Skip to main content
SpringerLink
Log in

Effect of Cyclodextrin Complexation on the Liposome Permeability of a Model Hydrophobic Weak Acid

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

Abstract

Purpose

This study examines the effect of a chemically modified β-cyclodextrin on the liposome bilayer permeability of a liposomally entrapped model hydrophobic weak acid, DB-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin).

Materials and Methods

Permeability studies were conducted in liposomes prepared by hydration–extrusion in the presence or absence of entrapped hydroxypropyl-β-cyclodextrin (HPβCD). A gradient HPLC method with evaporative light scattering detection was developed for analysis of HPβCD. DB-67 was analyzed by HPLC with fluorescence detection.

Results

HPβCD entrapped in the aqueous compartment of liposomes was found to be membrane impermeable. Gel phase liposomes were stable in the presence of HPβCD. HPβCD complexation did not significantly alter the apparent permeability of DB67 lactone, due to its high membrane binding. However, lactone ring-opening and ionization significantly decreased the apparent permeability and improved the liposomal retention of DB-67, an effect that was amplified in the presence of 50 mM HPβCD.

Conclusions

In liposomes, cyclodextrin complexation competes with liposomal membrane binding which may temper the potential benefit of complexation in prolonging hydrophobic drug retention. Cyclodextrin complexation combined with drug ionization may nevertheless significantly enhance the retention of ionizable hydrophobic drugs in liposomes as complexation may compete more favorably with membrane binding when the drug is ionized.

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
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

  1. A. A. Gabizon. Liposomal drug carrier systems in cancer chemotherapy: current status and future prospects. J. Drug Target. 10:535–538 (2002). doi:10.1080/1061186021000043061.

    Article  PubMed  CAS  Google Scholar 

  2. D. D. Lasic, B. Ceh, M. C. Stuart, L. Guo, P. M. Frederik, and Y. Barenholz. Transmembrane gradient driven phase transitions within vesicles: lessons for drug delivery. Biochim Biophys Acta. 1239:145–156 (1995). doi:10.1016/0005-2736(95)00159-Z.

    Article  PubMed  Google Scholar 

  3. E. Maurer-Spurej, K. F. Wong, N. Maurer, D. B. Fenske, and P. R. Cullis. Factors influencing uptake and retention of amino-containing drugs in large unilamellar vesicles exhibiting transmembrane pH gradients. Biochim. Biophys. Acta. 1416:1–10 (1999) doi:10.1016/S0005-2736(98)00204-1.

    Article  PubMed  CAS  Google Scholar 

  4. R. P. Hertzberg, M. J. Caranfa, and S. M. Hecht. On the mechanism of topoisomerase I inhibition by camptothecin: evidence for binding to an enzyme–DNA complex. Biochemistry. 28:4629–4638 (1989). doi:10.1021/bi00437a018.

    Article  PubMed  CAS  Google Scholar 

  5. V. Joguparthi, and B. D. Anderson. Liposomal delivery of hydrophobic weak acids: enhancement of drug retention using a high intraliposomal pH. J. Pharm. Sci. 97:433–454 (2008). doi:10.1002/jps.21135.

    Article  PubMed  CAS  Google Scholar 

  6. V. Joguparthi, T. X. Xiang, and B. D. Anderson. Liposome transport of hydrophobic drugs: gel phase lipid bilayer permeability and partitioning of the lactone form of a hydrophobic camptothecin, DB-67. J. Pharm. Sci. 97:400–420 (2008). doi:10.1002/jps.21125.

    Article  PubMed  CAS  Google Scholar 

  7. V. Joguparthi, S. Feng, and B. D. Anderson. Determination of intraliposomal pH and its effect on membrane partitioning and passive loading of a hydrophobic camptothecin, DB-67. Int. J. Pharm. 352:17–28 (2008). doi:10.1016/j.ijpharm.2007.10.003.

    Article  PubMed  CAS  Google Scholar 

  8. B. McCormack, and G. Gregoriadis. Entrapment of cyclodextrin–drug complexes into liposomes: potential advantages in drug delivery. J. Drug Target. 2:449–454 (1994). doi:10.3109/10611869408996821.

    Article  PubMed  CAS  Google Scholar 

  9. B. McCormack, and G. Gregoriadis. Comparative studies of the fate of free and liposome-entrapped hydroxypropyl-b-cyclodextrin/drug complexes after intravenous injection into rats: implications in drug delivery. Biochim. Biophys. Acta. 1291:237–244 (1996).

    PubMed  CAS  Google Scholar 

  10. H. Chen, J. Gao, F. Wang, and W. Liang. Preparation, characterization and pharmacokinetics of liposomes-encapsulated cyclodextrins inclusion complexes for hydrophobic drugs. Drug Deliv. 14:201–208 (2007). doi:10.1080/10717540601036880.

    Article  PubMed  CAS  Google Scholar 

  11. D. G. Fatouros, K. Hatzidimitriou, and S. G. Antimisiaris. Liposomes encapsulating prednisolone and prednisolone–cyclodextrin complexes: comparison of membrane integrity and drug release. Eur. J. Pharm. Sci. 13:287–296 (2001) doi:10.1016/S0928-0987(01)00114-2.

    Article  PubMed  CAS  Google Scholar 

  12. Y. Hagiwara, H. Arima, Y. Miyamoto, F. Hirayama, and K. Uekama. Preparation and pharmaceutical evaluation of liposomes entrapping salicylic acid/gamma-cyclodextrin conjugate. Chem. Pharm. Bull (Tokyo). 54:26–32 (2006). doi:10.1248/cpb.54.26.

    Article  CAS  Google Scholar 

  13. F. Maestrelli, M. L. Gonzalez-Rodriguez, A. M. Rabasco, and P. Mura. Effect of preparation technique on the properties of liposomes encapsulating ketoprofen-cyclodextrin complexes aimed for transdermal delivery. Int. J. Pharm. 312:53–60 (2006). doi:10.1016/j.ijpharm.2005.12.047.

    Article  PubMed  CAS  Google Scholar 

  14. G. Piel, M. Piette, V. Barillaro, D. Castagne, B. Evrard, and L. Delattre. Betamethasone-in-cyclodextrin-in-liposome: the effect of cyclodextrins on encapsulation efficiency and release kinetics. Int. J. Pharm. 312:75–82 (2006). doi:10.1016/j.ijpharm.2005.12.044.

    Article  PubMed  CAS  Google Scholar 

  15. I. I. Salem, and N. Duzgunes. Efficacies of cyclodextrin-complexed and liposome-encapsulated clarithromycin against Mycobacterium avium complex infection in human macrophages. Int. J. Pharm. 250:403–414 (2003). doi:10.1016/S0378-5173(02)00552-5.

    Article  PubMed  CAS  Google Scholar 

  16. P. Hatzi, S. Mourtas, P. G. Klepetsanis, and S. G. Antimisiaris. Integrity of liposomes in presence of cyclodextrins: effect of liposome type and lipid composition. Int. J. Pharm. 333:167–176 (2007). doi:10.1016/j.ijpharm.2006.09.059.

    Article  PubMed  CAS  Google Scholar 

  17. S. L. Niu, and B. J. Litman. Determination of membrane cholesterol partition coefficient using a lipid vesicle–cyclodextrin binary system: effect of phospholipid acyl chain unsaturation and headgroup composition. Biophys. J. 83:3408–3415 (2002).

    Article  PubMed  CAS  Google Scholar 

  18. H. Ohvo, and J. P. Slotte. Cyclodextrin-mediated removal of sterols from monolayers: effects of sterol structure and phospholipids on desorption rate. Biochemistry. 35:8018–8024 (1996). doi:10.1021/bi9528816.

    Article  PubMed  CAS  Google Scholar 

  19. J. Nishijo, and H. Mizuno. Interactions of cyclodextrins with DPPC liposomes. Differential scanning calorimetry studies. Chem. Pharm. Bull. (Tokyo). 46:120–124 (1998).

    CAS  Google Scholar 

  20. G. Puglisi, M. Fresta, and C. Ventura. Interaction of natural and modified b-cyclodextrins with biological membrane model of dipalmitoylphosphatidylcholine. J. Colloid Interface Sci. 180:542–547 (1996). doi:10.1006/jcis.1996.0335.

    Article  CAS  Google Scholar 

  21. J. Nishijo, S. Shiota, K. Mazima, Y. Inoue, H. Mizuno, and J. Yoshida. Interactions of cyclodextrins with dipalmitoyl, distearoyl, and dimyristoyl phosphatidyl choline liposomes. A study by leakage of carboxyfluorescein in inner aqueous phase of unilamellar liposomes. Chem. Pharm. Bull. (Tokyo). 48:48–52 (2000).

    CAS  Google Scholar 

  22. G. Piel, M. Piette, V. Barillaro, D. Castagne, B. Evrard, and L. Delattre. Study of the relationship between lipid binding properties of cyclodextrins and their effect on the integrity of liposomes. Int. J. Pharm. 338:35–42 (2007). doi:10.1016/j.ijpharm.2007.01.015.

    Article  PubMed  CAS  Google Scholar 

  23. J. Fassberg, and V. J. Stella. A kinetic and mechanistic study of the hydrolysis of camptothecin and some analogues. J. Pharm. Sci. 81:676–684 (1992). doi:10.1002/jps.2600810718.

    Article  PubMed  CAS  Google Scholar 

  24. P. S. Uster, T. M. Allen, B. E. Daniel, C. J. Mendez, M. S. Newman, and G. Z. Zhu. Insertion of poly(ethylene glycol) derivatized phospholipid into pre-formed liposomes results in prolonged in vivo circulation time. FEBS Lett. 386:243–246 (1996). doi:10.1016/0014-5793(96)00452-8.

    Article  PubMed  CAS  Google Scholar 

  25. T. X. Xiang, and B. D. Anderson. Stable supersaturated aqueous solutions of silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin via chemical conversion in the presence of a chemically modified b-cyclodextrin. Pharm. Res. 19:1215–1222 (2002). doi:10.1023/A:1019862629357.

    Article  PubMed  CAS  Google Scholar 

  26. J. R. Silvius, and M. J. Zuckermann. Interbilayer transfer of phospholipid-anchored macromolecules via monomer diffusion. Biochemistry. 32:3153–3161 (1993). doi:10.1021/bi00063a030.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was financially supported by a grant from NIH (NCI RO1 CA87061). VJ would like to thank Virginia Fields and Mikolaj Milewski for performing preliminary experiments in this work.

Author information

Author notes

  1. Vijay Joguparthi

    Present address: Boehringer-Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, Connecticut, 06877, USA

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Kentucky, A323A ASTeCC Bldg., Lexington, Kentucky, 40536-0082, USA

    Vijay Joguparthi & Bradley D. Anderson

Authors
  1. Vijay Joguparthi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bradley D. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bradley D. Anderson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Joguparthi, V., Anderson, B.D. Effect of Cyclodextrin Complexation on the Liposome Permeability of a Model Hydrophobic Weak Acid. Pharm Res 25, 2505–2515 (2008). https://doi.org/10.1007/s11095-008-9664-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-008-9664-6

KEY WORDS

Search

Navigation