A novel nanomicelle composed from PEGylated TB di-peptide could be successfully used as a BCG booster

Document Type : Original Article

Authors

1 Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran

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

4 Immunobiochemistry Laboratory, Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Tuberculosis affects one-third of the world’s population and leads to a high rate of morbidity and mortality. Bacillus Chalmette–Guerin (BCG) as the only approved vaccine for the Mycobacterium tuberculosis (Mtb) does not show enough protection in the vaccinated population. 
Materials and Methods: The main aim of this study was to prepare a self-assembled nanomicelle composed from a di-block polymer in which, a di-fusion peptide was the hydrophobic block and polyethylene glycol (PEG) was the hydrophilic block. The micelles were characterized in vitro and in vivo as an antigen delivery system/adjuvant both with and without a prime BCG. 
Results: The micellar nanovaccine was able to elicit good dendritic cell maturation. Nanomicelles could efficiently induce systemic cytokines as well as nasal secretory predominant antibody titers (sIgA). The expression pattern of cytokines indicated the superiority of cellular immunity. Nasal administration of two doses of nanomicelles after a prime subcutaneous administration of BCG induced the highest mucosal and systemic immune responses. 
Conclusion: Based on our results PEG-HspX/EsxS self-assembled nanomicelle is highly immunogenic and can be considered a potential vaccine candidate against Mtb to boost BCG efficiency.

Keywords

References

1. Gröschel MN, Prabowo SA,  Cardona PJ,  Stanford JL, and van der Werf TS., Therapeutic vaccines for tuberculosis--a systematic review. Vaccine 2014; 32: 3162-3168.
2. Cohen A, Mathiasen VD,  Schön T, Wejse C, The global prevalence of latent tuberculosis: a systematic review and meta-analysis. Eur Respir J 2019; 54: e1900655. 
3. Stylianou E, Griffiths KL, Poyntz HC, Harrington-Kandt R, Dicks MD, Stockdale L, Betts G, McShane H. Improvement of BCG protective efficacy with a novel chimpanzee adenovirus and a modified vaccinia Ankara virus both expressing Ag85A. Vaccine 2015; 33: 6800-6808.
4. Brandt L, Cunha JF,  Olsen AW, Chilima B,  Hirsch P, Appelberg R, Andersen P. Failure of the Mycobacterium bovis BCG vaccine: Some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infec Immun 2002; 70: 672-678.
5. Ottenhoff THM, Kaufmann SHE. Vaccines against tuberculosis: Where are we and where do we need to go? PLoS Pathog 2012; 8: e1002607.
6. Brazier B, and McShane H. Towards new TB vaccines. in Seminars in Immunopathology. Semin Immunopathol 2020; 42: 315-331.
7. Yamashita Y,  Oe T, Kawakami K, Osada-Oka M,  Ozeki Y,  Terahara K, et al. Ariyoshi K, CD4+ T responses other than Th1 type are preferentially induced by latency-associated antigens in the state of latent Mycobacterium tuberculosis infection. Front Immunol  2019;10: e2807.
8. Pathakumari B, Devasundaram S, and Raja A. Altered expression of antigen‐specific memory and regulatory T‐cell subsets differentiate latent and active tuberculosis. Immunology 2018; 153:325-336.
9. Geluk A, Lin MY, Meijgaarden KEV, Leyten EMS, Franken KLMC, Ottenhoff THM, et al. T-cell recognition of the HspX protein of Mycobacterium tuberculosis correlates with latent M. tuberculosis infection but not with M. bovis BCG vaccination. Infect Immun 2007; 75: 2914-2921.
10. Amini Y, Tafaghodi M, Jamehdar SA, Meshkat Z, Moradi B, and Sankian M. Heterologous expression, purification, and characterization of the HspX, Ppe44, and EsxV proteins of Mycobacterium tuberculosis Rep Biochem Mol Biol 2018: 6: 125. 
11. Bal SM, Hortensius S, Ding Z, Jiskoot W,. Bouwstra JA, Co-encapsulation of antigen and Toll-like receptor ligand in cationic liposomes affects the quality of the immune response in mice after intradermal vaccination Vaccine 2011; 29 :1045-1052. 
12. Zhao L, Seth A, Wibowo N, Zhao CX, Mitter N, Yu CZ, Middelberg APJ. Nanoparticle vaccines Vaccine 2014; 32;  327-337.
13. Yazdani M, Hatamipour M, Alani B, Nikzad H, Roshan NM,  Verdi J et al. Liposomal gp100 vaccine combined with CpG ODN sensitizes established B16F10 melanoma tumors to anti PD-1 therapy. Iran J Basic Med Sci 2020; 23:1065-1077.
14. Khademi F, Yousefi-Avarvand A, Derakhshan M,  Abbaspour MR,  Sadri K, Tafaghodi M. Formulation and optimization of a new cationic lipid-modified PLGA nanoparticle as delivery system for Mycobacterium tuberculosis HspX/EsxS fusion protein: An experimental design. IJPR 2019; 18: 446–458.
15. Trimaille T, Lacroix C, and Verrier B, Self-assembled amphiphilic copolymers as dual delivery system    for immunotherapy. Eur J Pharm Biopharm  2019; 142: 232-239.
16. Khademi F, Avarvand AY, Derakhshan M,  Abbaspour MR, Sadri K, and M. Tafaghodi M, Formulation and optimization of a new cationic lipid-modified PLGA nanoparticle as delivery system for Mycobacterium tuberculosis HspX/EsxS fusion protein: An experimental design. Iran J Pharm Sci 2019; 18: 446–458.
17. Fishman AR, Acton A, Lee‐Ruff E. A simple preparation of PEG‐carboxylates by direct oxidation. Synthetic communications Bioorg Med Chem Lett  2004; 34: 2309-2312.
18. Massolo E, Pirola M, and Benaglia M, Amide bond formation strategies: Latest advances on a dateless transformation. Eur J Org Chem  2020; 30 ; 4641-4651.
19. Valeur E and Bradley M, Amide bond formation: beyond the myth of coupling reagents. Chem Soc Rev 2009;38: 606-631.
20. Eskandari R, Asoodeh A, Mousavi SD, Firouzi Z. The effect of a novel drug delivery system using encapsulated antimicrobial peptide protonectin (IL-12) into nano micelle PEG-PCL on A549 adenocarcinoma lung cell line. J Polym Res 2021; 28: 1-12.
21. Yazdani M, Gholizadeh Z, Nikpoor AR, Hatamipour M, Alani B,  Nikzad H, et al. Vaccination with dendritic cells pulsed ex vivo with gp100 peptide-decorated liposomes enhances the efficacy of anti PD-1 therapy in a mouse model of melanoma. Vaccine  2020. 38:5665-5677.
22. Khademi F, Derakhshan M,  Avarvand AY, Najafi N,  Tafaghodi M. Multi-stage subunit vaccines against Mycobacterium tuberculosis: An alternative to the BCG vaccine or a BCG-prime boost? Expert Rev Vaccines 2018; 17:31-44.
23. Nascimento IP, Leite LCC. Recombinant vaccines and the development of new vaccine strategies. Braz J Med Biolo Res 2012; 45:1102–1111.
24. Amini Y, Tebianian M, Mosavari N, Ramandi MF,  Ebrahimi SM, H. Najminejad et al. Development of an effective delivery system for intranasal immunization against Mycobacterium tuberculosis ESAT-6 antigen. Artifi Cells Nanomed Biotechnol 2017;45: 291-296.
25. Khademi F, Derakhshan M, Avarvand  AY, Najafi N  and  Tafaghodi M, A novel antigen of Mycobacterium tuberculosis and MPLA adjuvant co-entrapped into PLGA: DDA hybrid nanoparticles stimulates mucosal and systemic immunity. Microb Pathog 2018; 125: 507-513.
26. Mansury D,  Ghazvini K,  Jamehdar SA, Badiee A,  Tafaghodi M, Nikpoor AR, et al. Enhancement of the effect of BCG vaccine against tuberculosis using DDA/TDB liposomes containing a fusion protein of HspX, PPE44, and EsxV. Artif Cells Nanomed Biotechnol 2019; 47: 370–377. 
27. da Costa AC,  Nogueira SV,  Kipnis A and Kipnis APJ, Recombinant BCG: innovations on an old vaccine. Scope of BCG strains and strategies to improve long-lasting memory. Fron Immunol 2014; 5: e00152.
28. Tafaghodi M, Khademi F and Firouzi Z, Polymer-based nanoparticles as delivery systems for treatment and vaccination of tuberculosis. Chapter Book: Nanotechnology Based Approaches for Tuberculosis Treatment. Elsevier  2020; 123-142.
29. Storni T,  Kündig TM, Senti G, Johansen P, Immunity in response to particulate antigen-delivery systems. Adv Drug Deliv Rev  2005; 57: 333-355.
30. Lu Y,  Yue Z, Xie J,  Wang W, Zhu H, Zhanget E al. Micelles with ultralow critical micelle concentration as carriers for drug delivery. Nat Biomed Eng 2018; 2: 318-325.
31. Al-Ashmawy GMZ, Dendritic cell subsets, maturation and function. Dendritic Cells Inch Open 2018; 11-24.
32. Mbongue JC,  Nieves HA, Torrez TW and Langridge WHR, The role of dendritic cell maturation in the induction of insulin-dependent diabetes mellitus. Front Immunol 2017;8: e00327.
33. Tafaghodi M, Khamesipour A, and Jaafari MR, Immunization against leishmaniasis by PLGA nanospheres encapsulated with autoclaved Leishmania major (ALM) and CpG-ODN. Parasitol Res 2011; 108:1265-1273.
34. da Silva MV, Tiburcio MGS, Machado JR, Silva DAA, Rodrigues DBR, Rodrigues V et al. Complexity and controversies over the cytokine profiles of T helper cell subpopulations in tuberculosis. J Immunol Res 2015. e639107
35. Zhang D. Role of Th17 cell in tubercle bacillus infection in IOP conference series. Environ Earth Sci 2018; e042115. 
36. Shen H, Chen ZW. The crucial roles of Th17-related cytokines/signal pathways in Mycobacterium Tuberculosis infection. Cell Mol Immunol 2018; 15:216-225.
37. Luo J, Zhang M, Yana B, Zhang K,. Chen M, Deng S. Imbalance of Th17 and Treg in peripheral blood mononuclear cells of active tuberculosis patients. Braz J Infect Dis 2017; 21: 155-161.
38. Torrado E, and Cooper, AM IL-17 and Th17 cells in tuberculosis. Cytokine Growth Factor Rev 2010; 21: 455-462.
39. Whitlow E, Mustafa AS, Hanif SNM. An overview of the development of new vaccines for tuberculosis. Vaccines 2020; 8: e8040586.
40. Pati R, Shevtsov M, and Sonawane A, Nanoparticle vaccines against infectious diseases. Front Immunol 2018;9: e02224.
41. González LD, Campo LC, Paul MJ, Singh M, Reljic R, Alonso MJ, Á.G. Fernández, RSVázquez. Design of polymeric nanocapsules for intranasal vaccination against Mycobacterium Tuberculosis: Influence of the polymeric shell and antigen positioning. Pharmaceutics 2020;12; 489.
42. Gupta N,  Garg S,  Vedi S, Kunimoto DY, Kumar R, and  Agrawal B, Future path toward TB vaccine development: boosting BCG or re-educating by a new subunit vaccine. Front Immunol 2018;9: e2371.
43. Hellfritzsch M, and Scherließ R, Mucosal vaccination via the respiratory tract. Pharmaceutics 2019 ;11: 375.
44. Neutra MR, and Kozlowski PA, Mucosal vaccines: the promise and the challenge. Nat Rev Immunol 2006; 6: 148-158.
45. Huckaby JT, Lai SK, PEGylation for enhancing nanoparticle diffusion in mucus. Adv Drug Deliv Rev 2018; 124: 125-139.
46. Davidovich-Pinhas M, Bianco-Peled H. Novel mucoadhesive system based on sulfhydryl-acrylate interactions. J Mater Sci Mater Med 2010; 21:2027-2034.
Iranian Journal of Basic Medical Sciences
Volume 25, Issue 2
February 2022
Pages 223-231

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