Advertisement

Targeting tuberculosis infection in macrophages using chitosan oligosaccharide nanoplexes

  • Uday Koli
  • Kayzad Nilgiriwala
  • Kalpana Sriraman
  • Ratnesh JainEmail author
  • Prajakta DandekarEmail author
Research Paper
  • 112 Downloads

Abstract

Targeting bacterial infections using RNA interference (RNAi) has been a relatively nascent area of research as compared with cancer and viral infections. Exploring this area is especially vital due to the prevalence of numerous challenging bacterial infections that have been persistent despite treatment with antibiotics or antibiotic-loaded delivery systems. In this investigation, we formulate siRNA nanoparticle complexes, using cationic water-soluble chitosan polymer, for intracellular delivery into macrophages that serve as reservoirs of numerous pathogenic bacteria, including Mycobacterium tuberculosis (Mtb). Cationic chitosan oligosaccharide nanoparticles of size 215.3 ± 4.19 nm were formulated by ionotropic gelation and were effectively delivered along with siRNA into the macrophages, without any obvious cytotoxicity. The siRNA-loaded nanoparticles resulted in more than two-fold down-regulation of the host gene, Bfl1/A1, as compared with untreated controls. Since the over expression of host gene Bfl1/A1 favours for survival of Mtb within macrophages, the nanoparticles present a promising potential for developing anti-tuberculosis therapy.

Keywords

Mycobacteria Bfl-1/a1 siRNA delivery Chitosan oligosaccharides Macrophages Nanomedicine 

Notes

Funding information

Mr. Uday Koli was financially supported by the Department of Biotechnology (BT/PR5372/MED/29/489/2012), Govt. of India and the Department of Atomic Energy (DAE: 2012/20/37B/08/BRNS) for fellowship. Dr. Prajakta Dandekar was financially supported by the Ramanujan Fellowship Grant (SR/S2/RJN-139/2011), DST, Govt. of India. Dr. Ratnesh Jain was financially supported by the Ramalingaswami Fellowship (BT/RLF/RE-ENTRY/51/2011), DBT, Govt. of India.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. Abed N, Saïd-Hassane F, Zouhiri F, Mougin J, Nicolas V, Desmaële D, Gref R, Couvreur P (2015) An efficient system for intracellular delivery of beta-lactam antibiotics to overcome bacterial resistance. Sci Rep 5Google Scholar
  2. Agnihotri SA, Mallikarjuna NN, Aminabhavi TM (2004) Recent advances on chitosan-based micro-and nanoparticles in drug delivery. J Control Release 100(1):5–28CrossRefGoogle Scholar
  3. Alexandru-Flaviu T, Cornel C (2014) Macrophages targeted drug delivery as a key therapy in infectious disease. BMBN 2(1):17–20Google Scholar
  4. Bellich B, D’Agostino I et al (2016) “The good, the bad and the ugly” of chitosans. Mar Drugs 14(5):99CrossRefGoogle Scholar
  5. Bennet D, Kim S (2014) Polymer Nanoparticles for Smart Drug Delivery. In: Polymer nanoparticles for smart drug delivery. Nanotechnology in Drug Delivery, Application ofCrossRefGoogle Scholar
  6. Brennan PJ, Nikaido H (1995) The envelope of mycobacteria. Annu Rev Biochem 64(1):29–63CrossRefGoogle Scholar
  7. Chen C-S, Liau W-Y et al (1998) Antibacterial effects of N-sulfonated and N-sulfobenzoyl chitosan and application to oyster preservation. J Food Prot 61(9):1124–1128CrossRefGoogle Scholar
  8. Cheung RCF, Ng TB et al (2015) Chitosan: an update on potential biomedical and pharmaceutical applications. Mar Drugs 13(8):5156–5186CrossRefGoogle Scholar
  9. Chiu Y-L, Ali A, Chu CY, Cao H, Rana TM (2004) Visualizing a correlation between siRNA localization, cellular uptake, and RNAi in living cells. Chem Biol 11(8):1165–1175CrossRefGoogle Scholar
  10. Clemens DL, Lee B-Y, Xue M, Thomas CR, Meng H, Ferris D, Nel AE, Zink JI, Horwitz MA (2012) Targeted intracellular delivery of antituberculosis drugs to Mycobacterium tuberculosis-infected macrophages via functionalized mesoporous silica nanoparticles. Antimicrob Agents Chemother 56(5):2535–2545CrossRefGoogle Scholar
  11. Dandekar P, Jain R, Stauner T, Loretz B, Koch M, Wenz G, Lehr CM (2012) A hydrophobic starch polymer for nanoparticle-mediated delivery of docetaxel. Macromol Biosci 12(2):184–194CrossRefGoogle Scholar
  12. Dandekar P, Jain R, Keil M, Loretz B, Koch M, Wenz G, Lehr CM (2015) Enhanced uptake and siRNA-mediated knockdown of a biologically relevant gene using cyclodextrin polyrotaxane. J Mater Chem B 3(13):2590–2598CrossRefGoogle Scholar
  13. del Carpio-Perochena A, Bramante CM, Duarte MAH, de Moura MR, Aouada FA, Kishen A (2015) Chelating and antibacterial properties of chitosan nanoparticles on dentin. Restorative dentistry & endodontics 40(3):195–201CrossRefGoogle Scholar
  14. Dey A, Koli U, Dandekar P, Jain R (2016) Investigating behaviour of polymers in nanoparticles of chitosan oligosaccharides coated with hyaluronic acid. Polymer 93:44–52CrossRefGoogle Scholar
  15. Frieden TR, S. S. M, Sterling TR, Watt CJ, Dye C (2003) Tuberculosis. Lancet 362(9387):887–889CrossRefGoogle Scholar
  16. Goy RC, Britto DD et al (2009) A review of the antimicrobial activity of chitosan. Polímeros 19(3):241–247CrossRefGoogle Scholar
  17. Griffiths G, Nyström B et al (2010) Nanobead-based interventions for the treatment and prevention of tuberculosis. Nat Rev Microbiol 8(11):827CrossRefGoogle Scholar
  18. Hadwiger L, Kendra D et al (1986) Chitosan both activates genes in plants and inhibits RNA synthesis in fungi. Chitin Nat Technol:209–214Google Scholar
  19. Haltiwanger R, Hill RL (1986) The ligand binding specificity and tissue localization of a rat alveolar macrophage lectin. J Biol Chem 261(33):15696–15702Google Scholar
  20. Hao C, Gao L, Zhang Y, Wang W, Yu G, Guan H, Zhang L, Li C (2015) Acetylated chitosan oligosaccharides act as antagonists against glutamate-induced PC12 cell death via Bcl-2/Bax signal pathway. Marine drugs 13(3):1267–1289CrossRefGoogle Scholar
  21. Hao C, Wang W, Wang S, Zhang L, Guo Y (2017) An overview of the protective effects of chitosan and acetylated chitosan oligosaccharides against neuronal disorders. Marine drugs 15(4):89CrossRefGoogle Scholar
  22. Jain NK, Mishra V, Mehra NK (2013) Targeted drug delivery to macrophages. Expert opinion on drug delivery 10(3):353–367CrossRefGoogle Scholar
  23. Jain R, Dandekar P, Loretz B, Koch M, Lehr CM (2015) Dimethylaminoethyl methacrylate copolymer-siRNA nanoparticles for silencing a therapeutically relevant gene in macrophages. MedChemComm 6(4):691–701CrossRefGoogle Scholar
  24. Jean M, Alameh M, de Jesus D, Thibault M, Lavertu M, Darras V, Nelea M, Buschmann MD, Merzouki A (2012) Chitosan-based therapeutic nanoparticles for combination gene therapy and gene silencing of in vitro cell lines relevant to type 2 diabetes. Eur J Pharm Sci 45(1):138–149CrossRefGoogle Scholar
  25. Jeon SJ, Oh M, Yeo WS, Galvão KN, Jeong KC (2014) Underlying mechanism of antimicrobial activity of chitosan microparticles and implications for the treatment of infectious diseases. PLoS One 9(3):e92723CrossRefGoogle Scholar
  26. Kakizawa Y, Furukawa S, Kataoka K (2004) Block copolymer-coated calcium phosphate nanoparticles sensing intracellular environment for oligodeoxynucleotide and siRNA delivery. J Control Release 97(2):345–356CrossRefGoogle Scholar
  27. Kong M, Chen XG, Xing K, Park HJ (2010) Antimicrobial properties of chitosan and mode of action: a state of the art review. Int J Food Microbiol 144(1):51–63CrossRefGoogle Scholar
  28. Largent B, Walton K, Hoppe CA, Lee YC, Schnaar RL (1984) Carbohydrate-specific adhesion of alveolar macrophages to mannose-derivatized surfaces. J Biol Chem 259(3):1764–1769Google Scholar
  29. Lim YH, Tiemann KM, Hunstad DA, Elsabahy M, Wooley KL (2016) Polymeric nanoparticles in development for treatment of pulmonary infectious diseases. Wiley Interdiscip Rev: Nanomed Nanobiotechnol 8(6):842–871Google Scholar
  30. Liu Y, Tan J, Thomas A, Ou-Yang D, Muzykantov VR (2012) The shape of things to come: importance of design in nanotechnology for drug delivery. Ther Deliv 3(2):181–194CrossRefGoogle Scholar
  31. Man DK, Chow MY et al (2016) Potential and development of inhaled RNAi therapeutics for the treatment of pulmonary tuberculosis. Adv Drug Deliv Rev 102:21–32CrossRefGoogle Scholar
  32. Nasiruddin M, Neyaz MK et al (2017) Nanotechnology-based approach in tuberculosis treatment. Tuberculosis research and treatment 2017Google Scholar
  33. Neyrolles O, Wolschendorf F, Mitra A, Niederweis M (2015) Mycobacteria, metals, and the macrophage. Immunol Rev 264(1):249–263CrossRefGoogle Scholar
  34. O’brien J, Wilson I et al (2000) Investigation of the Alamar blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. FEBS J 267(17):5421–5426Google Scholar
  35. Papineau AM, Hoover DG, Knorr D, Farkas DF (1991) Antimicrobial effect of water-soluble chitosans with high hydrostatic pressure. Food Biotechnol 5(1):45–57CrossRefGoogle Scholar
  36. Park S, Cho J-E et al (2012) Bfl-1/A1 molecules are induced in Mycobacterium infected THP-1 cells in the early time points. J Exp Biomed Sci 18(3):201–209Google Scholar
  37. Patil P, Chavanke D et al (2012) A review on ionotropic gelation method: novel approach for controlled gastroretentive gelispheres. Int J Pharm Pharm Sci 4(4):27–32Google Scholar
  38. Pieters J (2008) Mycobacterium tuberculosis and the macrophage: maintaining a balance. Cell Host Microbe 3(6):399–407CrossRefGoogle Scholar
  39. Plasterk RH (2002) RNA silencing: the genome’s immune system. Science 296(5571):1263–1265CrossRefGoogle Scholar
  40. Prajakta D, Ratnesh J, Chandan K, Suresh S, Grace S, Meera V, Vandana P (2009) Curcumin loaded pH-sensitive nanoparticles for the treatment of colon cancer. J Biomed Nanotechnol 5(5):445–455CrossRefGoogle Scholar
  41. Ríos-Barrera VA, Campos-Peña V et al (2006) Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: their relationship to mycobacterial virulence. Eur J Immunol 36(2):345–353CrossRefGoogle Scholar
  42. Rodrigues MF, Barsante MM et al (2009) Apoptosis of macrophages during pulmonary Mycobacterium bovis infection: correlation with intracellular bacillary load and cytokine levels. Immunology 128(1pt2)Google Scholar
  43. Rohan D, Mahesh K, Manoj R, Sekhar M (2008) Inhibition of bfl-1/A1 by siRNA inhibits mycobacterial growth in THP-1 cells by enhancing phagosomal acidification. Biochim Biophys Acta (BBA)-General Subjects 1780(4):733–742CrossRefGoogle Scholar
  44. Samal SK, Dash M, van Vlierberghe S, Kaplan DL, Chiellini E, van Blitterswijk C, Moroni L, Dubruel P (2012) Cationic polymers and their therapeutic potential. Chem Soc Rev 41(21):7147–7194CrossRefGoogle Scholar
  45. Shahidi F, Arachchi JKV, Jeon YJ (1999) Food applications of chitin and chitosans. Trends Food Sci Technol 10(2):37–51CrossRefGoogle Scholar
  46. Sudarshan N, Hoover D et al (1992) Antibacterial action of chitosan. Food Biotechnol 6(3):257–272CrossRefGoogle Scholar
  47. Tsai G-J, Su W-H (1999) Antibacterial activity of shrimp chitosan against Escherichia coli. J Food Prot 62(3):239–243CrossRefGoogle Scholar
  48. Vandana M, Sahoo SK (2009) Optimization of physicochemical parameters influencing the fabrication of protein-loaded chitosan nanoparticles. Nanomedicine 4(7):773–785CrossRefGoogle Scholar
  49. Wang AZ, Gu F, Zhang L, Chan JM, Radovic-Moreno A, Shaikh MR, Farokhzad OC (2008) Biofunctionalized targeted nanoparticles for therapeutic applications. Expert Opin Biol Ther 8(8):1063–1070CrossRefGoogle Scholar
  50. WHO (2017) WHO report on tuberculosis. Retrieved 1st September 2017, from http://www.who.int/mediacentre/factsheets/fs104/en/
  51. Yeeprae W, Kawakami S, Yamashita F, Hashida M (2006) Effect of mannose density on mannose receptor-mediated cellular uptake of mannosylated O/W emulsions by macrophages. J Control Release 114(2):193–201CrossRefGoogle Scholar
  52. Young DH, Kauss H (1983) Release of calcium from suspension-cultured Glycine max cells by chitosan, other polycations, and polyamines in relation to effects on membrane permeability. Plant Physiol 73(3):698–702CrossRefGoogle Scholar
  53. Zhang Z, Feng S-S (2006) The drug encapsulation efficiency, in vitro drug release, cellular uptake and cytotoxicity of paclitaxel-loaded poly (lactide)–tocopheryl polyethylene glycol succinate nanoparticles. Biomaterials 27(21):4025–4033CrossRefGoogle Scholar
  54. Zhang J, Jiang R, Takayama H, Tanaka Y (2005) Survival of virulent Mycobacterium tuberculosis involves preventing apoptosis induced by Bcl-2 upregulation and release resulting from necrosis in J774 macrophages. Microbiol Immunol 49(9):845–852CrossRefGoogle Scholar
  55. Zhang J, Xia W, Liu P, Cheng Q, Tahi T, Gu W, Li B (2010) Chitosan modification and pharmaceutical/biomedical applications. Marine drugs 8(7):1962–1987CrossRefGoogle Scholar
  56. Zhu L, Mahato RI (2010) Lipid and polymeric carrier-mediated nucleic acid delivery. Expert Opin Drug Deliv 7(10):1209–1226CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences and TechnologyInstitute of Chemical Technology (ICT)MumbaiIndia
  2. 2.Foundation of Medical ResearchMumbaiIndia
  3. 3.Department of Chemical EngineeringInstitute of Chemical Technology (ICT)MumbaiIndia

Personalised recommendations