Carbonyl and carboxylate crosslinked cyclodextrin as a nanocarrier for resveratrol: in silico, in vitro and in vivo evaluation

  • R. PushpalathaEmail author
  • S. Selvamuthukumar
  • D. Kilimozhi
Original Article


The purpose of the study was to explore the effect of different type of crosslinked cyclodextrins for the delivery of poorly soluble, photosensitive drug, resveratrol. Crosslinkers, diphenyl carbonate and pyromellitic dianhydride were used to prepare carbonyl (NS-I) and carboxylate (NS-II) crosslinked cyclodextrin respectively. The solubility and in silico molecular interaction of resveratrol with these NS at different crosslinker ratio were studied. The results showed enhanced solubility and better interaction of resveratrol with nanosponges prepared with 1:4 Cyclodextrin: crosslinker ratio. The drug-loaded nanosponges (RES-NS-I and II) prepared using 1:4 crosslinked NS-I and II were characterized using DSC, PXRD, SEM, FTIR and evaluated for particle size, zeta potential, photodegradation, in vitro drug release, in vitro cytotoxicity and in vivo oral bioavailability in rats. Physical characterization confirmed the molecular inclusion of drug with NS. The release of the drug was increased to 2.5–3 folds in the dissolution medium, with initial drug release faster with RES-NS-II. Photostability was enhanced to 2.3 fold with RES-NS-II. The cytotoxicity test exhibited 1.5 fold reduction in IC50 with drug-loaded NS. RES-NS-II exhibited 2.5 fold increase in Cmax and fourfold decrease in Tmax. Carboxylate crosslinked Cyclodextrin using pyromellitic dianhydride proves to be an effective nanocarrier for resveratrol.


Cyclodextrin nanosponge Resveratrol Bioavailability enhancement Nanocarrier Pyromellitic dianhydride Diphenyl carbonate 









  1. 1.
    Siddiqui, I.A., Sanna, V., Ahmad, N., Sechi, M., Mukhtar, H.: Resveratrol nanoformulation for cancer prevention and therapy. Ann. N. Y. Acad. Sci. 1348(1), 20–31 (2015)CrossRefGoogle Scholar
  2. 2.
    Sanna, V., Siddiqui, I.A., Sechi, M., Mukhtar, H.: Resveratrol-loaded nanoparticles based on poly (epsilon-caprolactone) and poly (d, l-lactic-co-glycolic acid)–poly (ethylene glycol) blend for prostate cancer treatment. Mol. Pharm. 10(10), 3871–3881 (2013)CrossRefGoogle Scholar
  3. 3.
    Summerlin, N., Soo, E., Thakur, S., Qu, Z., Jambhrunkar, S., Popat, A.: Resveratrol nanoformulations: challenges and opportunities. Int. J. Pharm. 479(2), 282–290 (2015)CrossRefGoogle Scholar
  4. 4.
    Dong, Q., Yuan, H.-L., Qian, J.-J., Zhang, C.-Y., Chen, W.-D.: Preparation and in vitro–in vivo characterization of trans-resveratrol nanosuspensions. Bio-Med. Mater. Eng. 29(3), 333–345 (2018)CrossRefGoogle Scholar
  5. 5.
    Nassir, A.M., Shahzad, N., Ibrahim, I.A., Ahmad, I., Md, S., Ain, M.R.: Resveratrol-loaded PLGA nanoparticles mediated programmed cell death in prostate cancer cells. Saudi Pharm. J. 26(6), 876–885 (2018)CrossRefGoogle Scholar
  6. 6.
    Shen, Y., Cao, B., Snyder, N.R., Woeppel, K.M., Eles, J.R., Cui, X.T.: ROS responsive resveratrol delivery from LDLR peptide conjugated PLA-coated mesoporous silica nanoparticles across the blood–brain barrier. J. Nanobiotechnol. 16(1), 13 (2018)CrossRefGoogle Scholar
  7. 7.
    Pinho, E., Grootveld, M., Soares, G., Henriques, M.: Cyclodextrins as encapsulation agents for plant bioactive compounds. Carbohydr. Polym. 101, 121–135 (2014)CrossRefGoogle Scholar
  8. 8.
    Lu, Z., Cheng, B., Hu, Y., Zhang, Y., Zou, G.: Complexation of resveratrol with cyclodextrins: solubility and antioxidant activity. Food Chem. 113(1), 17–20 (2009)CrossRefGoogle Scholar
  9. 9.
    Duarte, A., Martinho, A., Luís, Â, Figueiras, A., Oleastro, M., Domingues, F.C., Silva, F.: Resveratrol encapsulation with methyl-β-cyclodextrin for antibacterial and antioxidant delivery applications. LWT-Food Sci. Technol. 63(2), 1254–1260 (2015)CrossRefGoogle Scholar
  10. 10.
    Troche-Pesqueira, E., Pérez-Juste, I., Navarro-Vázquez, A., Cid, M.M.: A β-cyclodextrin–resveratrol inclusion complex and the role of geometrical and electronic effects on its electronic induced circular dichroism. RSC Adv. 3(26), 10242–10250 (2013)CrossRefGoogle Scholar
  11. 11.
    Swaminathan, S., Cavalli, R., Trotta, F.: Cyclodextrin-based nanosponges: a versatile platform for cancer nanotherapeutics development. Wiley Interdisc. Rev. 8(4), 579–601 (2016)Google Scholar
  12. 12.
    Trotta, F.: Cyclodextrin nanosponges and their applications. In: Cyclodextrins in Pharmaceutics, Cosmetics, and Biomedicine: Current and Future Industrial Applications, pp. 323–342. Wiley, New York (2011)CrossRefGoogle Scholar
  13. 13.
    Ansari, K.A., Vavia, P.R., Trotta, F., Cavalli, R.: Cyclodextrin-based nanosponges for delivery of resveratrol: in vitro characterisation, stability, cytotoxicity and permeation study. Aaps Pharmscitech 12(1), 279–286 (2011)CrossRefGoogle Scholar
  14. 14.
    Swaminathan, S., Pastero, L., Serpe, L., Trotta, F., Vavia, P., Aquilano, D., Trotta, M., Zara, G., Cavalli, R.: Cyclodextrin-based nanosponges encapsulating camptothecin: physicochemical characterization, stability and cytotoxicity. Eur. J. Pharm. Biopharm. 74(2), 193–201 (2010)CrossRefGoogle Scholar
  15. 15.
    Rao, M., Bajaj, A., Khole, I., Munjapara, G., Trotta, F.: In vitro and in vivo evaluation of β-cyclodextrin-based nanosponges of telmisartan. J. Incl. Phenom. Macrocycl. Chem. 77(1–4), 135–145 (2013)CrossRefGoogle Scholar
  16. 16.
    Anandam, S., Selvamuthukumar, S.: Fabrication of cyclodextrin nanosponges for quercetin delivery: physicochemical characterization, photostability, and antioxidant effects. J. Mater. Sci. 49(23), 8140–8153 (2014)CrossRefGoogle Scholar
  17. 17.
    Shringirishi, M., Mahor, A., Gupta, R., Prajapati, S.K., Bansal, K., Kesharwani, P.: Fabrication and characterization of nifedipine loaded β-cyclodextrin nanosponges: an in vitro and in vivo evaluation. J. Drug Deliv. Sci. Technol. 41, 344–350 (2017)CrossRefGoogle Scholar
  18. 18.
    Shende, P.K., Trotta, F., Gaud, R., Deshmukh, K., Cavalli, R., Biasizzo, M.: Influence of different techniques on formulation and comparative characterization of inclusion complexes of ASA with β-cyclodextrin and inclusion complexes of ASA with PMDA cross-linked β-cyclodextrin nanosponges. J. Incl. Phenom. Macrocycl. Chem. 74(1–4), 447–454 (2012)CrossRefGoogle Scholar
  19. 19.
    Shende, P.K., Gaud, R., Bakal, R., Patil, D.: Effect of inclusion complexation of meloxicam with β-cyclodextrin-and β-cyclodextrin-based nanosponges on solubility, in vitro release and stability studies. Colloids Surf. B 136, 105–110 (2015)CrossRefGoogle Scholar
  20. 20.
    Shende, P., Chaphalkar, R., Deshmukh, K., Gaud, R.: Physicochemical investigation of engineered nanosuspensions containing model drug, lansoprazole. J. Dispersion Sci. Technol. 37(4), 504–511 (2016)CrossRefGoogle Scholar
  21. 21.
    Pushpalatha, R., Selvamuthukumar, S., Kilimozhi, D.: Cross-linked, cyclodextrin-based nanosponges for curcumin delivery-physicochemical characterization, drug release, stability and cytotoxicity. J. Drug Deliv. Sci. Technol. 45, 45–53 (2018)Google Scholar
  22. 22.
    Pushpalatha, R., Selvamuthukumar, S., Kilimozhi, D.: Hierarchy analysis of different cross-linkers used for the preparation of cross-linked cyclodextrin as drug nanocarriers. Chem. Eng. Commun. 205(6), 759–771 (2018)CrossRefGoogle Scholar
  23. 23.
    Trotta, F., Tumiatti, V., Cavalli, R., Rogero, C., Mognetti, B., Berta, G.: Cyclodextrin-based nanosponges as a vehicle for antitumoral drugs. WO 3656, A1 (2009)Google Scholar
  24. 24.
    Rao, M.R., Bhingole, R.C.: Nanosponge-based pediatric-controlled release dry suspension of Gabapentin for reconstitution. Drug Dev Ind Pharm 41(12), 2029–2036 (2015)CrossRefGoogle Scholar
  25. 25.
    Mele, A., Castiglione, F., Malpezzi, L., Ganazzoli, F., Raffaini, G., Trotta, F., Rossi, B., Fontana, A., Giunchi, G.: HR MAS NMR, powder XRD and Raman spectroscopy study of inclusion phenomena in βCD nanosponges. J. Incl. Phenom. Macrocycl. Chem. 69(3–4), 403–409 (2011)CrossRefGoogle Scholar
  26. 26.
    Gabr, M.M., Mortada, S.M., Sallam, M.A.: Carboxylate cross-linked cyclodextrin: a nanoporous scaffold for enhancement of rosuvastatin oral bioavailability. Eur. J. Pharm. Sci. 111, 1–12 (2018)CrossRefGoogle Scholar
  27. 27.
    Higuchi, T., Connors, K.A.: Phase solubility techniques. In: Advances Analytical Chemistry and Instrumentation, vol. 4. pp. 117–212. Wiley, New York (1965)Google Scholar
  28. 28.
    Swaminathan, S., Vavia, P., Trotta, F., Torne, S.: Formulation of betacyclodextrin based nanosponges of itraconazole. J. Incl. Phenom. Macrocycl. Chem. 57(1–4), 89–94 (2007)CrossRefGoogle Scholar
  29. 29.
    Denizot, F., Lang, R.: Rapid colorimetric assay for cell growth and survival: modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Methods 89(2), 271–277 (1986)CrossRefGoogle Scholar
  30. 30.
    Li, T.-P., Wong, W.-P., Chen, L.-C., Su, C.-Y., Chen, L.-G., Liu, D.-Z., Ho, H.-O., Sheu, M.-T.: Physical and pharmacokinetic characterizations of trans-resveratrol (t-Rev) encapsulated with self-assembling lecithin-based mixed polymeric micelles (sa LMPMs). Sci. Rep. 7(1), 10674 (2017)CrossRefGoogle Scholar
  31. 31.
    Trotta, F., Zanetti, M., Cavalli, R.: Cyclodextrin-based nanosponges as drug carriers. Beilstein J. Org. Chem. 8, 2091 (2012)CrossRefGoogle Scholar
  32. 32.
    Venuti, V., Rossi, B., Mele, A., Melone, L., Punta, C., Majolino, D., Masciovecchio, C., Caldera, F., Trotta, F.: Tuning structural parameters for the optimization of drug delivery performance of cyclodextrin-based nanosponges. Expert Opin. Drug Deliv. 14(3), 331–340 (2017)CrossRefGoogle Scholar
  33. 33.
    Dora, C.P., Trotta, F., Kushwah, V., Devasari, N., Singh, C., Suresh, S., Jain, S.: Potential of erlotinib cyclodextrin nanosponge complex to enhance solubility, dissolution rate, in vitro cytotoxicity and oral bioavailability. Carbohydr. Polym. 137, 339–349 (2016)CrossRefGoogle Scholar
  34. 34.
    Jeffrey, G.A., Jeffrey, G.A.: An Introduction to Hydrogen Bonding, vol. 32. Oxford University Press, New York (1997)Google Scholar
  35. 35.
    Brewster, M.E., Loftsson, T.: Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev. 59(7), 645–666 (2007)CrossRefGoogle Scholar
  36. 36.
    Löbenberg, R., Amidon, G.L.: Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur. J. Pharm. Biopharm. 50(1), 3–12 (2000)CrossRefGoogle Scholar
  37. 37.
    Torne, S., Darandale, S., Vavia, P., Trotta, F., Cavalli, R.: Cyclodextrin-based nanosponges: effective nanocarrier for Tamoxifen delivery. Pharm. Dev. Technol. 18(3), 619–625 (2013)CrossRefGoogle Scholar

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© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Department of PharmacyAnnamalai UniversityAnnamalai NagarIndia

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