Skip to main content
SpringerLink
Log in

Rapid Colorimetric Screening of Drug Interaction and Penetration Through Lipid Barriers

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

Purpose

The aims of this study are to develop a rapid colorimetric assay for evaluating membrane interactions and penetration through lipid barriers and to create a platform, amenable to high-throughput screening formats, for predicting the extent of penetration of pharmaceutical compounds through lipid layers.

Methods

The colorimetric platform comprises vesicles of phospholipids and the chromatic lipid–mimetic polymer polydiacetylene. The polymer undergoes visible, concentration-dependent blue–red transformations induced through interactions of the vesicles with the molecules examined.

Results

We observe rapid colorimetric transitions induced by addition of pharmaceutical compounds to the chromatic vesicle solutions. We find that the concentration ranges for which the color transitions are induced in the lipid/polymer vesicles are correlated with the degree of lipid interactions and bilayer penetration of the tested compounds. The colorimetric platform could distinguish between three primary types of membrane-permeation profiles: bilayer-surface attachment, membrane penetration, and absence of lipid interactions. Application of complementary bioanalytical techniques corroborated the interpretation of the colorimetric data. Different pharmaceutical compounds were tested by the new assay. The results indicated clearly distinct membrane interaction profiles for molecules expected by conventional methods to have similar membrane-insertion properties (i.e., close log D/log P values). In addition, the new colorimetric assay pointed to similar membrane activities for molecules having highly divergent log Ds.

Conclusions

The colorimetric assay facilitates “color coding” that could distinguish among different membrane permeation profiles. The data point to the usefulness of the platform for characterization of drug compound interactions with lipid assemblies. The new colorimetric technology constitutes a generic, extremely fast, and easily applicable approach for predicting and screening interactions of pharmaceutical compounds with lipid barriers.

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

Similar content being viewed by others

Abbreviations

DMPC:

dimyristoylphosphatidylcholine

DMPS:

dimyristoylphosphatidylserine

DSC:

differential scanning calorimetry

NBD-PE:

N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)1,2-dihexadecanoyl-sn-glycero-3-phospo-ethanolamin

PDA:

polydiacetylene

TFE:

trifluoroethanol

References

  1. I. Tetko P. Bruneau (2004) ArticleTitleApplication of ALOPGPS to predict 1-octanol/water distribution coefficients, logP, and logD, of AstraZeneca in-house database J. Pharm. Sci. 93 3103–3110 Occurrence Handle10.1002/jps.20217 Occurrence Handle1:CAS:528:DC%2BD2cXhtVKlsrnI Occurrence Handle15514985

    Article  CAS  PubMed  Google Scholar 

  2. L. Escuder-Gilabert M. Molero-Monfort R. M. Villanueva-Camanas S. Sagrado M. J. Medina-Hernandez (2004) ArticleTitlePotential of biopartitioning micellar chromatography as an in vitro technique for predicting drug penetration across the blood–brain barrier J. Chromatogr. 807 193–201 Occurrence Handle1:CAS:528:DC%2BD2cXltVKis7s%3D

    CAS  Google Scholar 

  3. P. Garberg M. Ball N. Borg R. Cecchelli L. Fenart R. Hurst T. Lindmark A. Mabondzo J. Nilsson T. Raub D. Stanimirovic T. Terasaki J. Oberg T. Osterberg (2005) ArticleTitleIn vitro models for the blood–brain barrier Toxicol. In Vitro 19 299–334 Occurrence Handle10.1016/j.tiv.2004.06.011 Occurrence Handle1:CAS:528:DC%2BD2MXhtlCrurg%3D Occurrence Handle15713540

    Article  CAS  PubMed  Google Scholar 

  4. C. Masungi C. Borremans B. Willems J. Mensch A. Dijck ParticleVan P. Auguctijns M. Brewster M. Noppe (2004) ArticleTitleUsefulness of a novel caco2 cell perfusion system. I. In vitro prediction of the absorption potential of passively diffused compounds J. Pharm. Sci. 93 2507–2521 Occurrence Handle10.1002/jps.20149 Occurrence Handle1:CAS:528:DC%2BD2cXotl2gt74%3D Occurrence Handle15349960

    Article  CAS  PubMed  Google Scholar 

  5. C. Wu L. Benet (2005) ArticleTitlePredicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system Pharm. Res. 22 11–23 Occurrence Handle1:CAS:528:DC%2BD2MXhtlCks70%3D Occurrence Handle15771225

    CAS  PubMed  Google Scholar 

  6. H. Ringsdorf B. Schlarb J. Venzmer (1988) ArticleTitleMolecular architecture and function of polymeric oriented systems: models for the study of organization, surface recognition, and dynamics of biomembranes Angew. Chem. Int. Ed. Engl. 27 113–158 Occurrence Handle10.1002/anie.198801131

    Article  Google Scholar 

  7. S. Okada S. Peng W. Spevak D. Charych (1998) ArticleTitleColor and chromism of polydiacetylene vesicles Acc. Chem. Res. 31 229–239 Occurrence Handle10.1021/ar970063v Occurrence Handle1:CAS:528:DyaK1cXislShs7g%3D

    Article  CAS  Google Scholar 

  8. D. H. Charych J. O. Nagy W. Spevak M. D. Bednarski (1993) ArticleTitleDirect colorimetric detection of a receptor–ligand interaction by a polymerized bilayer assembly Science 261 585–588 Occurrence Handle1:CAS:528:DyaK3sXlslOjurw%3D Occurrence Handle8342021

    CAS  PubMed  Google Scholar 

  9. S. Kolusheva L. Boyer R. Jelinek (2000) ArticleTitleA colorimetric assay for rapid screening of antimicrobial peptides Nat. Biotechnol. 18 225–227 Occurrence Handle10.1038/72697 Occurrence Handle1:CAS:528:DC%2BD3cXhtVOksLc%3D Occurrence Handle10657134

    Article  CAS  PubMed  Google Scholar 

  10. S. Kolusheva T. Shahal R. Jelinek (2000) ArticleTitlePeptide–membrane interactions studied by a new phospholipid/polydiacetylene colorimetric vesicle assay Biochemistry 39 15851–15859 Occurrence Handle10.1021/bi000570b Occurrence Handle1:CAS:528:DC%2BD3cXosVantr4%3D Occurrence Handle11123911

    Article  CAS  PubMed  Google Scholar 

  11. S. Y. Okada R. Jelinek D. Charych (1999) ArticleTitleInduced color change of conjugated polymeric vesicles by interfacial catalysis of phospholipase a2 Angew. Chem. Int. Ed. 38 655–659 Occurrence Handle10.1002/(SICI)1521-3773(19990301)38:5<655::AID-ANIE655>3.0.CO;2-4 Occurrence Handle1:CAS:528:DyaK1MXhvFarsLo%3D

    Article  CAS  Google Scholar 

  12. A. Chattopadhyay E. London (1987) ArticleTitleParallax method for direct measurement of membrane penetration depth utilizing fluorescence quenching by spin-labeled phospholipids Biochemistry 26 39–45 Occurrence Handle10.1021/bi00375a006 Occurrence Handle1:STN:280:BiiC2MjmtlA%3D Occurrence Handle3030403

    Article  CAS  PubMed  Google Scholar 

  13. J. C. McIntyre R. G. Sleight (1991) ArticleTitleFluorescence assay for phospholipid membrane asymmetry Biochemistry 30 11819–11827 Occurrence Handle10.1021/bi00115a012 Occurrence Handle1:CAS:528:DyaK38XjtVGm Occurrence Handle1751498

    Article  CAS  PubMed  Google Scholar 

  14. S. W. Hui N.-B. He (1983) ArticleTitleMolecular organization in cholesterol–lecithin bilayers by x-ray and electron diffraction measurements Biochemistry 22 1159–1164 Occurrence Handle1:CAS:528:DyaL3sXhtVejtLs%3D Occurrence Handle6838844

    CAS  PubMed  Google Scholar 

  15. S. Kolusheva E. Wachtel R. Jelinek (2003) ArticleTitleBiomimetic lipid/polymer colorimetric membranes: molecular and cooperative properties J. Lipid Res. 44 65–71 Occurrence Handle1:CAS:528:DC%2BD3sXlslOhtw%3D%3D Occurrence Handle12518024

    CAS  PubMed  Google Scholar 

  16. D. Papahadjopoulos (1977) ArticleTitleEffects of bivalent cations and proteins on thermotropic properties of phospholipid membranes. Implications for the molecular mechanism of fusion and endocytosis J. Colloid Interface Sci. 58 459–470 Occurrence Handle10.1016/0021-9797(77)90157-6 Occurrence Handle1:CAS:528:DyaE2sXhs1Kktbo%3D

    Article  CAS  Google Scholar 

  17. R. Volinsky S. Kolusheva A. Berman R. Jelinek (2004) ArticleTitleMicroscopic visualization of alamethicin incorporation intos model membrane monolayers Langmuir 20 11084–11091 Occurrence Handle10.1021/la0477486 Occurrence Handle1:CAS:528:DC%2BD2cXptF2ksbo%3D Occurrence Handle15568861

    Article  CAS  PubMed  Google Scholar 

  18. D. P. Satchell T. Sheynis Y. Shirafuji S. Kolusheva A. Ouellette R. Jelinek (2003) ArticleTitleInteractions of mouse Paneth cell-defensins with membranes studied by a biomimetic lipid/polymer colorimetric assay J. Biol. Chem. 278 13838–13846 Occurrence Handle10.1074/jbc.M212115200 Occurrence Handle1:CAS:528:DC%2BD3sXjtVSitL8%3D Occurrence Handle12574157

    Article  CAS  PubMed  Google Scholar 

  19. M. Katz H. Tsubery S. Kolusheva A. Shames M. Fridkin R. Jelinek (2003) ArticleTitleLipid binding and membrane penetration of polymyxin B derivatives studied in a biomimetic vesicle system Biochem. J. 375 405–413 Occurrence Handle10.1042/BJ20030784 Occurrence Handle1:CAS:528:DC%2BD3sXnvF2rs7k%3D Occurrence Handle12848621

    Article  CAS  PubMed  Google Scholar 

  20. Y. Kobayashi K. Fukada (1998) ArticleTitleCharacterization of swollen lamellar phase of dimyristoylphosphatidylcholine–gramicidin a mixed membranes by DSC, SAXS, and densimetry Biochim. Biophys. Acta 1371 363–370 Occurrence Handle1:CAS:528:DyaK1cXjvVSms7w%3D Occurrence Handle9630724

    CAS  PubMed  Google Scholar 

  21. L. Fraceto L. Pinto L. Franzoni A. Braga A. Spisni S. Schreier E. Paula Particlede (2002) ArticleTitleSpectroscopic evidence for a preferential location of lidocaine inside phospholipid bilayers Biophys. Chem. 99 229–243 Occurrence Handle1:CAS:528:DC%2BD38Xot1eqtLc%3D Occurrence Handle12408938

    CAS  PubMed  Google Scholar 

  22. P. Suomalainen C. Johans T. Soederlund P. Kinnunen (2004) ArticleTitleActivity profiling of drugs applied to the prediction of blood–brain barrier permeability J. Med. Chem. 47 1783–1788 Occurrence Handle10.1021/jm0309001 Occurrence Handle1:CAS:528:DC%2BD2cXhs1ylsL4%3D Occurrence Handle15027870

    Article  CAS  PubMed  Google Scholar 

  23. Y. Sudoh E. Cahoon P. Gerner G. Wang (2003) ArticleTitleTricyclic antidepressants as long-acting local anesthetics Pain 103 49–55 Occurrence Handle10.1016/S0304-3959(02)00375-5 Occurrence Handle1:CAS:528:DC%2BD3sXjs1Crs7s%3D Occurrence Handle12749958

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

Generous financial assistance from the Israel Ministry of Trade and Industry through the MAGNET Program, Consortium Pharmalogica, is acknowledged.

Author information

Authors and Affiliations

  1. Ilse Katz Center for Meso- and Nano-Scale Science and Technology, Ben Gurion University, Beer Sheva, 84105, Israel

    Marina Katz, Izek Ben-Shlush & Sofiya Kolusheva

  2. Department of Chemistry, Ben Gurion University, Beer Sheva, 84105, Israel

    Raz Jelinek

Authors
  1. Marina Katz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Izek Ben-Shlush
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sofiya Kolusheva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Raz Jelinek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raz Jelinek.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Katz, M., Ben-Shlush, I., Kolusheva, S. et al. Rapid Colorimetric Screening of Drug Interaction and Penetration Through Lipid Barriers. Pharm Res 23, 580–588 (2006). https://doi.org/10.1007/s11095-006-9569-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-006-9569-1

Key Words

Search

Navigation