Curcumin and quercetin co-encapsulated in nanoemulsions for nasal administration: a promising therapeutic and prophylactic treatment for viral respiratory infections
Daniela Pastorim Vaiss, Jamile Lima Rodrigues, Virginia Campello Yurgel, Frank Do Carmo Guedes, Lauanda Larissa Mendonça Da Matta, Paula Alice Bezerra Barros, Gustavo Richter Vaz, Raíssa Nunes Dos Santos, Bibiana Franzen Matte, Larine Kupski, Jaqueline Garda-Buffon, Juliana Bidone, Ana Luiza Muccillo-Baisch, Fabio Sonvico, Cristiana Lima Dora
European Journal of Pharmaceutical Sciences, doi:10.1016/j.ejps.2024.106766
One of the most frequent causes of respiratory infections are viruses. Viruses reaching the airways can be absorbed by the human body through the respiratory mucosa and mainly infect lung cells. Several viral infections are not yet curable, such as coronavirus-2 (SARS-CoV-2). Furthermore, the side effect of synthetic antiviral drugs and reduced efficacy against resistant variants have reinforced the search for alternative and effective treatment options, such as plant-derived antiviral molecules. Curcumin (CUR) and quercetin (QUE) are two natural compounds that have been widely studied for their health benefits, such as antiviral and antiinflammatory activity. However, poor oral bioavailability limits the clinical applications of these natural compounds. In this work, nanoemulsions (NE) co-encapsulating CUR and QUE designed for nasal administration were developed as promising prophylactic and therapeutic treatments for viral respiratory infections. The NEs were prepared by high-pressure homogenization combined with the phase inversion temperature technique and evaluated for their physical and chemical characteristics. In vitro assays were performed to evaluate the nanoemulsion retention into the porcine nasal mucosa. In addition, the CUR and QUE-loaded NE antiviral activity was tested against a murine β-COV, namely MHV-3. The results evidenced that CUR and QUE loaded NE had a particle size of 400 nm and retention in the porcine nasal mucosa. The antiviral activity of the NEs showed a percentage of inhibition of around 99%, indicating that the developed NEs has interesting properties as a therapeutic and prophylactic treatment against viral respiratory infections.
experiments, analyzed the data, contributed reagents/materials/analysis tools, writingoriginal draft preparation, writing-review and editing, visualization, supervision, project administration and funding acquisition. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
Conflicts of Interest: The authors declare no conflict of interest.
References
Aggarwal, Sung, Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets, Trends Pharmacol. Sci,
doi:10.1016/j.tips.2008.11.002Agrawal, Agrawal, Blunden, Quercetin: Antiviral Significance and Possible COVID-19 Integrative Considerations, Nat. Prod. Commun,
doi:10.1177/1934578x20976293Anderson, Sivalingam, Kang, Ananthanarayanan, Arumugam et al., Povidone-Iodine Demonstrates Rapid In Vitro Virucidal Activity Against SARS-CoV-2, The Virus Causing COVID-19 Disease, Infect. Dis. Ther,
doi:10.1007/s40121-020-00316-3Andres, Pevny, Ziegenhagen, Bakhiya, Schäfer et al., Safety Aspects of the Use of Quercetin as a Dietary Supplement, Mol. Nutr. Food Res,
doi:10.1002/mnfr.201700447Anggakusuma, Colpitts, Schang, Rachmawati, Frentzen et al., Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells, Gut,
doi:10.1136/gutjnl-2012-304299Anvisa, Dispõe sobre os ensaios de desempenho in vitro de medicamentos nasais e inalatórios orais, nos termos da Resolução da Diretoria Colegiada -RDC n o 278, de 16 de
Bachar, Mazumder, Bachar, Aktar, Mahtab, A Review of Medicinal Plants with Antiviral Activity Available in Bangladesh and Mechanistic Insight Into Their Bioactive Metabolites on SARS-CoV-2, HIV and HBV, Front. Pharmacol,
doi:10.3389/fphar.2021.732891Balducci, Ferraro, Bortolotti, Nastruzzi, Colombo et al., Antidiuretic effect of desmopressin chimera agglomerates by nasal administration in rats, Int J Pharm,
doi:10.1016/j.ijpharm.2012.09.049Bandyopadhyay, Farmer to pharmacist: curcumin as an anti-invasive and antimetastatic agent for the treatment of cancer1, Front. Chem,
doi:10.3389/fchem.2014.00113Basnet, Skalko-Basnet, Curcumin: An Anti-Inflammatory Molecule from a Curry Spice on the Path to Cancer Treatment, Molecules,
doi:10.3390/molecules16064567Baumann, Bachert, Högger, Development of a novel model for comparative evaluation of intranasal pharmacokinetics and effects of anti-allergic nasal sprays, Eur. J. Pharm. Biopharm,
doi:10.1016/j.ejpb.2011.09.003Ben-Shabat, Yarmolinsky, Porat, Dahan, Antiviral effect of phytochemicals from medicinal plants: Applications and drug delivery strategies, Drug Deliv. Transl. Res,
doi:10.1007/s13346-019-00691-6Benam, Denney, Ho, How the Respiratory Epithelium Senses and Reacts to Influenza Virus, Am. J. Respir. Cell Mol. Biol,
doi:10.1165/rcmb.2018-0247trBiancatelli, Berrill, Catravas, Marik, Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19), Front. Immunol,
doi:10.3389/fimmu.2020.01451Bormann, Alt, Schipper, Sand, Van De, Le-Trilling et al., Turmeric Root and Its Bioactive Ingredient Curcumin Effectively Neutralize SARS-CoV-2 In Vitro, Viruses,
doi:10.3390/v13101914Boroumand, Samarghandian, Hashemy, Immunomodulatory, antiinflammatory, and antioxidant effects of curcumin, J. Herbmed Pharmacol,
doi:10.15171/jhp.2018Bortolotti, Fabrizio, Balducci, Giulia, Sonvico et al., In vitro permeation of desmopressin across rabbit nasal mucosa from liquid nasal sprays: The enhancing effect of potassium sorbate, Eur J Pharm Sci,
doi:10.1016/j.ejps.2008.12.015Cder, Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products -Chemistry, Manufacturing, and Controls Documentation
Chen, Yang, Distinct codon usage bias evolutionary patterns between weakly and strongly virulent respiratory viruses, iScience,
doi:10.1016/j.isci.2021.103682Cheng, Hsu, Lin, Hsu, Ho et al., Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions, Anticancer Res
Cheng, Huang, Pang, Wu, Cheng, Quercetin Inhibits the Production of IL-1β-Induced Inflammatory Cytokines and Chemokines in ARPE-19 Cells via the MAPK and NF-κB Signaling Pathways, Int. J. Mol. Sci,
doi:10.3390/ijms20122957Chenthamara, Subramaniam, Ramakrishnan, Krishnaswamy, Essa et al., Therapeutic efficacy of nanoparticles and routes of administration, Biomater. Res,
doi:10.1186/s40824-019-0166-xChiow, Phoon, Putti, Tan, Chow, Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection, Asian Pac. J. Trop. Med,
doi:10.1016/j.apjtm.2015.12.002Chmp, Guideline on the pharmaceutical quality of inhalation and nasal products
Derman, Uzunoglu, Acar, Arasoglu, Ucak et al., Antioxidant Activity and Hemocompatibility Study of Quercetin Loaded Plga Nanoparticles, Iran. J. Pharm. Res,
doi:10.22037/ijpr.2020.1101000Dhanya, Quercetin for managing type 2 diabetes and its complications, an insight into multitarget therapy, Biomed. Pharmacother,
doi:10.1016/j.biopha.2021.112560Forbes, Bommer, Goole, Hellfritzsch, Kruijf et al., A consensus research agenda for optimising nasal drug delivery, Expert Opin Drug Del,
doi:10.1080/17425247.2020.1714589Ghadi, Dinarvand, Asemi, Amiri, Ebrahimnejad, Preparation, characterization and in vivo evaluation of novel hyaluronan containing niosomes tailored by Box-Behnken design to co-encapsulate curcumin and quercetin, Eur. J. Pharm. Sci,
doi:10.1016/j.ejps.2019.01.035Giuliani, Balducci, Zironi, Colombo, Bortolotti et al., In vivo nose-to-brain delivery of the hydrophilic antiviral ribavirin by microparticle agglomerates, Drug Deliv,
doi:10.1080/10717544.2018.1428242Goc, Rath, Niedzwiecki, Composition of naturally occurring compounds decreases activity of Omicron and SARS-CoV-2 RdRp complex, Eur. J. Microbiol. Immunol,
doi:10.1556/1886.2022.00009Guo-Parke, Linden, Weldon, Kidney, Taggart, Deciphering Respiratory-Virus-Associated Interferon Signaling in COPD Airway Epithelium, Medicina,
doi:10.3390/medicina58010121Hartwell, Melo, Xiao, Lemnios, Li et al., Intranasal vaccination with lipid-conjugated immunogens promotes antigen transmucosal uptake to drive mucosal and systemic immunity, Sci. Transl. Med,
doi:10.1126/scitranslmed.abn1413Harwood, Danielewska-Nikiel, Borzelleca, Flamm, Williams et al., A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties, Food Chem. Toxicol,
doi:10.1016/j.fct.2007.05.015Hou, Zhang, Gao, Sun, Wang et al., Anti-inflammatory effects of quercetin in a mouse model of MC903-induced atopic dermatitis, Int. Immunopharmacol,
doi:10.1016/j.intimp.2019.105676Ich, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceutics for Human Use
Invernizzi, Lloyd, Molyneaux, Respiratory microbiome and epithelial interactions shape immunity in the lungs, Immunology,
doi:10.1111/imm.13195Jiang, Jiang, Yichuan, Ding, Yu, Investigation of the "Nose-to-Brain" Pathways in Intranasal HupA Nanoemulsions and Evaluation of Their in vivo Pharmacokinetics and Brain-Targeting Ability, Int. J. Nanomed,
doi:10.2147/ijn.s369978Kakad, Gangurde, Kshirsagar, Mundhe, Nose to brain delivery of nanosuspensions with first line antiviral agents is alternative treatment option to Neuro-AIDS treatment, Heliyon,
doi:10.1016/j.heliyon.2022.e09925Karimi, Ghodsi, Kooshki, Karimi, Asghariazar et al., Therapeutic effects of curcumin on sepsis and mechanisms of action: A systematic review of preclinical studies, Phytotherapy Res,
doi:10.1002/ptr.6467Keller, Merkel, Popp, Intranasal drug delivery: opportunities and toxicologic challenges during drug development, Drug Deliv. Transl. Res,
doi:10.1007/s13346-020-00891-5Khizar, Alrushaid, Khan, Zine, Jaffrezic-Renault et al., Nanocarriers based novel and effective drug delivery system, Int. J. Pharm,
doi:10.1016/j.ijpharm.2022.122570Kleinehr, Wilden, Boergeling, Ludwig, Hrincius, Metabolic Modifications by Common Respiratory Viruses and Their Potential as New Antiviral Targets, Viruses,
doi:10.3390/v13102068Kunnumakkara, Bordoloi, Padmavathi, Monisha, Roy et al., Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases, Br. J. Pharmacol,
doi:10.1111/bph.13621Li, Wang, Liu, Luo, Lei et al., Antiviral and virucidal effects of curcumin on transmissible gastroenteritis virus in vitro, J. Gen. Virol,
doi:10.1099/jgv.0.001466Marx, Williams, Birkhoff, Intranasal Drug Administration -An Attractive Delivery Route for Some Drugs,
doi:10.5772/59468Marín-Palma, Tabares-Guevara, Zapata-Cardona, Flórez-Álvarez, Yepes et al., Curcumin Inhibits In Vitro SARS-CoV-2 Infection In Vero E6 Cells through Multiple Antiviral Mechanisms, Molecules,
doi:10.3390/molecules26226900Mazumder, Raghavan, Weinstein, Kohn, Pommier, Inhibition of human immunodeficiency virus type-1 integrase by curcumin, Biochem. Pharmacol,
doi:10.1016/0006-2952(95)98514-aMitchell, Billingsley, Haley, Wechsler, Peppas et al., Engineering precision nanoparticles for drug delivery, Nat. Rev. Drug Discov,
doi:10.1038/s41573-020-0090-8Nabavi, Thiagarajan, Rastrelli, Daglia, Sobarzo-Sánchez et al., Curcumin: A Natural Product for Diabetes and its Complications, Curr. Top. Med. Chem,
doi:10.2174/1568026615666150619142519Nair, Kandaswami, Mahajan, Chadha, Chawda et al., The flavonoid, quercetin, differentially regulates Th-1 (IFNγ) and Th-2 (IL4) cytokine gene expression by normal peripheral blood mononuclear cells, Biochim. Biophys. Acta (BBA) -Mol. Cell Res,
doi:10.1016/s0167-4889(02)00328-2Orellana, Kasinski, Sulforhodamine B (SRB) Assay in Cell Culture to Investigate Cell Proliferation, BIO-Protoc,
doi:10.21769/bioprotoc.1984Patel, Acharya, Ray, Agrawal, Raghuwanshi et al., Cellular and molecular mechanisms of curcumin in prevention and treatment of disease, Crit. Rev. Food Sci. Nutr,
doi:10.1080/10408398.2018.1552244Perrone, Ardito, Giannatempo, Dioguardi, Troiano et al., Biological and therapeutic activities, and anticancer properties of curcumin, Exp. Ther. Med,
doi:10.3892/etm.2015.2749Pires, Fortuna, Alves, Falcão, Intranasal Drug Delivery: How, Why and What for?, J. Pharm. Pharm. Sci,
doi:10.18433/J3NC79Praditya, Kirchhoff, Brüning, Rachmawati, Steinmann et al., Antiinfective Properties of the Golden Spice Curcumin, Front. Microbiol,
doi:10.3389/fmicb.2019.00912Roshdy, Rashed, Kandeil, Mostafa, Moatasim et al., EGYVIR: An immunomodulatory herbal extract with potent antiviral activity against SARS-CoV-2, PLoS ONE,
doi:10.1371/journal.pone.0241739Rueda-Fernández, Melguizo-Rodríguez, Costela-Ruiz, González-Acedo, Ramos-Torrecillas et al., The current status of COVID-19 vaccines. A scoping review, Drug Discov Today,
doi:10.1016/j.drudis.2022.08.004Salade, Wauthoz, Goole, Amighi, How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods, Int. J. Pharm,
doi:10.1016/j.ijpharm.2019.02.026Salehi, Machin, Monzote, Sharifi-Rad, Ezzat et al., Therapeutic Potential of Quercetin: New Insights and Perspectives for Human Health, ACS Omega,
doi:10.1021/acsomega.0c01818Scherließ, Nasal formulations for drug administration and characterization of nasal preparations in drug delivery, Ther. Deliv,
doi:10.4155/tde-2019-0086Sonvico, Colombo, Quarta, Guareschi, Banella et al., Nasal delivery as a strategy for the prevention and treatment of COVID-19, Expert Opin. Drug Deliv,
doi:10.1080/17425247.2023.2263363Tayeb, Felimban, Almaghrabi, Hasaballah, Nanoemulsions: Formulation, characterization, biological fate, and potential role against COVID-19 and other viral outbreaks, Colloid Interface Sci. Commun,
doi:10.1016/j.colcom.2021.100533Uchide, Toyoda, Antioxidant Therapy as a Potential Approach to Severe Influenza-Associated Complications, Molecules,
doi:10.3390/molecules16032032Ujjan, Khan, Nigar, Ahmed, Ahmad et al., The possible therapeutic role of curcumin and quercetin in the early-stage of COVID-19-Results from a pragmatic randomized clinical trial, Front. Nutr,
doi:10.3389/fnut.2022.1023997Umuhoza, Oyugi, Mancuso, Ahmed, Bulimo, Morbidity burden, seasonality and factors associated with the human respiratory syncytial virus, human parainfluenza virus, and human adenovirus infections in Kenya, IJID Reg,
doi:10.1016/j.ijregi.2021.10.001Vaz, Carrasco, Batista, Barros, Oliveira et al., Curcumin and Quercetin-Loaded Lipid Nanocarriers: Development of Omega-3 Mucoadhesive Nanoemulsions for Intranasal Administration, Nanomaterials,
doi:10.3390/nano12071073Vaz, Clementino, Bidone, Villetti, Falkembach et al., Curcumin and Quercetin-Loaded Nanoemulsions: Physicochemical Compatibility Study and Validation of a Simultaneous Quantification Method, Nanomaterials,
doi:10.3390/nano10091650Vaz, Clementino, Mitsou, Ferrari, Buttini et al., In Vitro Evaluation of Curcumin-and Quercetin-Loaded Nanoemulsions for Intranasal Administration: Effect of Surface Charge and Viscosity, Pharmaceutics,
doi:10.3390/pharmaceutics14010194Vaz, Hädrich, Bidone, Rodrigues, Falkembach et al., Development of Nasal Lipid Nanocarriers Containing Curcumin for Brain Targeting, J. Alzheimer's Dis. Preprint,
doi:10.3233/jad-160355Verma, Kumar, Singh, Goswami, Ch et al., Repurposing potential of Ayurvedic medicinal plants derived active principles against SARS-CoV-2 associated target proteins revealed by molecular docking, molecular dynamics and MM-PBSA studies, Biomed. Pharmacother,
doi:10.1016/j.biopha.2021.111356Wang, Prather, Sznitman, Jimenez, Lakdawala et al., Airborne transmission of respiratory viruses, Science,
doi:10.1126/scienceWen, Kuo, Jan, Liang, Wang et al., Specific Plant Terpenoids and Lignoids Possess Potent Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus, J. Med. Chem,
doi:10.1021/jm070295sYang, Lin, Tsai, Hsu, Shih et al., Nanotechnology advances in pathogen-and host-targeted antiviral delivery: multipronged therapeutic intervention for pandemic control, Drug Deliv. Transl. Res,
doi:10.1007/s13346-021-00965-yYang, Wang, Long, Li, Quercetin: Its Main Pharmacological Activity and Potential Application in Clinical Medicine, Oxidative Med. Cell. Longev,
doi:10.1155/2020/8825387
