Skip to main content
SpringerLink
Log in

Inclusion Complex of Novel Curcumin Analogue CDF and β-Cyclodextrin (1:2) and Its Enhanced In Vivo Anticancer Activity Against Pancreatic Cancer

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Several formulations have been proposed to improve the systemic delivery of novel cancer therapeutic compounds, including cyclodextrin derivatives. We aimed to synthesize and characterize of CDF-β-cyclodextrin inclusion complex (1:2) (CDFCD).

Methods

The compound was characterized by Fourier transform infrared, differential scanning calorimetry, powder X-ray diffraction studies, H1 & C13 NMR studies and scanning electron microscopic analysis. Its activity was tested against multiple cancer cell lines, and in vivo bioavailability was checked.

Results

CDF-β-cyclodextrin was found to lower IC50 value by half when tested against multiple cancer cell lines. It preferentially accumulated in the pancreas, where levels of CDF-β-cyclodextrin in mice were 10 times higher than in serum, following intravenous administration of an aqueous CDF-β-cyclodextrin preparation.

Conclusions

Novel curcumin analog CDF preferentially accumulates in the pancreas, leading to its potent anticancer activity against pancreatic cancer cells. Synthesis of such CDF-β-cyclodextrin self-assembly is an effective strategy to enhance its bioavailability and tissue distribution, warranting further evaluation for CDF delivery in clinical settings for treatment of human malignancies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Shishodia S, Sethi G, Aggarwal BB. Curcumin: getting back to the roots. Ann N Y Acad Sci. 2005;1056:206–17.

    Article  PubMed  CAS  Google Scholar 

  2. Ravindran J, Prasad S, Aggarwal BB. Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J. 2009;11:495–510.

    Article  PubMed  CAS  Google Scholar 

  3. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4:807–18.

    Article  PubMed  CAS  Google Scholar 

  4. Padhye S, Banerjee S, Chavan D, Pandye S, Swamy KV, Ali S, et al. Fluorocurcumins as cyclooxygenase-2 inhibitor: molecular docking, pharmacokinetics and tissue distribution in mice. Pharm Res. 2009;26:2438–45.

    Article  PubMed  CAS  Google Scholar 

  5. Padhye S, Yang H, Jamadar A, Cui QC, Chavan D, Dominiak K, et al. New difluoro Knoevenagel condensates of curcumin, their Schiff bases and copper complexes as proteasome inhibitors and apoptosis inducers in cancer cells. Pharm Res. 2009;26:1874–80.

    Article  PubMed  CAS  Google Scholar 

  6. Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, Schaffert JM, et al. Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer Res. 2010;70:3606–17.

    Article  PubMed  CAS  Google Scholar 

  7. Bao B, Ali S, Kong D, Sarkar SH, Wang Z, Banerjee S, et al. Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer. PLoS One. 2011;6:e17850.

    Article  PubMed  CAS  Google Scholar 

  8. Bao B, Ali S, Banerjee S, Wang Z, Logna F, Azmi AS, et al. Curcumin analog CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res. 2012;72:335–45.

    Article  PubMed  CAS  Google Scholar 

  9. Li Y, Kong D, Wang Z, Ahmad A, Bao B, Padhye S, et al. Inactivation of AR/TMPRSS2-ERG/Wnt signaling networks attenuates the aggressive behavior of prostate cancer cells. Cancer Prev Res (Phila). 2011;4:1495–506.

    Article  CAS  Google Scholar 

  10. Kanwar SS, Yu Y, Nautiyal J, Patel BB, Padhye S, Sarkar FH, et al. Difluorinated-curcumin (CDF): a novel curcumin analog is a potent inhibitor of colon cancer stem-like cells. Pharm Res. 2011;28:827–38.

    Article  PubMed  CAS  Google Scholar 

  11. Yallapu MM, Dobberpuhl MR, Maher DM, Jaggi M, Chauhan SC. Design of Curcumin loaded Cellulose Nanoparticles for Prostate Cancer. Curr Drug Metab. 2011.

  12. Mazzarino L, Silva LF, Curta JC, Licinio MA, Costa A, Pacheco LK, et al. Curcumin-loaded lipid and polymeric nanocapsules stabilized by nonionic surfactants: an in vitro and In vivo antitumor activity on B16-F10 melanoma and macrophage uptake comparative study. J Biomed Nanotechnol. 2011;7:406–14.

    Article  PubMed  CAS  Google Scholar 

  13. Pandelidou M, Dimas K, Georgopoulos A, Hatziantoniou S, Demetzos C. Preparation and characterization of lyophilised egg PC liposomes incorporating curcumin and evaluation of its activity against colorectal cancer cell lines. J Nanosci Nanotechnol. 2011;11:1259–66.

    Article  PubMed  CAS  Google Scholar 

  14. Dhule SS, Penfornis P, Frazier T, Walker R, Feldman J, Tan G et al. Curcumin-loaded gamma-cyclodextrin liposomal nanoparticles as delivery vehicles for osteosarcoma. Nanomedicine. 2011.

  15. Harada T, Pham DT, Leung MH, Ngo HT, Lincoln SF, Easton CJ, et al. Cooperative binding and stabilization of the medicinal pigment curcumin by diamide linked gamma-cyclodextrin dimers: a spectroscopic characterization. J Phys Chem B. 2011;115:1268–74.

    Article  PubMed  CAS  Google Scholar 

  16. Hegge AB, Schuller RB, Kristensen S, Tonnesen HH. In vitro release of curcumin from vehicles containing alginate and cyclodextrin. Studies of curcumin and curcuminoides. XXXIII. Pharmazie. 2008;63:585–92.

    PubMed  CAS  Google Scholar 

  17. Yadav VR, Suresh S, Devi K, Yadav S. Effect of cyclodextrin complexation of curcumin on its solubility and antiangiogenic and anti-inflammatory activity in rat colitis model. AAPS PharmSciTech. 2009;10:752–62.

    Article  PubMed  CAS  Google Scholar 

  18. Yadav VR, Prasad S, Kannappan R, Ravindran J, Chaturvedi MM, Vaahtera L, et al. Cyclodextrin-complexed curcumin exhibits anti-inflammatory and antiproliferative activities superior to those of curcumin through higher cellular uptake. Biochem Pharmacol. 2010;80:1021–32.

    Article  PubMed  CAS  Google Scholar 

  19. Yallapu MM, Jaggi M, Chauhan SC. beta-Cyclodextrin-curcumin self-assembly enhances curcumin delivery in prostate cancer cells. Colloids Surf B Biointerfaces. 2010;79:113–25.

    Article  PubMed  CAS  Google Scholar 

  20. Higuchi T, Connors KA. Phase solubility techniques. Adv Anal Chem Instrum. 1965;4:117–212.

    CAS  Google Scholar 

  21. Renner S, Schwab CH, Gasteiger J, Schneider G. Impact of conformational flexibility on three-dimensional similarity searching using correlation vectors. J Chem Inf Model. 2006;46:2324–32.

    Article  PubMed  CAS  Google Scholar 

  22. Anderson AM, Mitchell MS, Mohan RS. Isolation of curcumin from turmeric. J Chem Ed. 2000;77:359–60.

    Article  CAS  Google Scholar 

  23. Shen YL, Ying W, Yang SH, Wu LM. Determinations of the inclusion complex between gossypol and beta-cyclodextrin. Spectrochim Acta A Mol Biomol Spectrosc. 2006;65:169–72.

    Article  PubMed  Google Scholar 

  24. Wu H, Liang H, Yuan Q, Wang T, Yan X. Preparation and Stability investigation of the inclusion complex of sulforaphane with hydroxypropyl-beta-cyclodextrin. Carbohydr Polym. 2010;82:613–7.

    Article  CAS  Google Scholar 

  25. Song LX, Wang HM, Guo XQ, Bai L. A comparative study on the binding behaviors of beta-cyclodextrin and its two derivatives to four fanlike organic guests. J Org Chem. 2008;73:8305–16.

    Article  CAS  Google Scholar 

  26. Uner M. Preparation, characterization and physico-chemical properties of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC): their benefits as colloidal drug carrier systems. Pharmazie. 2006;61:375–86.

    PubMed  CAS  Google Scholar 

  27. Santander-Ortega MJ, Bastos-Gonzalez D, Ortega-Vinuesa JL, Alonso MJ. Insulin-loaded PLGA nanoparticles for oral administration: an in vitro physico-chemical characterization. J Biomed Nanotechnol. 2009;5:45–53.

    Article  PubMed  CAS  Google Scholar 

  28. Craparo EF, Cavallaro G, Bondi ML, Mandracchia D, Giammona G. PEGylated Nanoparticles based on a polyaspartamide. preparation, physico-chemical characterization, and intracellular uptake. Biomacromolecules. 2006;7:3083–92.

    Article  PubMed  CAS  Google Scholar 

  29. Lemarchand C, Gref R, Lesieur S, Hommel H, Vacher B, Besheer A, et al. Physico-chemical characterization of polysaccharide-coated nanoparticles. J Control Release. 2005;108:97–111.

    Article  PubMed  CAS  Google Scholar 

  30. Horvath G, Premkumar T, Boztas A, Lee E, Jon S, Geckeler KE. Supramolecular nanoencapsulation as a tool: solubilization of the anticancer drug trans-dichloro(dipyridine)platinum(II) by complexation with beta-cyclodextrin. Mol Pharm. 2008;5:358–63.

    Article  PubMed  CAS  Google Scholar 

  31. Yallapu MM, Jaggi M, Chauhan SC. Poly(beta-cyclodextrin)/curcumin self-assembly: a novel approach to improve curcumin delivery and its therapeutic efficacy in prostate cancer cells. Macromol Biosci. 2010;10:1141–51.

    Article  PubMed  CAS  Google Scholar 

  32. Komura T, Yamaguchi T, Noda K, Hayashi S. Inclusion complexation of (11-ferrocenylundecyl)trimethylammonium bromide by beta-cyclodextrin and its effects on elctrochemical behavior of the surfactant. Electrochim Acta. 2002;47:3315–25.

    Article  CAS  Google Scholar 

  33. Kolivoska V, Ga'l M, Hromadova M, Valasek M, Pospisil L. Correlation of the formation constant of ferrocene-cyclodextrin complexes with dielectric properties of the aqueous DMSO solution. J Organomet Chem. 2011;696:1404–8.

    Article  CAS  Google Scholar 

  34. Srinivasan K, Kayalvizhi K, Sivakumar K, Stalin T. Study of inclusion complex of beta-cyclodextrin and diphenylamine: photophysical and electrochemical behaviors. Spectrochim Acta A Mol Biomol Spectrosc. 2011;79:169–78.

    Article  PubMed  CAS  Google Scholar 

  35. Garnero C, Zoppi A, Genovese D, Longhi M. Studies on trimethoprim:hydroxypropyl-beta-cyclodextrin: aggregate and complex formation. Carbohydr Res. 2010;345:2550–6.

    Article  PubMed  CAS  Google Scholar 

  36. Inoue Y. NMR studies of the structure and properties of cyclodextrins and their inclusion complexes. Annu Re NMR Spectrosc. 1993;27:59–101.

    Article  CAS  Google Scholar 

  37. Bernini A, Spiga O, Ciutti A, Scarselli M, Bottoni G, Mascagni P, et al. NMR studies of the inclusion complex between beta-cyclodextrin and paroxetine. Eur J Pharm Sci. 2004;22:445–50.

    Article  PubMed  CAS  Google Scholar 

  38. Marcolino VA, Zanin GM, Durrant LR, Benassi MT, Matioli G. Interaction of curcumin and bixin with beta-cyclodextrin: complexation methods, stability, and applications in food. J Agric Food Chem. 2011;59:3348–57.

    Article  PubMed  CAS  Google Scholar 

  39. Faucci MT, Melani F, Mura P. Computer-aided molecular modeling techniques for predicting the stability of drug-cyclodextrin inclusion complexes in aqueous solutions. Cmeical Physics Letters. 2002;358:383–90.

    Article  CAS  Google Scholar 

  40. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments & Disclosures

P.D. acknowledges CSIR, New Delhi, INDIA for providing Senior Research Fellowship. SP is thankful to Mr. P. A. Inamdar for his keen interest and encouragement. We acknowledge Department of Physics, University of Pune and R. C. Patel Institute of Pharmaceutical Education & Research, Shirpur, for providing SEM, PXRD and DSC facilities.

Author information

Authors and Affiliations

  1. ISTRA, Department of Chemistry, MCE Society’s Abeda Inamdar Senior College of Arts, Science and Commerce, Pune, 411001, India

    Prasad R. Dandawate, Alok Vyas & Subhash Padhye

  2. Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Tathawade, Pune, 411044, India

    Alok Vyas, Jyoti Deshpande & K. Venkateswara Swamy

  3. Department of Pathology, Barbara Ann Karmanos Cancer Center Wayne State University School of Medicine, 740 HWCRC, Detroit, Michigan, 48201, USA

    Aamir Ahmad, Sanjeev Banerjee, Subhash Padhye & Fazlul H. Sarkar

  4. Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK

    Abeda Jamadar & Anne Catherine Dumhe-Klaire

Authors
  1. Prasad R. Dandawate
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alok Vyas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aamir Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sanjeev Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jyoti Deshpande
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. Venkateswara Swamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Abeda Jamadar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anne Catherine Dumhe-Klaire
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Subhash Padhye
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fazlul H. Sarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Subhash Padhye or Fazlul H. Sarkar.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Esm 1

(DOC 68 kb)

Esm 2

(DOC 67 kb)

Esm 3

(TIFF 184 kb)

Esm 4

(TIFF 126 kb)

Esm 5

(TIFF 89 kb)

Esm 6

(TIFF 93 kb)

Esm 7

(TIFF 93 kb)

Esm 8

(TIFF 106 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dandawate, P.R., Vyas, A., Ahmad, A. et al. Inclusion Complex of Novel Curcumin Analogue CDF and β-Cyclodextrin (1:2) and Its Enhanced In Vivo Anticancer Activity Against Pancreatic Cancer. Pharm Res 29, 1775–1786 (2012). https://doi.org/10.1007/s11095-012-0700-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-012-0700-1

Key words

Search

Navigation