Skip to main content

In silico design and pharmacological evaluation of conjugates of atenolol with modified saccharide for cardiovascular targeting

Glycoconjugate Journal volume 38, pages 261–271 (2021)Cite this article

Abstract

Amongst a wide range of biological macromolecules, saccharides exhibit the potential to be specifically recognized by cell-surface receptors and hence can be utilized as ligands in targeted drug delivery. The current study aims to use saccharides viz. Galactose, Pectin and Chitosan to improve targeting of Atenolol by oxalyl chloride mediated grafting. Conjugates were engineered by grafting Atenolol, a cardiovascular agent with the modified saccharide units. The conjugates were characterized by FTIR, DSC and 1H NMR study. Drug release analysis and cellular uptake study was carried out using H9c2 cell lines which represent that concentration of drug in cells treated with all atenolol-saccharide conjugates is enhanced by almost two-folds in comparison with cells treated with atenolol solution. Thus cell line study confers the evidence of selective cardiac delivery. No significant cytotoxicity was observed in case of all synthesized conjugates in the Brine shrimp lethality bioassay. Possible binding of the developed conjugates with the GLUT-4 receptors was assessed by in silico analysis using homology model developed by Swiss Model server. Hence it was concluded that the application of these conjugates with saccharides in selective cardiovascular drug delivery can be a promising approach to increase bioavailability, minimize drug loss by degradation and prevent harmful side effects by increasing specific cell targeting.

Graphical abstract

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Scheme 1
Scheme 2
Scheme 3
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Galagudza, M.: Cardiac protection with targeted drug delivery to ischemic-reperfused myocardium. Novel Strategies in Ischemic Heart Disease, vol. 29, pp. 253–274 (2012)

  2. Brian, J., Sharon, M., Zhong, X., Matthew, S., Nancy, J., Johnsamuel, J.et al: Marchant surface modification of liposomes for selective cell targeting in cardiovascular drug delivery. J Control Release 78, 235–247 (2002)

    Article  Google Scholar 

  3. Lukyanov, A.N., Hartner, W.C., Torchilin, V.P.: Increased accumulation of PEG-PE micelles in the area of experimental myocardial infarction in rabbits. J Control Release94, 187–193 (2004)

    Google Scholar 

  4. Agnihotri, J., Saraf, S., Khale, A.: Targeting: New potential carriers for targeted drug delivery system. Int. J Pharm. Sci. Rev. Res 8, 117–123 (2011)

    CAS  Google Scholar 

  5. Hyo Kyung, H.: Targeted Prodrug design to optimize drug delivery. AAPS PharmSciTech 2(i), 6 (2000)

    Google Scholar 

  6. Bristow, M.R.: Pharmacogenetic targeting of drugs for heart failure. Pharmacol. Ther. 134, 107–115 (2012)

    CAS  Article  Google Scholar 

  7. Lemarchanda, C., Ruxandra, G., Patrick, C.: Polysaccharide-decorated nanoparticles. Eur. J. Pharm. Biopharm. 58, 327–341 (2004)

    Article  Google Scholar 

  8. Caroline, D., Jovenka, H., Muller, G.: Self-assembly and hydrophobic clusters of amphiphilic polysaccharides. Colloids Surf. 220, 105–115 (2003)

    Article  Google Scholar 

  9. Fei, D., Yongmin, Z.: Biomedical applications of Glycoconjugates. Mini-Rev. Med. Chem. 18(18), 1508–1523 (2018)

    Article  Google Scholar 

  10. Abdel-Mageed, H.M., El-Laithy, H.M., Mahran, L.G., Fahmy, A.S., Mader, K., Mohamed, S.A.: Development of novel flexible sugar ester vesicles as carrier systems for the antioxidant enzyme catalase for wound healing applications. Process Biochem. 47, 1155–1162 (2012)

    CAS  Article  Google Scholar 

  11. Benjamin, G.D., Mark, A.R.: Drug delivery systems based on sugar-macromolecule conjugates. Curr. Opin. Drug Disc 5(2), 279–288 (2002)

    Google Scholar 

  12. Sabyasachi, M., Somdipta, R., Biswanath, S.: Polysaccharide based graft copolymers in controlled drug delivery. Int. J of PharmTech. Res 2(2), 1350–1358 (2010)

    Google Scholar 

  13. Lestini, B.J., Sagnella, S.M., Zhong, X., Shive, M.S., Richter, N.J., Johnsamuel, J., et al.: Surface modification of liposomes for selective cell targeting in cardiovascular drug delivery. J. Control Release 78, 235–247 (2002)

    CAS  Article  Google Scholar 

  14. Basu, A., Kona Reddy, K., Abtew, E., Domb, A.J.: Polysaccharides based conjugates for biomedical applications. Bioconjugate Chem 26(8), 1396–1412 (2015)

    CAS  Article  Google Scholar 

  15. Qian, J., Yinsong, W., Jian, W., Lingrong, L., Zhimin, Z., Wenzhi, Y.: Self-assembled nanostructure of cholesterol-saccharide conjugate which acts as amphiphilic gelator of organic solvents. Curr. Nanosci 5(2), 245–251 (2009)

    Article  Google Scholar 

  16. Pant, S., Malviya, R., Shama, P.: Commercialization and biomedical applications of pectin and its formulation in pharmaceutical drug delivery system. Drug Deliv. Lett. 5(1), 9–18 (2015)

    CAS  Article  Google Scholar 

  17. Abdel-Mageed, H.M., Fouad, S.A., Teaima, M.H., Abdel-Aty, A.M., Fahmy, A.S., Shaker, D.S., et al.: Optimizations of nano spray drying parameters for production of α-amylase nanopowder for biotheraputic applications using factorial design. Dry Technol. 37, 2152–2160 (2019)

    CAS  Article  Google Scholar 

  18. Bajpai, J., Gurvindar, K.M., Bajpai, A.K.: Preparation, characterization and water uptake behavior of polysaccharide based nanoparticles.Progres. Nanotechnol. Nanomater. 1(1), 9–17 (2012)

    Google Scholar 

  19. Xia, Y.: Galactose modified selenium nanoparticles for targeted delivery of doxorubicin to hepatocellular carcinoma. J. Drug. Deliv. 26(1), 1–11 (2019)

    CAS  Article  Google Scholar 

  20. Calce, E.: Solvent-free synthesis of modified pectin compounds promoted by microwave irradiation. Molecules 17, 12234–12242 (2012)

  21. Bhatia, M., Deshmukh, R., Choudhari, P., Bhatia, N.: Chemical modification of pectin, characterization and evaluation for drug delivery. Sci. Pharm. 76, 775–784 (2008)

  22. Almeida, E.: Synthesis and characterization of pectin derivative with antitumor property against Coca-2 colon cancer cells. Carbohydr. Polym. 115, 139–145 (2015)

    CAS  Article  Google Scholar 

  23. Xiao, H.T., Ran, M.S., Zhang, X.M., Fan, F.: Study of pectin-adriamycin conjugate to cardiac toxicity in rats. Chin. Pharmacol. Bull. 32(8), 1075–1080 (2016)

    Google Scholar 

  24. Lather, V., Saini, V., Pandita, D.: Polymeric micelles of modified chitosan block copolymer as nanocarrier for delivery of paclitaxel. Curr. Nanomed. 9(1), 86–96 (2019)

    CAS  Article  Google Scholar 

  25. Chen, G.L., Desai, K., Chen, X., Park, H.J.: Linolenic acid modified chitosan for formation of self-assembled nanoparticles. J. Agric. Food Chem. 53(2), 437–441 (2005)

    Article  Google Scholar 

  26. Atenolol.: Indian pharmacopoeia, The Indian Pharmacopoeia Commission, Ghaziabad, vol. 2, pp. 748–749 (2007)

  27. Bhowmik, A., Nijhu, R., Ahmed, T., Sultana, S.: Design and development of atenolol matrix tablet employing natural and synthetic polymers. J. Appl. Pharm. Sci. 3(09), 103–108 (2013)

    Google Scholar 

  28. Oxalic acid, Indian Pharmacopoeia: The Indian Pharmacopoeia Commission, Ghaziabad, vol. 1, p. 516 (2007)

  29. Menalda, F.: Quantitative investigation of the Schotten-Baumann reaction. Recl. Trav. Chim. Pays-Bas. 49(10), 967–995 (2010)

  30. Bhatia, M., Deshmukh, R., Choudhari, P., Bhatia, N.: Chemical modification of pectin, characterization and evaluation for drug delivery. Sci. Pharm. 76, 775–784 (2008)

    CAS  Article  Google Scholar 

  31. Vogel, A., Furniss, B.S., Hannaford, A.J., Smith, P.G., Tatchell, A.R.: Vogel’s textbook of practical organic chemistry, 5th Ed, pp. 692. Person Publications, London (1996)

  32. Martin, A.: Physical Pharmacy, 4th Ed, pp. 237–242. Lippincott Publications, Philadelphia (1993)

  33. Colombo, P., Bettini, R., Peppas, N.: Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug. J. Control Release 61, 83–91 (1999)

    CAS  Article  Google Scholar 

  34. Furniss, B.S., Hannaford, A.J., Smith, P.G., Tatchell, A.R.: Determination of physical constants. In: Vogel’s textbook of organic chemistry, England, 5th Ed., pp. 236–238. Longman group publication, Harlow (1989)

  35. Silverstein, R.M., Webster, F.X.: Infrared spectrometry. In: Spectrometric Identification of organic compounds, 5th Ed. pp. 71–143. Wiley, Mississauga (1998)

  36. Willard, H.H., Merritt, L.L., Dean, J.A., Settle, F.A.: Instrumental methods of analysis, 7th Ed, pp. 770–773. CBS Publishers and Distributers, West Bengal (1988)

  37. Kemp, W.: Nuclear magnetic resonance spectroscopy, 3rd edn., pp. 191–238. Inorganic Spectroscopy, New York Palgrave (1991)

  38. Zordoky, B., El- Kadi, A.: H9c2 cell line is a valuable in vitro model to study the drug metabolizing enzymes in the heart. J Pharmacol. Toxocol. Methods 56(3), 317–322 (2007)

    CAS  Article  Google Scholar 

  39. Perumal, R., Ramasamy, A., Gangadhara, P., Elangovan, V.: Synthesis and cardio protective biological applications of glucodendrimers by H9C2 cell studies. Carbohyd. Polym. 99, 403–414 (2014)

    Article  Google Scholar 

  40. Berghot, M.A., Kandeel, E.M., Abdel-Rahman, A.H., Abdel-Motaal, M.: Synthesis, antioxidant and cytotoxic activities of novel naphthoquinone derivatives from 2,3-dihydro-2,3-epoxy-1,4- naphthoquinone. Med. Chem. 4, 381–388 (2014)

    Google Scholar 

  41. Riser, M.J., Gu, Z.M., Fang, X.P., Zeng, L., Wood, K.V., Mclaughlin, J.L.: Five novel mono-tetrahydrofuran ring acetogenins from the seeds of Annona muricata. J. Nat. Prod. 59(2), 100–108 (1996)

    Article  Google Scholar 

  42. Jadhav, S.D., Choudhari, P.B., Bhatia, M.S.: In silico design, synthesis, characterization and pharmacological evaluation of captopril conjugates in the treatment of renal fibrosis. New J. Chem. 43, 504–513 (2019)

    CAS  Article  Google Scholar 

  43. Waterhouse, A., Bertoni, M., Bienert, S., Studer, G., Tauriello, G., Gumienny, R., et al.: SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 46(W1), W296–W303 (2018)

    CAS  Article  Google Scholar 

  44. Bienert, S., Waterhouse, A., De Beer, T.A.P., Tauriello, G., Studer, G., Bordoli, L., et al.: The SWISS-MODEL Repository-new features and functionality. Nucleic Acids Res. 45, D313–D319 (2017)

    CAS  Article  Google Scholar 

  45. Guex, N., Peitsch, M.C., Schwede, T.: Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: A historical perspective. Electrophoresis 30, S162-S173 (2009)

  46. Benkert, P., Biasini, M., Schwede, T.: Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics 27, 343–350 (2011)

    CAS  Article  Google Scholar 

  47. Bertoni, M., Kiefer, F., Biasini, M., Bordoli, L., Schwede, T.: Modeling protein quaternary structure of homo- and hetero-oligomers beyond binary interactions by homology. Sci. Rep. 7, 10480 (2017)

    Article  Google Scholar 

Download references

Acknowledgements

Authors are thankful to the Principal, Ashokrao Mane College of Pharmacy, Peth Vadgaon, for providing facility to carry out this research project. Authors are thankful to Principal, DSTS Mandal’s College of Pharmacy, Solapur and Bharati Vidyapeeth College of Pharmacy, Kolhapur for supporting this research work.

Author information

Affiliations

  1. Department of Pharmaceutical Chemistry, DSTS Mandal’s College of Pharmacy, Solapur, Maharashtra, India

    Smita Tukaram Kumbhar

  2. Department of Pharmaceutics, Ashokrao Mane College of Pharmacy , Peth Vadgaon, India

    Shitalkumar Shivgonda Patil

  3. Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Kolhapur, India

    Manish Sudesh Bhatia

Authors
  1. Smita Tukaram Kumbhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shitalkumar Shivgonda Patil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manish Sudesh Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Smita Tukaram Kumbhar.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kumbhar, S.T., Patil, S.S. & Bhatia, M.S. In silico design and pharmacological evaluation of conjugates of atenolol with modified saccharide for cardiovascular targeting. Glycoconj J 38, 261–271 (2021). https://doi.org/10.1007/s10719-021-09983-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10719-021-09983-x

Keywords

  • Sugar macromolecules
  • Chemical grafting
  • Targeted delivery