Chitosan-drug encapsulation as a potential candidate for COVID-19 drug delivery systems: A review

Abstract

Since the outbreak of COVID-19, the World Health Organization (WHO), Centre for Disease Control (CDC), and other health organizations around the world have coordinated the flow of information and given out preventive directives measures and guidelines to reduce the impact and spread of the disease. Meanwhile, bodies of scientists and researchers around the world are still working ceaselessly to study the virus, mode of transmission mechanisms, and are rapidly developing therapeutic antiviral drugs and vaccines. Thus, the urgent need for the fabrication of biocompatible and biodegradable composite materials as drug delivery vehicles for the efficient loading, targeted delivery and controlled release of antiviral drugs to the target site is been inspired. Therefore, this review highlights the antimicrobial and antiviral activities of chitosan as well as the potency of a combined therapy via electrostatic/hydrogen bonding encapsulation onto the WHO suggested clinical trial drugs and possible chelation with metal ions to form new improved antiviral compounds as a promising agent for the targeted drug delivery.

Keywords

• COVID-19
• Biopolymeric chitosan
• Antiviral agent
• Drug delivery
• Biocompatible
• Antibiotics
• Antibiotics

References

1. 1. Fang L, Karakiulakis G, Roth M. Antihypertensive drugs and risk of COVID-19? – Authors’ reply. Lancet Respir Med [Internet]. 2020;2600(20):19–20. Available from: http://dx.doi.org/10.1016/S2213-2600(20)30159-4
2. 2. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265–9.
3. 3. Das UN. Can Bioactive Lipids Inactivate Coronavirus (COVID-19)? Arch Med Res [Internet]. 2020; Available from: https://doi.org/10.1016/j.arcmed.2020.03.004
4. 4. Mackenzie JS, Smith DW. COVID-19: a novel zoonotic disease caused by a coronavirus from China: what we know and what we don’t. Microbiol Aust. 2020;
5. 5. Yang Y, Peng F, Wang R, Guan K, Jiang T, Xu G, et al. The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China. J Autoimmun [Internet]. 2020;102434. Available from: https://doi.org/10.1016/j.jaut.2020.102434
6. 6. McCuaig C. What We Know So Far (As of March 26, 2020) About COVID-19 – An MRT Point of View. J Med Imaging Radiat Sci [Internet]. 2020; Available from: http://www.sciencedirect.com/science/article/pii/S1939865420300394
7. 7. Driggin E, Madhavan M V., Bikdeli B, Chuich T, Laracy J, Bondi-Zoccai G, et al. Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the Coronavirus Disease 2019 (COVID-19) Pandemic. J Am Coll Cardiol [Internet]. 2020;2019. Available from: https://doi.org/10.1016/j.jacc.2020.03.031
8. 8. Zarracina J, Rodriguez A. A visual guide of coronavirus infection, symptoms of COVID-19 and the effects of the virus inside the body, in graphics. USA TODAY [Internet]. 2020 Mar 17; Available from: https://www.usatoday.com/in-depth/news/2020/03/13/what-coronavirus-does-body-covid-19-infection-process-symptoms/5009057002/

9. 9. Yan Bai, Yao L, Wei T, Tian F, Jin D-Y, Chen L, et al. Presumed Asymptomatic Carrier Transmission of COVID-19. letters. 2020;382(13):1199–207.
10. 10. Lai CC, Liu YH, Wang CY, Wang YH, Hsueh SC, Yen MY, et al. Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths. J Microbiol Immunol Infect [Internet]. 2020;2(xxxx). Available from: https://doi.org/10.1016/j.jmii.2020.02.012
11. 11. World Health Organization (WHO). What is the WHO position on the use of chloroquine and hydroxylchloroquine in the context of the COVID-19 response? [Internet]. 2020 [cited 2020 Apr 13]. Available from: https://www.who.int/news-room/q-a-detail/malaria-and-the-covid-19-pandemic
12. 12. World Health Organization. 19th WHO Model List of Essential Medicines. Http://WwwWhoInt/Medicines/Publications/Essentialmedicines/En [Internet]. 2015;1–43. Available from: http://www.who.int/medicines/organization/par/edl/expcom13/eml13%7B_%7Den.pdf
13. 13. Kandeel M, Al-Nazawi M. Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease. Life Sci [Internet]. 2020;251:117627. Available from: https://doi.org/10.1016/j.lfs.2020.117627
14. 14. Smith T, Bushek J, LeClaire A, Prosser T. COVID-19 Drug Therapy. Elsevier - Nov Coronavirus Inf Cent [Internet]. 2020;(CDC):1–21. Available from: https://www.elsevier.com/connect/coronavirus-information-center#research
15. 15. Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care [Internet]. 2020;3–7. Available from: https://doi.org/10.1016/j.jcrc.2020.03.005
16. 16. Duan Y, Zhu H-L, Zhou C. Advance of promising targets and agents against 2019-nCoV in China. Drug Discov Today [Internet]. 2020;00(00):10–2. Available from: https://doi.org/10.1016/j.drudis.2020.02.011
17. 17. Choy K-T, Yin-Lam Wong A, Kaewpreedee P, Sia S-F, Chen D, Yan Hui KP, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res [Internet]. 2020;104786. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32251767
18. 18. Smereka J, Szarpak L. COVID 19 a challenge for emergency medicine and every health care professional. Am J Emerg Med. 2020;(xxxx):2–3.
19. 19. Lim YX, Ng YL, Tam JP, Liu DX. Human Coronaviruses : A Review of Virus – Host Interactions. Diseases. 2016;4(26):1–28.
20. 20. Kang S, Peng W, Zhu Y, Lu S, Zhou M, Lin W, et al. Recent Progress in understanding 2019 Novel Coronavirus associated with Human Respiratory Disease: Detection, Mechanism and Treatment. Int J Antimicrob Agents [Internet]. 2020;105950. Available from: https://doi.org/10.1016/j.ijantimicag.2020.105950
21. 21. Wu C-I, Postema PG, Arbelo E, Behr ER, Bezzina CR, Napolitano C, et al. SARS-CoV-2, COVID-19 and inherited arrhythmia syndromes. Hear Rhythm [Internet]. 2020; Available from: http://www.sciencedirect.com/science/article/pii/S154752712030285X
22. 22. Simmons G, Reeves JD, Rennekamp AJ, Amberg SM, Piefer AJ, Bates P. Characterization of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) spike glycoprotein-mediated viral entry. Proc Natl Acad Sci U S A. 2004;101(12):4240–5.
23. 23. De Wit E, Van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: Recent insights into emerging coronaviruses. Nat Rev Microbiol [Internet]. 2016;14(8):523–34. Available from: http://dx.doi.org/10.1038/nrmicro.2016.81
24. 24. Perlman S, Netland J. Coronaviruses post-SARS: Update on replication and pathogenesis. Nat Rev Microbiol. 2009;7(6):439–50.
25. 25. Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal [Internet]. 2020;19(xxxx):1–7. Available from: https://doi.org/10.1016/j.jpha.2020.03.001
26. 26. Udugama B, Kadhiresan P, Kozlowski HN, Malekjahani A, Osborne M, Li VYC, et al. Diagnosing COVID-19: The Disease and Tools for Detection. ACS Nano. 2020;
27. 27. Kageyama T, Kojima S, Shinohara M, Uchida K, Fukushi S, Hoshino FB, et al. Broadly reactive and highly sensitive assay for Norwalk-like viruses based on real-time quantitative reverse transcription-PCR. J Clin Microbiol. 2003;41(4):1548–57.
28. 28. Lee EYP, Ng MY, Khong PL. COVID-19 pneumonia: what has CT taught us? Lancet Infect Dis. 2020;20(4):384–5.
29. 29. Bernheim A, Mei X, Huang M, Yang Y, Fayad ZA, Zhang N, et al. Chest CT Findings in Coronavirus Disease-19 (COVID-19): Relationship to Duration of Infection. Radiology. 2020;1–8.
30. 30. Beck BR, Shin B, Choi Y, Park S, Kang K. Predicting commercially available antiviral drugs that may act on the novel coronavirus (2019-nCoV), Wuhan, China through a drug-target interaction deep learning model. bioRxiv [Internet]. 2020;18:2020.01.31.929547. Available from: https://www.biorxiv.org/content/biorxiv/early/2020/02/02/2020.01.31.929547.full.pdf
31. 31. Fung TS, Liu DX. Human Coronavirus: Host-Pathogen Interaction. Annu Rev Microbiol. 2019;73(1).
32. 32. Srivastava V, Lee H. Chloroquine-based hybrid molecules as promising novel chemotherapeutic agents. Eur J Pharmacol [Internet]. 2015;762:472–86. Available from: http://dx.doi.org/10.1016/j.ejphar.2015.04.048
33. 33. Devaux CA, Rolain J-M, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents [Internet]. 2020;105938. Available from: https://doi.org/10.1016/j.ijantimicag.2020.105938
34. 34. Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of clinical immunologists from China. Clin Immunol [Internet]. 2020;214:108393. Available from: https://doi.org/10.1016/j.clim.2020.108393
35. 35. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res [Internet]. 2020;177:104762. Available from: https://doi.org/10.1016/j.antiviral.2020.104762
36. 36. Kashyap A, Kaur R, Baldi A, Kumar U, Chandra R, Madan J. Chloroquine diphosphate bearing dextran nanoparticles augmented drug delivery and overwhelmed drug resistance in Plasmodium falciparum parasites. Int J Biol Macromol [Internet]. 2018;114:161–8. Available from: https://doi.org/10.1016/j.ijbiomac.2018.03.102
37. 37. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;10:1–10.
38. 38. Barnard DL, Day CW, Bailey K, Heiner M, Montgomery R, Chan PKS, et al. Evaluation of immunomodulators , interferons and known in vitro SARS-CoV inhibitors for inhibition of SARS-CoV replication in BALB / c mice. Antivir Chem Chemother. 2006;275–84.
39. 39. Akpovwa H. Chloroquine could be used for the treatment of filoviral infections and other viral infections that emerge or emerged from viruses requiring an acidic pH for infectivity. Cell Biochem Funct. 2016;191–6.
40. 40. Lecuit M. Chloroquine and COVID-19, where do we stand? Médecine Mal Infect [Internet]. 2020;3–4. Available from: https://doi.org/10.1016/j.medmal.2020.03.004
41. 41. Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents [Internet]. 2020;(xxxx):105932. Available from: https://doi.org/10.1016/j.ijantimicag.2020.105932
42. 42. Singh AK, Singh A, Shaikh A, Singh R, Misra A. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab Syndr Clin Res Rev [Internet]. 2020;14(3):241–6. Available from: https://doi.org/10.1016/j.dsx.2020.03.011
43. 43. Colson P, Rolain J-M, Raoult D. Chloroquine for the 2019 novel coronavirus. Int J Antimicrob Agents [Internet]. 2020;105923. Available from: https://doi.org/10.1016/j.ijantimicag.2020.105923
44. 44. Lu H. Drug treatment options for the 2019-new coronavirus (2019- nCoV). Biosci Trends. 2020;P1–3.
45. 45. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Main point : Hydroxychloroquine was found to be more potent than chloroquine at inhibiting SARS-CoV-2 in vit. Clin Infect Dis. 2020;2:1–25.
46. 46. Picot S, Marty A, Bienvenu A-L, Blumberg LH, Dupouy-Camet J, Carnevale P, et al. Coalition: Advocacy for prospective clinical trials to test the post-exposure potential of hydroxychloroquine against COVID-19. One Heal [Internet]. 2020; Available from: https://doi.org/10.1016/j.onehlt.2020.100131
47. 47. Gabriels J, Saleh M, Chang D, Epstein LM. Inpatient Use of Mobile Continuous Telemetry for COVID-19 Patients Treated with Hydroxychloroquine and Azithromycin. Hear Case Reports [Internet]. 2020;(PG-). Available from: http://www.sciencedirect.com/science/article/pii/S2214027120300580 NS -
48. 48. Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents [Internet]. 2020;105949. Available from: https://doi.org/10.1016/j.ijantimicag.2020.105949
49. 49. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269–71.
50. 50. Meynard JL, Moinot L, Landman R, Morand-Joubert L, Besseghir A, Kolta S, et al. Week 96 efficacy of lopinavir/ritonavir monotherapy in virologically suppressed patients with HIV: A randomized non-inferiority trial (ANRS 140 DREAM). J Antimicrob Chemother. 2018;73(6):1672–6.
51. 51. Chu CM, Cheng VCC, Hung IFN, Wong MML, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax. 2004;59(3):252–6.
52. 52. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering [Internet]. 2020;(xxxx):4–10. Available from: https://doi.org/10.1016/j.eng.2020.03.007
53. 53. Lythgoe MP, Middleton P. Ongoing Clinical Trials for the Management of the COVID-19 Pandemic. Trends Pharmacol Sci [Internet]. 2020;xx(xx):1–20. Available from: https://doi.org/10.1016/j.tips.2020.03.006
54. 54. Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci [Internet]. 2020;117592. Available from: https://doi.org/10.1016/j.lfs.2020.117592
55. 55. Baron SA, Devaux C, Colson P, Raoult D, Rolain J-M. Teicoplanin: an alternative drug for the treatment of COVID-19? Int J Antimicrob Agents [Internet]. 2020;2(xxxx):105944. Available from: https://doi.org/10.1016/j.ijantimicag.2020.105944
56. 56. Sallard E, Lescure FX, Yazdanpanah Y, Mentre F, Peiffer-Smadja N. Type 1 interferons as a potential treatment against COVID-19. Antiviral Res. 2020;178. 57. Chan JFW, Yao Y, Yeung M-L, Deng W, Bao L, Jia L, et al. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a non-human primate model of common marmoset. J Infecteous Dis. 2015;212(12):1904–13.
57. 58. Brown BL, Mccullough J. Treatment for emerging viruses: Convalescent plasma and COVID-19. Transfus Apher Sci [Internet]. 2020;102790. Available from: https://doi.org/10.1016/j.transci.2020.102790
58. 59. Mohamed T, El-aziz A, Stockand JD. Recent progress and challenges in drug development against COVID-19 coronavirus ( SARS-CoV-2 ) - an update on the status. Infect Genet Evol [Internet]. 2020;83:104327. Available from: https://doi.org/10.1016/j.meegid.2020.104327
59. 60. Tripathy S, Kar S, Chattopadhyay S, Das S. A novel chitosan based antimalarial drug delivery against Plasmodium berghei infection. Acta Trop [Internet]. 2013;128(3):494–503. Available from: http://dx.doi.org/10.1016/j.actatropica.2013.07.011
60. 61. Adewuyi S, Sanyaolu NO, Amolegbe SA, Sobola AO, Folarin OM. Poly[β-(1→4)-2-amino-2-deoxy-D-ghicopyranose] based zero valent nickel nanocomposite for efficient reduction of nitrate in water. J Environ Sci (China). 2012;24(9):1702–8.
61. 62. Ahmed F, Soliman FM, Adly MA, Soliman HAM, El-Matbouli M, Saleh M. Recent progress in biomedical applications of chitosan and its nanocomposites in aquaculture: A review. Res Vet Sci [Internet]. 2019;126:68–82. Available from: https://doi.org/10.1016/j.rvsc.2019.08.005
62. 63. Chylińska M, Kaczmarek H, Burkowska-But A. Preparation and characteristics of antibacterial chitosan films modified with N-halamine for biomedical application. Colloids Surfaces B Biointerfaces. 2019;176:379–86.
63. 64. Ejeromedoghene, Onome., Alayande, J. Olalekan., Olatunji, D. Emmanuel ., Alli , A. Yakubu., and Adewuyi S. Synthesis of Chitosan-Zirconium(IV) Complexes as an Antifungal Spraying Agent Against Tomato Infected Aspergillus Niger. J Chem Soc Niger [Internet]. 2019;44(1):125–9. Available from: http://journals.chemsociety.org.ng/index.php/jcsn/article/view/253
64. 65. Wang X, Du Y, Fan L, Liu H, Hu Y. Chitosan- metal complexes as antimicrobial agent : Synthesis , characterization and Structure-activity study. Polym Bull. 2005;113:105–13.
65. 66. Huang J, Cheng Y, Wu Y, Shi X, Du Y, Deng H. Chitosan/tannic acid bilayers layer-by-layer deposited cellulose nanofibrous mats for antibacterial application. Int J Biol Macromol [Internet]. 2019;139:191–8. Available from: https://doi.org/10.1016/j.ijbiomac.2019.07.185
66. 67. Fotoran WL, Müntefering T, Kleiber N, Miranda BNM, Liebau E, Irvine DJ, et al. A multilamellar nanoliposome stabilized by interlayer hydrogen bonds increases antimalarial drug efficacy. Nanomedicine Nanotechnology, Biol Med [Internet]. 2019;22:102099. Available from: https://doi.org/10.1016/j.nano.2019.102099
67. 68. Adewuyi S, Kareem KT, Atayese AO, Amolegbe SA, Akinremi CA. Chitosan-cobalt(II) and nickel(II) chelates as antibacterial agents. Int J Biol Macromol [Internet]. 2011;48(2):301–3. Available from: http://dx.doi.org/10.1016/j.ijbiomac.2010.12.004
68. 69. Loh XJ, Wu YL. Cationic star copolymers based on β-cyclodextrins for efficient gene delivery to mouse embryonic stem cell colonies. Chem Commun [Internet]. 2015;51(54):10815–8. Available from: http://dx.doi.org/10.1039/C5CC03686K
69. 70. Loh XJ, Ong SJ, Tung YT, Choo HT. Co-delivery of drug and DNA from cationic dual-responsive micelles derived from poly(DMAEMA-co-PPGMA). Mater Sci Eng C [Internet]. 2013;33(8):4545–50. Available from: http://dx.doi.org/10.1016/j.msec.2013.07.011
70. 71. Xiang Y, Nwe N, Oo L, Lee JP, Li Z, Loh XJ. Recent development of synthetic nonviral systems for sustained gene delivery. Drug Discov Today [Internet]. 2017;22(9):1318–35. Available from: http://dx.doi.org/10.1016/j.drudis.2017.04.001
71. 72. Ahsan SM, Thomas M, Reddy KK, Gopal S, Asthana A, Bhatnagar I. Chitosan as biomaterial in drug delivery and tissue engineering. Int J Biol Macromol [Internet]. 2018;110:97–109. Available from: http://dx.doi.org/10.1016/j.ijbiomac.2017.08.140
72. 73. Mao S, Sun W, Kissel T. Chitosan-based formulations for delivery of DNA and siRNA. Adv Drug Deliv Rev [Internet]. 2010;62(1):12–27. Available from: http://dx.doi.org/10.1016/j.addr.2009.08.004
73. 74. Mansouri S, Lavigne P, Corsi K, Benderdour M, Beaumont E, Fernandes JC. Chitosan-DNA nanoparticles as non-viral vectors in gene therapy : strategies to improve transfection efficacy. Eur J Pharm Biopharm. 2004;57:1–8.
74. 75. Buschmann MD, Merzouki A, Lavertu M, Thibault M, Jean M, Darras V. Chitosans for delivery of nucleic acids. Adv Drug Deliv Rev [Internet]. 2013;65(9):1234–70. Available from: http://dx.doi.org/10.1016/j.addr.2013.07.005
75. 76. Tripathy S, Das S, Prasad S, Kumar S, Pramanik P, Roy S. Synthesis , characterization of chitosan – tripolyphosphate conjugated chloroquine nanoparticle and its in vivo anti-malarial efficacy against rodent parasite : A dose and duration dependent approach. Int J Pharm [Internet]. 2012;434(1–2):292–305. Available from: http://dx.doi.org/10.1016/j.ijpharm.2012.05.064
76. 77. Magalhães GA, Moura E, Sombra VG, Richter AR, Abreu CMWS, Feitosa JPA, et al. Chitosan / Sterculia striata polysaccharides nanocomplex as a potential chloroquine drug release device. Int J Biol Macromol [Internet]. 2016;88:244–53. Available from: http://dx.doi.org/10.1016/j.ijbiomac.2016.03.070
77. 78. Usman M, Akhyar Farrukh M. Formulation of polymeric iron nano-chloroquine phosphate anti-malarial drug via polyol method. Mater Today Proc [Internet]. 2018;5(7):15595–602. Available from: https://doi.org/10.1016/j.matpr.2018.04.168
78. 79. Fantini J, Scala C Di, Chahinian H, Yahi N. Structural and molecular modeling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents [Internet]. 2020;105960. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32251731
79. 80. Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines Against Coronavirus Disease 2019 (COVID-19): Chloroquine or Hydroxychloroquine. Int J Antimicrob Agents [Internet]. 2020;2019(xxxx):105945. Available from: https://doi.org/10.1016/j.ijantimicag.2020.105945
80. 81. Jorge AM, Melles RB, Zhang Y, Lu N, Rai SK, Young LH, et al. Hydroxychloroquine prescription trends and predictors for excess dosing per recent ophthalmology guidelines. Arthritis Res Ther. 2018;20(1):4–11.
81. 82. Lim HS, Im JS, Cho JY, Bae KS, Klein TA, Yeom JS, et al. Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by plasmodium vivax. Antimicrob Agents Chemother. 2009;53(4):1468–75.
82. 83. Ravi PR, Vats R, Balija J, Adapa SPN, Aditya N. Modified pullulan nanoparticles for oral delivery of lopinavir: Formulation and pharmacokinetic evaluation. Carbohydr Polym [Internet]. 2014;110:320–8. Available from: http://dx.doi.org/10.1016/j.carbpol.2014.03.099
83. 84. Kozhikhova K V., Ivantsova MN, Tokareva MI, Shulepov ID, Tretiyakov A V., Shaidarov L V., et al. Preparation of chitosan-coated liposomes as a novel carrier system for the antiviral drug Triazavirin. Pharm Dev Technol [Internet]. 2018;23(4):334–42. Available from: http://dx.doi.org/10.1080/10837450.2016.1242624
84. 85. Cánepa C, Imperiale JC, Berini CA, Lewicki M, Sosnik A, Biglione MM. Development of a Drug Delivery System Based on Chitosan Nanoparticles for Oral Administration of Interferon-α. Biomacromolecules. 2017;18(10):3302–9.
85. 86. Donalisio M, Leone F, Civra A, Spagnolo R, Ozer O, Lembo D, et al. Acyclovir-loaded chitosan nanospheres from nano-emulsion templating for the topical treatment of herpesviruses infections. Pharmaceutics. 2018;10(2):1–12.
86. 87. Ulla F, Javed F, Khan AN, Kudus MHA, Jamila N, Minhaz A, et al. Synthesis and surface modification of chitosan built nanohydrogel with antiviral and antimicrobial agent for controlled drug delivery. Biointerface Res Appl Chem [Internet]. 2019;9(6):4439–45. Available from: https://doi.org/10.33263/BRIAC96.439445
87. 88. Russo E, Gaglianone N, Baldassari S, Parodi B, Cafaggi S, Zibana C, et al. Preparation, characterization and in vitro antiviral activity evaluation of foscarnet-chitosan nanoparticles. Colloids Surfaces B Biointerfaces [Internet]. 2014;118:117–25. Available from: http://dx.doi.org/10.1016/j.colsurfb.2014.03.037
88. 89. Yang L, Chen L, Zeng R, Li C, Qiao R, Hu L, et al. Synthesis, nanosizing and in vitro drug release of a novel anti-HIV polymeric prodrug: Chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate. Bioorganic Med Chem [Internet]. 2010;18(1):117–23. Available from: http://dx.doi.org/10.1016/j.bmc.2009.11.013
89. 90. Yan JK, Wang YY, Qiu WY, Wu JY. Construction and characterization of nanosized curdlan sulfate/chitosan polyelectrolyte complex toward drug release of zidovudine. Carbohydr Polym [Internet]. 2017;174:209–16. Available from: http://dx.doi.org/10.1016/j.carbpol.2017.06.082
90. 91. Cazorla-Luna R, Notario-Pérez F, Martín-Illana A, Ruiz-Caro R, Tamayo A, Rubio J, et al. Chitosan-based mucoadhesive vaginal tablets for controlled release of the anti-HIV drug tenofovir. Pharmaceutics. 2019;11(1).
91. 92. Wu D, Ensinas A, Verrier B, Primard C, Cuvillier A, Champier G, et al. Zinc-stabilized chitosan-chondroitin sulfate nanocomplexes for HIV-1 infection inhibition application. Mol Pharm. 2016;13(9):3279–91.
92. 93. Graham BS. Advances in antiviral vaccine development. Immunol Rev. 2013;255(1):230–42.
93. 94. Ellebedy AH, Ahmed R. Antiviral Vaccines: Challenges and Advances. In: The Vaccine Book: Second Edition. Second. Elsevier Inc.; 2016. p. 283–310.
94. 95. Ellebedy AH, Webby RJ. Influenza vaccines. Vaccine. 2009;27(SUPPL. 4):65–8.
95. 96. Muralidharan A, Russell MS, Larocque L, Gravel C, Sauvé S, Chen Z, et al. Chitosan alters inactivated respiratory syncytial virus vaccine elicited immune responses without affecting lung histopathology in mice. Vaccine [Internet]. 2019;37(30):4031–9. Available from: https://doi.org/10.1016/j.vaccine.2019.06.003
96. 97. Spinner JL, Oberoi HS, Yorgensen YM, Poirier DS, Burkhart DJ, Plante M, et al. Methylglycol chitosan and a synthetic TLR4 agonist enhance immune responses to influenza vaccine administered sublingually. Vaccine [Internet]. 2015;33(43):5845–53. Available from: http://dx.doi.org/10.1016/j.vaccine.2015.08.086
97. 98. Renu S, Feliciano-Ruiz N, Ghimire S, Han Y, Schrock J, Dhakal S, et al. Poly(I:C) augments inactivated influenza virus-chitosan nanovaccine induced cell mediated immune response in pigs vaccinated intranasally. Vet Microbiol [Internet]. 2020;242(January):108611. Available from: https://doi.org/10.1016/j.vetmic.2020.108611
98. 99. El-Sissi AF, Mohamed FH, Danial NM, Gaballah AQ, Ali KA. Chitosan and chitosan nanoparticles as adjuvant in local Rift Valley Fever inactivated vaccine. 3 Biotech [Internet]. 2020;10(3):1–11. Available from: https://doi.org/10.1007/s13205-020-2076-y