The dry powder formulation of mixed cross-linked dextran microspheres and tetanus toxoid-loaded trimethyl chitosan nanospheres as a potent adjuvant for nasal delivery system

Document Type : Short Communication

Authors

1 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

2 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

3 Clinical Research Development Unit, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

4 Biotechnology Center, Gilead Sciences, Foster City, USA

Abstract

Objective(s): The present study aimed to determine the immunoadjuvant efficacy of mixed cross-linked dextran microspheres (CDM) and tetanus toxoid (TT)-loaded trimethyl chitosan (TMC) nanospheres in dry powder form.
Materials and Methods: The TMC nanoparticles (NPs) containing TT were produced using the ionic gelation method. Co-administration of TT-loaded TMC NPs and CDM as an absorption enhancer was performed to improve immunity against the antigen. Dry powder formulations were delivered via the nasal route in a rabbit model.
Results: Among immunization groups, mixing of CDM with TT encapsulated in TMC NPs could elicit the highest titer of systemic IgG antibody. Furthermore, the addition of CDM to TT-loaded TMC enhanced the sIgA response relative to the TT solution.
Conclusion: The TMC NPs had a considerable effect on mucosal and systemic immunity against the TT antigen. Therefore, the CDM excipient can be utilized for nasal immunization to elevate systemic and mucosal responses.

Keywords


1. Chen H. Recent advances in mucosal vaccine development. J Control Release 2000; 67:117-128.
2. Lycke N. Recent progress in mucosal vaccine development: potential and limitations. Nat Rev Immunol 2012; 12:592-605.
3. Mannam P, Jones KF, Geller BL. Mucosal vaccine made from live, recombinant Lactococcus lactis protects mice against pharyngeal infection with Streptococcus pyogenes. Infect Immun 2004; 72:3444-3450.
4. Pavot V, Rochereau N, Genin C, Verrier B, Paul S. New insights in mucosal vaccine development. Vaccine 2012; 30:142-154.
5. Rhee JH, Lee SE, Kim SY. Mucosal vaccine adjuvants update. Clin Exp Vaccine Res 2012; 1:50-63.
6. Tafaghodi M, Tabassi SAS, Jaafari MR. Induction of systemic and mucosal immune responses by intranasal administration of alginate microspheres encapsulated with tetanus toxoid and CpG-ODN. Int J Pharm 2006; 319:37-43.
7. Ramvikas M, Arumugam M, Chakrabarti S, Jaganathan K. Nasal Vaccine Delivery.  Micro and Nanotechnology in Vaccine Development: Elsevier 2017; 279-301.
8. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 2014; 14:141-153.
9. Kiyono H, Fukuyama S. NALT-versus Peyer’s-patch-mediated mucosal immunity. Nat Rev Immunol 2004; 4:699-708.
10. Agnihotri SA, Mallikarjuna NN, Aminabhavi TM. Recent advances on chitosan-based micro-and nanoparticles in drug delivery. J Control Release 2004; 100:5-28.
11. Fernández-Urrusuno R, Calvo P, Remuñán-López C, Vila-Jato JL, Alonso MJ. Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharm Res 1999; 16:1576-1581.
12. Illum L, Jabbal-Gill I, Hinchcliffe M, Fisher A, Davis S. Chitosan as a novel nasal delivery system for vaccines. Adv Drug Deliv Rev 2001; 51:81-96.
13. Pan Y, Li Y-j, Zhao H-y, Zheng J-m, Xu H, Wei G, et al. Bioadhesive polysaccharide in protein delivery system: chitosan nanoparticles improve the intestinal absorption of insulin in vivo. Int J Pharm 2002; 249:139-147.
14. Pawar D, Jaganathan K. Mucoadhesive glycol chitosan nanoparticles for intranasal delivery of hepatitis B vaccine: enhancement of mucosal and systemic immune response. Drug Deliv 2016; 23:185-194.
15. Prasanth Koppolu B, Smith SG, Ravindranathan S, Jayanthi S, Kumar TKS, Zaharoff DA. Controlling chitosan-based encapsulation for protein and vaccine delivery. Biomaterials 2014; 35:4382-4389.
16. Channarong S, Chaicumpa W, Sinchaipanid N, Mitrevej A. Development and evaluation of chitosan-coated liposomes for oral DNA vaccine: the improvement of Peyer’s patch targeting using a polyplex-loaded liposomes. AAPS PharmSciTech 2011; 12:192-200.
17. Castro KCd, Costa JM, Campos MGN. Drug-loaded polymeric nanoparticles: a review. International Journal of Polymeric Materials and Polymeric Biomaterials 2020:1-13.
18. Matos BN, Pereira MN, Bravo MdO, Cunha-Filho M, Saldanha-Araújo F, Gratieri T, et al. Chitosan nanoparticles loading oxaliplatin as a mucoadhesive topical treatment of oral tumors: Iontophoresis further enhances drug delivery ex vivo. Int J Biol Macromol 2020; 154:1265-1275.
19. Sayın B, Somavarapu S, Li X, Thanou M, Sesardic D, Alpar H, et al. Mono-N-carboxymethyl chitosan (MCC) and N-trimethyl chitosan (TMC) nanoparticles for non-invasive vaccine delivery. Int J Pharm 2008; 363:139-148.
20. Van der Lubben IM, Verhoef JC, Borchard G, Junginger HE. Chitosan and its derivatives in mucosal drug and vaccine delivery. Eur J Pharm Sci 2001; 14:201-207.
21. Zhang H, Oh M, Allen C, Kumacheva E. Monodisperse chitosan nanoparticles for mucosal drug delivery. Biomacromolecules 2004; 5:2461-2468.
22. Casettari L, Illum L. Chitosan in nasal delivery systems for therapeutic drugs. J Control Release 2014; 190:189-200.
23. Yan Y, Sun Y, Wang P, Zhang R, Huo C, Gao T, et al. Mucoadhesive nanoparticles-based oral drug delivery systems enhance ameliorative effects of low molecular weight heparin on experimental colitis. Carbohydrate Polymers 2020; 246:116660.
24. Tsai L-C, Chen C-H, Lin C-W, Ho Y-C, Mi F-L. Development of mutlifunctional nanoparticles self-assembled from trimethyl chitosan and fucoidan for enhanced oral delivery of insulin. Int J Biol Macromol 2019; 126:141-150.
25. Amidi M, Romeijn SG, Borchard G, Junginger HE, Hennink WE, Jiskoot W. Preparation and characterization of protein-loaded N-trimethyl chitosan nanoparticles as nasal delivery system. J Control Release 2006; 111:107-116.
26. Bal SM, Slütter B, Verheul R, Bouwstra JA, Jiskoot W. Adjuvanted, antigen loaded N-trimethyl chitosan nanoparticles for nasal and intradermal vaccination: adjuvant-and site-dependent immunogenicity in mice. Eur J Pharm Sci 2012; 45:475-481.
27. Hagenaars N, Mania M, de Jong P, Que I, Nieuwland R, Slütter B, et al. Role of trimethylated chitosan (TMC) in nasal residence time, local distribution and toxicity of an intranasal influenza vaccine. J Control Release 2010; 144:17-24.
28. Amidi M, Romeijn SG, Verhoef JC, Junginger HE, Bungener L, Huckriede A, et al. N-trimethyl chitosan (TMC) nanoparticles loaded with influenza subunit antigen for intranasal vaccination: biological properties and immunogenicity in a mouse model. Vaccine 2007; 25:144-153.
29. Hagenaars N, Verheul RJ, Mooren I, de Jong PH, Mastrobattista E, Glansbeek HL, et al. Relationship between structure and adjuvanticity of N, N, N-trimethyl chitosan (TMC) structural variants in a nasal influenza vaccine. J Control Release 2009; 140:126-133.
30. Slütter B, Bal S, Keijzer C, Mallants R, Hagenaars N, Que I, et al. Nasal vaccination with N-trimethyl chitosan and PLGA based nanoparticles: nanoparticle characteristics determine quality and strength of the antibody response in mice against the encapsulated antigen. Vaccine 2010; 28:6282-6291.
31. Slütter B, Jiskoot W. Dual role of CpG as immune modulator and physical crosslinker in ovalbumin loaded N-trimethyl chitosan (TMC) nanoparticles for nasal vaccination. J Control Release 2010; 148:117-121.
32. Subbiah R, Ramalingam P, Ramasundaram S, Park K, Ramasamy MK, Choi KJ. N, N, N-Trimethyl chitosan nanoparticles for controlled intranasal delivery of HBV surface antigen. Carbohydr Polym 2012; 89:1289-1297.
33. Wang JJ, Zeng ZW, Xiao RZ, Xie T, Zhou GL, Zhan XR, et al. Recent advances of chitosan nanoparticles as drug carriers. Int J Nanomedicine 2011; 6:765-772.
34. Ariaee FM, Tafaghodi M. Mucosal adjuvant potential of Quillaja saponins and cross-linked dextran microspheres, co-administered with liposomes encapsulated with tetanus toxoid. Iran J Pharm Res 2012; 11:723-729.
35. Mohaghegh M, Tafaghodi M. Dextran microspheres could enhance immune responses against PLGA nanospheres encapsulated with tetanus toxoid and Quillaja saponins after nasal immunization in rabbit. Pharm Dev Technol 2011; 16:36-43.
36. Pirouzmand H, Khameneh B, Tafaghodi M. Immunoadjuvant potential of cross-linked dextran microspheres mixed with chitosan nanospheres encapsulated with tetanus toxoid. Pharm Biol 2017; 55:212-217.
37. Sahu KK, Pandey RS. Development and characterization of HBsAg-loaded Eudragit nanoparticles for effective colonic immunization. Pharm Dev Technol 2018:1-10.
38. Sieval A, Thanou M, Kotze A, Verhoef J, Brussee J, Junginger H. Preparation and NMR characterization of highly substitutedN-trimethyl chitosan chloride. Carbohydr Polym 1998; 36:157-165.
39. Diwan M, Tafaghodi M, Samuel J. Enhancement of immune responses by co-delivery of a CpG oligodeoxynucleotide and tetanus toxoid in biodegradable nanospheres. J Control Release 2002; 85:247-262.
40. Garmise RJ, Staats HF, Hickey AJ. Novel dry powder preparations of whole inactivated influenza virus for nasal vaccination. AAPS PharmSciTech 2007; 8:2-10.
41. Tafaghodi M, Rastegar S. Preparation and in vivo study of dry powder microspheres for nasal immunization. J Drug Target 2010; 18:235-242.
42. Scheerlinck J-PY, Greenwood DL. Virus-sized vaccine delivery systems. Drug Discov Today 2008; 13:882-887.
43. Zaman M, Good MF, Toth I. Nanovaccines and their mode of action. Methods 2013; 60:226-231.
44. Zhao L, Seth A, Wibowo N, Zhao C-X, Mitter N, Yu C, et al. Nanoparticle vaccines. Vaccine 2014; 32:327-337.
45. Kabiri M, Sankian M, Sadri K, Tafaghodi M. Robust mucosal and systemic responses against HTLV-1 by delivery of multi-epitope vaccine in PLGA nanoparticles. Eur J Pharm Biopharm 2018; 133:321-330.
46. Foged C, Brodin B, Frokjaer S, Sundblad A. Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model. Int J Pharm 2005; 298:315-322.
47. Nakanishi T, Kunisawa J, Hayashi A, Tsutsumi Y, Kubo K, Nakagawa S, et al. Positively charged liposome functions as an efficient immunoadjuvant in inducing cell-mediated immune response to soluble proteins. J Control Release 1999; 61:233-240.
48. Niikura K, Matsunaga T, Suzuki T, Kobayashi S, Yamaguchi H, Orba Y, et al. Gold nanoparticles as a vaccine platform: influence of size and shape on immunological responses in vitro and in vivo. ACS nano 2013; 7:3926-3938.
49. Illum L, Jørgensen H, Bisgaard H, Krogsgaard O, Rossing N. Bioadhesive microspheres as a potential nasal drug delivery system. Int J Pharm 1987; 39:189-199.
50. Türker S, Onur E, Ózer Y. Nasal route and drug delivery systems. Pharm World Sci 2004; 26:137-142.
51. Sajeesh S, Bouchemal K, Marsaud V, Vauthier C, Sharma CP. Cyclodextrin complexed insulin encapsulated hydrogel microparticles: An oral delivery system for insulin. J Control Release 2010; 147:377-384.
52. Tao Liang M, Davies NM, Blanchfield JT, Toth I. Particulate systems as adjuvants and carriers for peptide and protein antigens. Curr Drug Deliv 2006; 3:379-388.
53. Steinhoff U, Visekruna A. Mucosal immunity and inflammation.  Methods in Microbiology. 37: Elsevier; 2010. p. 353-367.
54. Kabiri M, Sankian M, Hosseinpour M, Tafaghodi M. The novel immunogenic chimeric peptide vaccine to elicit potent cellular and mucosal immune responses against HTLV-1. Int J Pharm 2018; 549:404-414.
55. Garmise RJ, Mar K, Crowder TM, Hwang CR, Ferriter M, Huang J, et al. Formulation of a dry powder influenza vaccine for nasal delivery. AAPS PharmSciTech 2006; 7: 131-137.
56. Şenel S. Current status and future of chitosan in drug and vaccine delivery. React Funct Polym 2019:104452.
57. Tabassi SAS, Tafaghodi M, Jaafari MR. Induction of high antitoxin titers against tetanus toxoid in rabbits by intranasal immunization with dextran microspheres. Int J Pharm 2008; 360:12-17.
58. Tafaghodi M, Eskandari M. The mucosal adjuvant potential of cross-linked dextran microspheres as dry powder. Iran J Basic Med Sci 2012; 15:873-881.
59. Chandler SG, Ilium L, Thomas NW. Nasal absorption in rats. II. Effect of enhancers on insulin absorption and nasal histology. Int J Pharm 1991; 76:61-70.