Skip to main content

Advertisement

Log in

Full depth measurement of tenofovir transport in rectal mucosa using confocal Raman spectroscopy and optical coherence tomography

Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

The prophylactic activity of antiretroviral drugs applied as microbicides against sexually transmitted HIV is dependent upon their concentrations in infectable host cells. Within mucosal sites of infection (e.g., vaginal and rectal mucosa), those cells exist primarily in the stromal layer of the tissue. Traditional pharmacokinetic studies of these drugs have been challenged by poor temporal and spatial specificity. Newer techniques to measure drug concentrations, involving Raman spectroscopy, have been limited by laser penetration depth into tissue. Utilizing confocal Raman spectroscopy (RS) in conjunction with optical coherence tomography (OCT), a new lateral imaging assay enabled concentration distributions to be imaged with spatial and temporal specificity throughout the full depth of a tissue specimen. The new methodology was applied in rectal tissue using a clinical rectal gel formulation of 1% tenofovir (TFV). Confocal RS revealed diffusion-like behavior of TFV through the tissue specimen, with significant partitioning of the drug at the interface between the stromal and adipose tissue layers. This has implications for drug delivery to infectable tissue sites. The new assay can be applied to rigorously analyze microbicide transport and delineate fundamental transport parameters of the drugs (released from a variety of delivery vehicles) throughout the mucosa, thus informing microbicide product design.

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

Access this article

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. Neves, Jd, Sarmento B. Drug delivery and development of anti-HIV microbicides: Pan Stanford; 2014.

  2. McGowan I. Rectal microbicides: a new focus for HIV prevention. Sex Transm Infect. 2008;84(6):413–7.

    Article  CAS  PubMed  Google Scholar 

  3. McGowan I, Cranston RD, Duffill K, Siegel A, Engstrom JC, Nikiforov A, et al. A phase 1 randomized, open label, rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of three formulations of tenofovir 1% gel (the CHARM-01 study). PLoS One. 2015;10(5):e0125363.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Leynaert B, Downs AM, de Vincenzi I, ESGoHTo HIV. Heterosexual transmission of human immunodeficiency virus: variability of infectivity throughout the course of infection. Am J Epidemiol. 1998;148(1):88–96.

    Article  CAS  PubMed  Google Scholar 

  5. Katz DF, Gao Y, Kang M. Using modeling to help understand vaginal microbicide functionality and create better products. Drug Deliv Transl Res. 2011;1(3):256–76.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Katz DF, Yuan A, Gao Y. Vaginal drug distribution modeling. Adv Drug Deliv Rev. 2015;92:2–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gao Y, Katz DF. Multicompartmental pharmacokinetic model of tenofovir delivery by a vaginal gel. PLoS One. 2013;8(9):e74404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gao Y, Katz DF. Multicompartmental pharmacokinetic model of tenofovir delivery to the rectal mucosa by an enema. PLoS One. 2017;12(1):e0167696.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gao Y, Yuan A, Chuchuen O, Ham A, Yang KH, Katz DF. Vaginal deployment and tenofovir delivery by microbicide gels. Drug Deliv Transl Res. 2015;5(3):279–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chuchuen O, Henderson MH, Sykes C, Kim MS, Kashuba AD, Katz DF. Quantitative analysis of microbicide concentrations in fluids, gels and tissues using confocal Raman spectroscopy. PLoS One. 2013;8(12):e85124.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329(5996):1168–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nel AM, Coplan P, Smythe SC, McCord K, Mitchnick M, Kaptur PE, et al. Pharmacokinetic assessment of dapivirine vaginal microbicide gel in healthy, HIV-negative women. AIDS Res Hum Retrovir. 2010;26(11):1181–90.

    Article  CAS  PubMed  Google Scholar 

  13. Hendrix CW, Chen BA, Guddera V, Hoesley C, Justman J, Nakabiito C, et al. MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments. PLoS One. 2013;8(1):e55013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schwartz JL, Rountree W, Kashuba AD, Brache V, Creinin MD, Poindexter A, et al. A multi-compartment, single and multiple dose pharmacokinetic study of the vaginal candidate microbicide 1% tenofovir gel. PLoS One. 2011;6(10):e25974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gao Y, Yuan A, Katz DF. Tenofovir diphosphate concentrations in human vaginal stroma after different dosage regimens with a vaginal gel: a modeling approach. AIDS Res Hum Retrovir. 2014;30(S1):A258–A9.

    Article  Google Scholar 

  16. Maher JR, Chuchuen O, Henderson MH, Kim S, Rinehart MT, Kashuba AD, et al. Co-localized confocal Raman spectroscopy and optical coherence tomography (CRS-OCT) for depth-resolved analyte detection in tissue. Biomed Opt Express. 2015;6(6):2022–35.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Squier CA, Mantz MJ, Schlievert PM, Davis CC. Porcine vagina ex vivo as a model for studying permeability and pathogenesis in mucosa. J Pharm Sci. 2008;97(1):9–21.

    Article  CAS  PubMed  Google Scholar 

  18. Patton DL, Thwin SS, Meier A, Hooton TM, Stapleton AE, Eschenbach DA. Epithelial cell layer thickness and immune cell populations in the normal human vagina at different stages of the menstrual cycle. Am J Obstet Gynecol. 2000;183(4):967–73.

    Article  CAS  PubMed  Google Scholar 

  19. Hussain L, Comparative LT. Investigation of Langerhans' cells and potential receptors for HIV in oral, genitourinary and rectal epithelia. Immunology. 1995;85(3):475–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Akil A, Devlin B, Cost M, Rohan LC. Increased dapivirine tissue accumulation through vaginal film codelivery of dapivirine and tenofovir. Mol Pharm. 2014;11(5):1533–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Balázs B, Sipos P, Danciu C, Avram S, Soica C, Dehelean C, et al. ATR-FTIR and Raman spectroscopic investigation of the electroporation-mediated transdermal delivery of a nanocarrier system containing an antitumour drug. Biomed Opt Express. 2016;7(1):67–78.

    Article  PubMed  Google Scholar 

  22. Chuchuen O, Maher JR, Simons MG, Peters JJ, Wax AP, Katz DF. Label-free measurements of tenofovir diffusion coefficients in a microbicide gel using Raman spectroscopy. J Pharm Sci. 2017;106(2):639–44.

    Article  CAS  PubMed  Google Scholar 

  23. Chuchuen O, Maher JR, Henderson MH, Desoto M, Rohan LC, Wax A, et al. Label-free analysis of tenofovir delivery to vaginal tissue using co-registered confocal Raman spectroscopy and optical coherence tomography. PLoS One. 2017;12(9):e0185633.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Fonner VA, Dalglish SL, Kennedy CE, Baggaley R, O’reilly KR, Koechlin FM, et al. Effectiveness and safety of oral HIV preexposure prophylaxis for all populations. AIDS (London, England). 2016;30(12):1973.

    Article  Google Scholar 

  25. AIDSinfo. Tenofovir (microbicide) [Web]. US Department of Health and Human Services; 2017 [updated May 2, 2017. Available from: https://aidsinfo.nih.gov/drugs/272/tenofovir--microbicide/0/professional.

  26. Bitterman W, Spencer RJ, Huizenga KA, Shorter RG. Contact pH of rectal mucosa in humans and dogs. Dis Colon rectum. 1969;12(2):96–8.

    Article  CAS  PubMed  Google Scholar 

  27. Hiruy H, Fuchs EJ, Marzinke MA, Bakshi RP, Breakey JC, Aung WS, et al. A phase 1 randomized, blinded comparison of the pharmacokinetics and colonic distribution of three candidate rectal microbicide formulations of tenofovir 1% gel with simulated unprotected sex (CHARM-02). AIDS Res Hum Retrovir. 2015;31(11):1098–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. McGowan I. Rectal microbicide development. Curr Opin HIV AIDS. 2012;7(6):526–33.

    Article  PubMed  Google Scholar 

  29. Krishnan R. Raman spectrum of quartz. Nature. 1945;155(3937):452.

    Article  CAS  Google Scholar 

  30. De Gelder J, De Gussem K, Vandenabeele P, Moens L. Reference database of Raman spectra of biological molecules. J Raman Spectrosc. 2007;38(9):1133–47.

    Article  Google Scholar 

  31. Berger AJ, Feld MS. Analytical method of estimating chemometric prediction error. Appl Spectrosc. 1997;51(5):725–32.

    Article  Google Scholar 

  32. Nejdfors P, Ekelund M, Jeppsson B, Weström BR. Mucosal in vitro permeability in the intestinal tract of the pig, the rat, and man: species- and region-related differences. Scand J Gastroenterol. 2000;35(5):501–7.

    Article  CAS  PubMed  Google Scholar 

  33. Bergholt MS, Zheng W, Ho KY, Teh M, Yeoh KG, So JBY, et al. Fiber-optic Raman spectroscopy probes gastric carcinogenesis in vivo at endoscopy. J Biophotonics. 2013;6(1):49–59.

    Article  CAS  PubMed  Google Scholar 

  34. Chuchuen O. Development and application of Raman spectroscopy-based assays for transport analysis of anti-HIV microbicides in gels and tissues 2015.

  35. Yang K-H, Hendrix C, Bumpus N, Elliott J, Tanner K, Mauck C, et al. A multi-compartment single and multiple dose pharmacokinetic comparison of rectally applied tenofovir 1% gel and oral tenofovir disoproxil fumarate. PLoS One. 2014;9(10):e106196.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Vitinghoff E, Douglas J, Judon F, McKiman D, MacQueen K, Buchinder SP. Per-contact risk of human immunodificiency virus transmission between male sexual partners. Am J Epidemiol. 1999;150(3):306–11.

    Article  Google Scholar 

  37. Preza GC, Tanner K, Elliott J, Yang OO, Anton PA, Ochoa M-T. Antigen-presenting cell candidates for HIV-1 transmission in human distal colonic mucosa defined by CD207 dendritic cells and CD209 macrophages. AIDS Res Hum Retrovir. 2014;30(3):241–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Van der Bijl P. Effect of freezing on the permeability of human buccal and vaginal mucosa. 1998.

  39. Gupta P, Ratner D, Patterson BK, Kulka K, Rohan LC, Parniak MA, et al. Use of frozen–thawed cervical tissues in the organ culture system to measure anti-HIV activities of candidate microbicides. AIDS Res Human Retrovir. 2006;22(5):419–24.

    Article  CAS  Google Scholar 

  40. Zidan AS, Habib MJ. Maximized mucoadhesion and skin permeation of anti-AIDS-loaded niosomal gels. J Pharm Sci. 2014;103(3):952–64.

    Article  CAS  PubMed  Google Scholar 

  41. McGowan I, Tanner K, Elliott J, Ibarrondo J, Khanukhova E, McDonald C, et al. Nonreproducibility of “snap-frozen” rectal biopsies for later use in ex vivo explant infectibility studies. AIDS Res Hum Retrovir. 2012;28(11):1509–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Deschout H, Raemdonck K, Demeester J, De Smedt SC, Braeckmans K. FRAP in pharmaceutical research: practical guidelines and applications in drug delivery. Pharm Res. 2014;31(2):255–70.

    Article  CAS  PubMed  Google Scholar 

  43. Seiffert S, Oppermann W. Systematic evaluation of FRAP experiments performed in a confocal laser scanning microscope. J Microsc. 2005;220(1):20–30.

    Article  CAS  PubMed  Google Scholar 

  44. Geonnotti AR, Furlow MJ, Wu T, DeSoto MG, Henderson MH, Kiser PF, et al. Measuring macrodiffusion coefficients in microbicide hydrogels via postphotoactivation scanning. Biomacromolecules. 2008;9(2):748–51.

    Article  CAS  PubMed  Google Scholar 

  45. Shattock RJ, Rosenberg Z. Microbicides: topical prevention against HIV. Cold Spring Harbor Perspec Med. 2012;2(2):a007385.

    Article  Google Scholar 

  46. Nunes R, Sarmento B, das Neves J. Formulation and delivery of anti-HIV rectal microbicides: advances and challenges. J Control Release. 2014;194:278–94.

    Article  CAS  PubMed  Google Scholar 

  47. Guilamo-Ramos V, Reading M, Bowman AS, Perlman DC, Barrett S. Multipurpose prevention technologies: a global sexual and reproductive health priority. J Assoc Nurses AIDS Care 2017.

Download references

Acknowledgements

We are grateful to Mrs. Jennifer Peters, Mr. Michael DeSoto, and Dr. Marcus Henderson (Duke University, Department of Biomedical Engineering) for their technical assistance and insight in this project. This work was supported by the National Institutes of Health [AI13127].

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David F. Katz.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflicts of interest, including no conflicting financial relationships with the National Institutes of Health, which sponsored this research under grant AI13127.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Presnell, A.L., Chuchuen, O., Simons, M.G. et al. Full depth measurement of tenofovir transport in rectal mucosa using confocal Raman spectroscopy and optical coherence tomography. Drug Deliv. and Transl. Res. 8, 843–852 (2018). https://doi.org/10.1007/s13346-018-0495-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-018-0495-7

Keywords

Navigation