684.

[22] Caruso G, Torrisi SA, Mogavero MP, Currenti W, Castellano S, Godos J, et al. Polyphenols and neuroprotection: Therapeutic implications for cognitive decline. Pharmacol Ther 2022; 232. doi: 10.1016/j.pharmthera.2021.108013.

[23] Caruso G, Godos J, Privitera A, Lanza G, Castellano S, Chillemi A, et al. Phenolic acids and prevention of cognitive decline: Polyphenols with a neuroprotective role in cognitive disorders and Alzheimer’s disease. Nutrients 2022; 14(4). doi: 10.3390/nu14040819.

[24] Ameen D, Michniak-Kohn B. Transdermal delivery of dimethyl fumarate for Alzheimer’s disease: Effect of penetration enhancers. Int J Pharm 2017; 529(1-2): 465-473.

[25] Mohammadi A, Hosseinzadeh Colagar A, Khorshidian A, Amini SM. The functional roles of curcumin on astrocytes in neurodegenerative diseases. Neuroimmunomodulation 2022; 29(1): 4-14. doi: 10.1159/000517901.

[26] Chen X, Pan W. The Treatment strategies for neurodegenerative diseases by integrative medicine. Integr Med Int 2015; 1(4): 223-225.

[27] Chopra H, Dey PS, Das D, Bhattacharya T, Shah M, Mubin S, et al. Curcumin nanoparticles as promising therapeutic agents for drug targets. Molecules 2021; 26(16). doi: 10.3390/molecules26164998.

[28] Tellone E, Galtieri A, Russo A, Giardina B, Ficarra S. Resveratrol: A focus on several neurodegenerative diseases. Oxid Med Cell Longev 2015; 2015. doi: 10.1155/2015/392169.

[29] Goyal A, Verma A, Dubey N, Raghav J, Agrawal A. Naringenin: A prospective therapeutic agent for Alzheimer’s and Parkinson’s disease. J Food Biochem 2022; 46(12). doi: 10.1111/jfbc.14415.

[30] Sankaramourthy D, Sankaranarayanan L, Subramanian K, Sadras SR. Neuroprotective potential of Celastrus paniculatus seeds against common neurological ailments: A narrative review. J Complement Integr Med 2022; 20(3): 530-536.

[31] Xavier V, Spréa R, Finimundy TC, Heleno SA, Amaral JS, Barros L, et al. Terpenes. In: Carocho M, Heleno SA, Barros L (eds.) Natural Secondary metabolites: From nature, through science, to industry. Switzerland: Cham: Springer International Publishing; 2023, p. 107-156.

[32] Ninkuu V, Zhang L, Yan J, Fu Z, Yang T, Zeng H. Biochemistry of terpenes and recent advances in plant protection. Int J Mol Sci 2021; 22(11). doi: 10.3390/ijms22115710.

[33] Eddin LB, Jha NK, Meeran MFN, Kesari KK, Beiram R, Ojha S. Neuroprotective potential of limonene and limonene containing natural products. Molecules 2021; 26(15). doi: 10.3390/molecules26154535.

[34] Machado KDC, Islam MT, Ali ES, Rouf R, Uddin SJ, Dev S, et al. A systematic review on the neuroprotective perspectives of beta-caryophyllene. Phytother Res 2018; 32(12): 2376-2388.

[35] Samarghandian S, Farkhondeh T, Samini F. A review on possible therapeutic effect of Nigella sativa and thymoquinone in neurodegenerative diseases. CNS Neurol Disord Drug Targets 2018; 17(6): 412-420.

[36] Isaev NK, Chetverikov NS, Stelmashook EV, Genrikhs EE, Khaspekov LG, Illarioshkin SN. Thymoquinone as a potential neuroprotector in acute and chronic forms of cerebral pathology. Biochemistry (Mosc) 2020; 85(2): 167-176.

[37] Jan R, Asaf S, Numan M, Lubna, Kim KM. Plant secondary metabolite biosynthesis and transcriptional regulation in response to biotic and abiotic stress conditions. Agronomy 2021; 11(5). doi: 10.7150/ijbs.23247. 10.3390/agronomy11050968.

[38] Hussain G, Rasul A, Anwar H, Aziz N, Razzaq A, Wei W, et al. Role of plant derived alkaloids and their mechanism in neurodegenerative disorders. Int J Biol Sci 2018; 14(3): 341-357.

[39] Roy S, Awasthi H. Herbal medicines as neuroprotective agent: A mechanistic approach. Int J Phar Pharm Sci 2017; 9(10): 1-7.

[40] Zhu XZ, Li XY, Liu J. Recent pharmacological studies on natural products in China. Eur J Pharmacol 2004; 500(1-3): 221-230.

[41] Zhang HY, Tang XC. Neuroprotective effects of huperzine A: New therapeutic targets for neurodegenerative disease. Trends Pharmacol Sci 2006; 27(12): 619-625.

[42] Derosa G, Maffioli P, Sahebkar A. Piperine and its role in chronic diseases. Adv Exp Med Biol 2016; 928: 173-184.

[43] Li R, Lu Y, Zhang Q, Liu W, Yang R, Jiao J, et al. Piperine promotes autophagy flux by P2RX4 activation in SNCA/alpha-synuclein-induced Parkinson disease model. Autophagy 2022; 18(3): 559-575.

[44] Ajeeshkumar KK, Aneesh PA, Raju N, Suseela M, Ravishankar CN, Benjakul S. Advancements in liposome technology: Preparation techniques and applications in food, functional foods, and bioactive delivery: A review. Compr Rev Food Sci Food Saf 2021; 20(2): 1280-1306.

[45] Li M, Du C, Guo N, Teng Y, Meng X, Sun H, et al. Composition design and medical application of liposomes. Eur J Med Chem 2019; 164: 640-653.

[46] Karpuz M, Silindir-Gunay M, Ozer AY, Ozturk SC, Yanik H, Tuncel M, et al. Diagnostic and therapeutic evaluation of folate-targeted paclitaxel and vinorelbine encapsulating theranostic liposomes for non-small cell lung cancer. Eur J Pharm Sci 2021; 156. doi: 10.1016/j.ejps.2020.105576.

[47] Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 1965; 13(1): 238-252.

[48] Andrade S, Loureiro JA, Pereira MC. Transferrin-functionalized liposomes for the delivery of gallic acid: A therapeutic approach for Alzheimer’s disease. Pharmaceutics 2022; 14(10). doi: 10.3390/pharmaceutics14102163.

[49] Kuo YC, Chen IY, Rajesh R. Use of functionalized liposomes loaded with antioxidants to permeate the blood-brain barrier and inhibit β-amyloid-induced neurodegeneration in the brain. J Taiwan Inst Chem Eng 2018; 87: 1-14.

[50] Chiu S, Terpstra KJ, Bureau Y, Hou J, Raheb H, Cernvosky Z, et al. Liposomal-formulated curcumin [Lipocurc] targeting HDAC (histone deacetylase) prevents apoptosis and improves motor deficits in Park 7 (DJ-1)-knockout rat model of Parkinson’s disease: Implications for epigenetics-based nanotechnology-driven drug platform. J Complement Integr Med 2013; 10. doi: 10.1515/jcim-2013-0020.

[51] Karpuz M, Gunay MS, Ozer AY. Liposomes and phytosomes for phytoconstituents. In: Singh MR, Singh D, Kanwar JR, Chauhan NS (eds.) Advances and avenues in the development of novel carriers for bioactives and biological agents. USA: Academic Press; 2020, p. 525-553.

[52] Lu M, Qiu Q, Luo X, Liu X, Sun J, Wang C, et al. Phyto-phospholipid complexes (phytosomes): A novel strategy to improve the bioavailability of active constituents. Asian J Pharm Sci 2019; 14(3): 265-274.

[53] Gültekin HE, Oner E, İlhan M, Karpuz M. Nanovesicles for intravenous drug delivery. In: Nayak AK, Hasnain MS, Aminabhavi TM, Torchilin VP (eds.) Applications of nanovesicular drug delivery. USA: Academic Press; 2022, p. 115-148.

[54] Ebada HMK, Nasra MMA, Elnaggar YSR, Nassra RA, Solaiman AA, Abdallah OY. Novel rhein integrate transphytosomes as non-invasive local therapy for osteoarthritis to ameliorate cartilage deterioration in MIA-arthritic rats. Colloids Surf B Biointerfaces 2021; 202. doi: 10.1016/j.colsurfb.2021.111713.

[55] Zhu S, Luo C, Feng W, Li Y, Zhu M, Sun S, et al. Selenium-deposited tripterine phytosomes ameliorate the antiarthritic efficacy of the phytomedicine via a synergistic sensitization. Int J Pharm 2020; 578. doi: 10.1016/j.ijpharm.2020.119104.

[56] Ju Ho P, Jun Sung J, Ki Cheon K, Jin Tae H. Anti-inflammatory effect of Centella asiatica phytosome in a mouse model of phthalic anhydride-induced atopic dermatitis. Phytomedicine 2018; 43: 110-119.

[57] Merchant NA, Kavya T, Srinivasa R, Rao P, Narayanan P, Bhat S. Ginsenoside Rg1 nanophytosome synthesis and their characterization: An initiative towards the treatment of amyotrophic lateral sclerosis. Montreal, Canada: 2021 IEEE 21st International Conference on Nanotechnology; 2021.

[58] Rajamma SS, Krishnaswami V, Prabu SL, Kandasamy R. Geophila repens phytosome-loaded intranasal gel with improved nasal permeation for the effective treatment of Alzheimer’s disease. J Drug Deliv Sci Tech 2022; 69. doi: 10.1016/j.jddst.2021.103087.

[59] Karpuz M, Silindir-Gunay M. Lipid-based drug delivery systems and their role in infection and inflammation imaging. In: Sana J, Sana J (eds.) Nanoengineering of biomaterials. Weinheim, Berlin: Wiley-VCH; 2022, p. 469-503.

[60] McClements DJ. Nanoemulsions versus microemulsions: Terminology, differences, and similarities. Soft Matter 2012; 8(6): 1719-1729.

[61] Koh Kai S, Wong Voon L. Introductory chapter: From microemulsions to nanoemulsions. In: Kai Seng K, Voon Loong W (eds.) Nanoemulsions. Rijeka: IntechOpen; 2019, p. 1.

[62] Sessa M, Balestrieri ML, Ferrari G, Servillo L, Castaldo D, D’Onofrio N, et al. Bioavailability of encapsulated resveratrol into nanoemulsion-based delivery systems. Food Chem 2014; 147: 42-50.

[63] Ahmad S, Hafeez A. Formulation and development of curcumin-piperine-loaded S-SNEDDS for the treatment of Alzheimer’s disease. Mol Neurobiol 2023; 60(2): 1067-1082.

[64] Das SS, Sarkar A, Chabattula SC, Verma PRP, Nazir A, Gupta PK, et al. Food-grade quercetin-loaded nanoemulsion ameliorates effects associated with Parkinson’s disease and cancer: Studies employing a transgenic C. elegans model and human cancer cell lines. Antioxidants 2022; 11(7). doi: 10.3390/antiox11071378.

[65] Hussein J, El-Bana M, Refaat E, El-Naggar ME. Synthesis of carvacrol-based nanoemulsion for treating neurodegenerative disorders in experimental diabetes. J Funct Foods 2017; 37: 441-448.

[66] Duan Y, Dhar A, Patel C, Khimani M, Neogi S, Sharma P, et al. A brief review on solid lipid nanoparticles: Part and parcel of contemporary drug delivery systems. RSC Adv 2020; 10(45): 26777-26791.

[67] Rosa-Alejandra HE, Gabriela NT, Elvia ZH, Patricia AB. Solid lipid nanoparticles (SLN). In: Ashutosh S (ed.) Nanocomposite materials for biomedical and energy storage applications. Rijeka: IntechOpen; 2022, p. 7.

[68] Khunt D, Gayakvad B, Modi V, Misra M, Prajapati B, Patel R, et al. Solid lipid nanoparticles. In: Prajapati B, Patel J (eds.) Lipid-based drug delivery systems. Singapore: Jenny Stanford Publishing; 2024, p. 27-46.

[69] Rishitha N, Muthuraman A. Therapeutic evaluation of solid lipid nanoparticle of quercetin in pentylenetetrazole induced cognitive impairment of zebrafish. Life Sci 2018; 199: 80-87.

[70] de Oliveira Junior ER, Truzzi E, Ferraro L, Fogagnolo M, Pavan B, Beggiato S, et al. Nasal administration of nanoencapsulated geraniol/ursodeoxycholic acid conjugate: Towards a new approach for the management of Parkinson’s disease. J Control Release 2020; 321: 540-552.

[71] Saini S, Sharma T, Jain A, Kaur H, Katare OP, Singh B. Systematically designed chitosan-coated solid lipid nanoparticles of ferulic acid for effective management of Alzheimer’s disease: A preclinical evidence. Colloid Surface B 2021; 205. doi: 10.1016/j.colsurfb.2021.111838.

[72] Taylor M, Moore S, Mourtas S, Niarakis A, Re F, Zona C, et al. Effect of curcumin-associated and lipid ligand-functionalized nanoliposomes on aggregation of the Alzheimer’s Aβ peptide. Nanomed Nanotechnol 2011; 7(5): 541-550.

[73] Mourtas S, Lazar AN, Markoutsa E, Duyckaerts C, Antimisiaris SG. Multifunctional nanoliposomes with curcumin-lipid derivative and brain targeting functionality with potential applications for Alzheimer disease. Eur J Med Chem 2014; 80: 175-183.

[74] Marino A, Battaglini M, Desii A, Lavarello C, Genchi G, Petretto A, et al. Liposomes loaded with polyphenol-rich grape pomace extracts protect from neurodegeneration in a rotenone-based in vitro model of Parkinson’s disease. Biomater Sci 2021; 9(24): 8171-8188.

[75] Hajizadeh Moghaddam A, Mosavi mehr M, Hasantabar V, Khanjani Jelodar S. Antioxidant and anti-anxiety effects of sumac nano-phytosome in rat model of Alzheimer’s disease: An experimental study. J Rafsanjan Uni Med Sci 2020; 19(7): 647-660.

[76] Naik SR, Pilgaonkar VW, Panda VS. Evaluation of antioxidant activity of Ginkgo biloba phytosomes in rat brain. Phytother Res 2006; 20(11): 1013-1016.

[77] Li T, Shu YJ, Cheng JY, Liang RC, Dian SN, Lv XX, et al. Pharmacokinetics and efficiency of brain targeting of ginsenosides Rg1 and Rb1 given as Nao-Qing microemulsion. Drug Dev Ind Pharm 2015; 41(2): 224-231.

[78] Etman SM, Elnaggar YSR, Abdelmonsif DA, Abdallah OY. Oral brain-targeted microemulsion for enhanced piperine delivery in Alzheimer’s disease therapy: In vitro appraisal, in vivo activity, and nanotoxicity. AAPS Pharm Sci Tech 2018; 19(8): 3698-3711.

[79] Mizrahi M, Friedman-Levi Y, Larush L, Frid K, Binyamin O, Dori D, et al. Pomegranate seed oil nanoemulsions for the prevention and treatment of neurodegenerative diseases: The case of genetic CJD. Nanomed 2014; 10(6): 1353-1363.

[80] Ismail N, Ismail M, Azmi NH, Bakar MFA, Yida Z, Abdullah MA, et al. Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats. Biomed Pharmacother 2017; 95: 780-788.

[81] Ismail N, Ismail M, Azmi NH, Bakar MFA, Yida Z, Stanslas J, et al. Beneficial effects of TQRF and TQ nano- and conventional emulsions on memory deficit, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble Aβ levels in high fat-cholesterol diet-induced rats. Chem Biol Interact 2017; 275: 61-73.

[82] Pangeni R, Sharma S, Mustafa G, Ali J, Baboota S. Vitamin E loaded resveratrol nanoemulsion for brain targeting for the treatment of Parkinson’s disease by reducing oxidative stress. Nanotechnol 2014; 25(48). doi: 10.1088/0957-4484/25/48/485102.

[83] Sandhir R, Yadav A, Mehrotra A, Sunkaria A, Singh A, Sharma S. Curcumin nanoparticles attenuate neurochemical and neurobehavioral deficits in experimental model of Huntington’s disease. Neuromolecular Med 2014; 16(1): 106-118.

[84] Loureiro JA, Andrade S, Duarte A, Neves AR, Queiroz JF, Nunes C, et al. Resveratrol and grape extract-loaded solid lipid nanoparticles for the treatment of Alzheimer’s disease. Molecules 2017; 22(2). doi: 10.3390/molecules22020277.

[85] Neves AR, Queiroz JF, Reis S. Brain-targeted delivery of resveratrol using solid lipid nanoparticles functionalized with apolipoprotein E. J Nanobiotechnology 2016; 14(1): 27. doi: 10.1186/s12951-016-0177-x.

[86] Kakkar V, Kaur IP. Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain. Food Chem Toxicol 2011; 49(11): 2906-2913.

[87] Nouri Z, Sajadimajd S, Hoseinzadeh L, Bahrami G, Arkan E, Moradi S, et al. Neuroprotective effect of naringenin-loaded solid lipid nanoparticles against streptozocin-induced neurotoxicity through autophagy blockage. J Food Biochem 2022; 46(12). doi: 10.1111/jfbc.14408.

[88] Kundu P, Das M, Tripathy K, Sahoo SK. Delivery of dual drug loaded lipid based nanoparticles across the blood-brain barrier impart enhanced neuroprotection in a rotenone induced mouse model of Parkinson’s disease. ACS Chem Neurosci 2016; 7(12): 1658-1670.

[89] Tsai MJ, Wu PC, Huang YB, Chang JS, Lin CL, Tsai YH, et al. Baicalein loaded in tocol nanostructured lipid carriers (tocol NLCs) for enhanced stability and brain targeting. Int J Pharm 2012; 423(2): 461-470.

[90] Yang CR, Zhao XL, Hu HY, Li KX, Sun X, Li L, et al. Preparation, optimization and characteristic of huperzine A loaded nanostructured lipid carriers. Chem Pharm Bull 2010; 58(5): 656-661.

[91] Hoppe JB, Coradini K, Frozza RL, Oliveira CM, Meneghetti AB, Bernardi A, et al. Free and nanoencapsulated curcumin suppress β-amyloid-induced cognitive impairments in rats: Involvement of BDNF and Akt/GSK-3β signaling pathway. Neurobiol Learn Mem 2013; 106: 134-144.

[92] Zanotto-Filho A, Coradini K, Braganhol E, Schröder R, de Oliveira CM, Simões-Pires A, et al. Curcumin-loaded lipid-core nanocapsules as a strategy to improve pharmacological efficacy of curcumin in glioma treatment. Eur J Pharm Biopharm 2013; 83(2): 156-167.