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Levels of sirolimus in saliva and blood following oral topical sustained-release varnish delivery system application

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Abstract

Purpose

Sirolimus (rapamycin) is a mammalian target of rapamycin pathway blocker. The efficacy of sirolimus is currently studied for its antiproliferative properties in various malignancies and particularly in squamous cell carcinoma and other oral disorders. Topical application at the oral cavity can augment sirolimus availability at the site of action by increasing sirolimus levels in saliva and hence efficacy, along with improved safety (low levels in the blood to avoid side effects) and compliance. Our purpose was to evaluate the release profile and safety of a topical sirolimus sustained-release varnish drug delivery system.

Subjects and methods

Sirolimus sustained-release varnish drug delivery system containing a total of 0.5 mg of the drug was applied to nine healthy male volunteers. Saliva and blood levels were determined utilizing mass spectrometry and chemiluminescent microparticle immunoassay, respectively. The prolonged release profile and safety were evaluated for the oral topical delivery system.

Results

After the application of the drug delivery system, a sustained-release profile was observed in the oral cavity. We have measured moderate sirolimus levels for up to 12 h. The safety was confirmed, and systemic sirolimus blood levels were negligible.

Conclusions

After an application of sirolimus sustained-release varnish drug delivery system, prolonged drug levels can be achieved in the saliva. The oral topical sirolimus concentrations were potentially therapeutic along with minimal systemic exposure. These results broaden the potential clinical use of sustained-release oral topical rapalogs.

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References

  1. Porta C, Paglino C, Mosca A (2014) Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 4:64. doi:10.3389/fonc.2014.00064

    Article  PubMed Central  PubMed  Google Scholar 

  2. Bose P, Brockton NT, Dort JC (2013) Head and neck cancer: from anatomy to biology. Int J Cancer 133(9):2013–2023. doi:10.1002/ijc.28112

    Article  CAS  PubMed  Google Scholar 

  3. Czerninski R, Amornphimoltham P, Patel V, Molinolo AA, Gutkind JS (2009) Targeting mammalian target of rapamycin by rapamycin prevents tumor progression in an oral-specific chemical carcinogenesis model. Cancer Prev Res 2(1):27–36. doi:10.1158/1940-6207.CAPR-08-0147

    Article  CAS  Google Scholar 

  4. Fruman DA, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13(2):140–156. doi:10.1038/nrd4204

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Scully C, Bagan J (2009) Oral squamous cell carcinoma: overview of current understanding of aetiopathogenesis and clinical implications. Oral Dis 15(6):388–399. doi:10.1111/j.1601-0825.2009.01563.x

    Article  CAS  PubMed  Google Scholar 

  6. ClinicalTrails.gov. Rapamycin therapy in head and neck squamous cell carcinoma. https://clinicaltrials.gov/ct2/show/NCT01195922?term=%22sirolimus%22+And+%22head+and+neck%22&rank=2. Accessed Nov 2014

  7. de Oliveira MA, Martins EMF, Wang Q, Sonis S, Demetri G, George S, Butrynski J, Treister NS (2011) Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol 47(10):998–1003. doi:10.1016/j.oraloncology.2011.08.009

    Article  PubMed  Google Scholar 

  8. Friedman M, Steinberg D (1990) Sustained-release delivery systems for treatment of dental diseases. Pharm Res 7(4):313–317

    Article  CAS  PubMed  Google Scholar 

  9. Steinberg D, Tal T, Friedman M (2006) Sustained-release delivery systems of triclosan for treatment of Streptococcus mutans biofilm. J Biomed Mater Res B Appl Biomater 77(2):282–286

    Article  PubMed  Google Scholar 

  10. Madke B (2013) Topical rapamycin (sirolimus) for facial angiofibromas. Indian Dermatol Online J 4(1):54–57. doi:10.4103/2229-5178.105488

    Article  PubMed Central  PubMed  Google Scholar 

  11. Kremer M, Sliva K, Klemke CD, Schnierle BS (2010) Cutaneous T-cell lymphoma cells are sensitive to rapamycin. Exp Dermatol 19(9):800–805. doi:10.1111/j.1600-0625.2010.01102.x

    Article  CAS  PubMed  Google Scholar 

  12. Nguyen QD, Ibrahim MA, Watters A, Bittencourt M, Yohannan J, Sepah YJ, Dunn JP, Naor J, Shams N, Shaikh O, Leder HA, Do DV (2013) Ocular tolerability and efficacy of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis: primary 6-month results of the SAVE Study. J Ophthalmic Inflamm Infect 3(1):32. doi:10.1186/1869-5760-3-32

    Article  PubMed Central  PubMed  Google Scholar 

  13. Soria A, Agbo-Godeau S, Taieb A, Frances C (2009) Treatment of refractory oral erosive lichen planus with topical rapamycin: 7 cases. Dermatology 218(1):22–25. doi:10.1159/000172830

    Article  CAS  PubMed  Google Scholar 

  14. Alayev A, Holz MK (2013) mTOR signaling for biological control and cancer. J Cell Physiol 228(8):1658–1664. doi:10.1002/jcp.24351

    Article  CAS  PubMed  Google Scholar 

  15. Nguyen SA, Walker D, Gillespie MB, Gutkind JS, Day TA (2012) mTOR inhibitors and its role in the treatment of head and neck squamous cell carcinoma. Curr Treat Options Oncol 13(1):71–81. doi:10.1007/s11864-011-0180-2

    Article  PubMed  Google Scholar 

  16. Pallet N, Beaune P, Legendre C, Anglicheau D (2006) Rapamycine and mTOR inhibitors: from bench to bedside. Ann Biol Clin 64(2):107–115

    CAS  Google Scholar 

  17. Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A (2006) Interventions for treating oral leukoplakia. The Cochrane database of systematic reviews (4):CD001829. doi:10.1002/14651858.CD001829.pub3

  18. Khuri FR, Lee JJ, Lippman SM, Kim ES, Cooper JS, Benner SE, Winn R, Pajak TF, Williams B, Shenouda G, Hodson I, Fu K, Shin DM, Vokes EE, Feng L, Goepfert H, Hong WK (2006) Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients. J Natl Cancer Inst 98(7):441–450. doi:10.1093/jnci/djj091

    Article  CAS  PubMed  Google Scholar 

  19. Lippman SM, Lee JJ, Martin JW, El-Naggar AK, Xu X, Shin DM, Thomas M, Mao L, Fritsche HA Jr, Zhou X, Papadimitrakopoulou V, Khuri FR, Tran H, Clayman GL, Hittelman WN, Hong WK, Lotan R (2006) Fenretinide activity in retinoid-resistant oral leukoplakia. Clin Cancer Res 12(10):3109–3114. doi:10.1158/1078-0432.CCR-05-2636

    Article  CAS  PubMed  Google Scholar 

  20. Nudelman Z, Friedman M, Barasch D, Nemirovski A, Findler M, Pikovsky A, Gutkind J, Czerninski R (2014) Levels of sirolimus in saliva and blood following mouthwash application. Oral Dis. doi:10.1111/odi.12229

    PubMed  Google Scholar 

  21. Courtais C, Dupuy AM, Sophie Bargnoux A, Pageaux GP, Fegueux N, Mourad G, Cristol JP (2010) Evaluation of two sirolimus assays using the ARCHITECT-i1000((R)) CMIA or RxL((R)) ACMIA methods in comparison with the IMx((R)) MEIA method. Clin Chem Lab Med 48(10):1523–1525. doi:10.1515/CCLM.2010.288

    Article  CAS  PubMed  Google Scholar 

  22. ClinicalTrails.gov. Rapalogs in clinical trials for the treatment of oral squamous cell carcinoma. https://clinicaltrials.gov/ct2/results?term=%22Sirolimus%22+and+%22squamous+cell+carcinoma+%22&Search=Search. Accessed Nov 2014

  23. Iglesias-Bartolome R, Patel V, Cotrim A, Leelahavanichkul K, Molinolo AA, Mitchell JB, Gutkind JS (2012) mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell 11(3):401–414. doi:10.1016/j.stem.2012.06.007

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Coppock JD, Wieking BG, Molinolo AA, Gutkind JS, Miskimins WK, Lee JH (2013) Improved clearance during treatment of HPV-positive head and neck cancer through mTOR inhibition. Neoplasia 15(6):620–630

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Beyth N, Redlich M, Harari D, Friedman M, Steinberg D (2003) Effect of sustained-release chlorhexidine varnish on Streptococcus mutans and Actinomyces viscosus in orthodontic patients. Am J Orthod Dentofac Orthop 123(3):345–348. doi:10.1067/mod.2003.19

    Article  Google Scholar 

  26. Steinberg D, Rozen R, Klausner EA, Zachs B, Friedman M (2002) Formulation, development and characterization of sustained release varnishes containing amine and stannous fluorides. Caries Res 36(6):411–416. doi:10.1159/000066539

    Article  CAS  PubMed  Google Scholar 

  27. Czerninski R, Sivan S, Steinberg D, Gati I, Kagan L, Friedman M (2010) A novel sustained-release clotrimazole varnish for local treatment of oral candidiasis. Clin Oral Investig 14(1):71–78. doi:10.1007/s00784-009-0275-3

    Article  PubMed  Google Scholar 

  28. Nudelman Z, Keshet N, Elhalal MD, Friedman M, Czerninski R (2013) Levels of sirolimus in saliva vs. blood—the rationale of topical oral use for oral malignancy. Anticancer Res 33(2):661–663

    CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a Project Grant from the Israel Cancer Research Fund.

Ethical standard

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University, POB 12065, 91120, Jerusalem, Israel

    Zakhar Nudelman, David Kirmayer & Michael Friedman

  2. The Department of Oral Medicine, Hebrew University-Hadassah School of Dental Medicine, PO Box 12272, 91120, Jerusalem, Israel

    Mordechai Findler, Anna Pikovsky & Rakefet Czerninski

  3. Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University, POB 12065, 91120, Jerusalem, Israel

    Dinorah Barasch & Alina Nemirovski

  4. Laboratory Division, Hadassah Medical Center, Jerusalem, Israel

    Maamoun Basheer

  5. Oral and Pharyngeal Cancer Branch, National Institute of Craniofacial and Dental Research, NIH, Bethesda, MD, USA

    J. Silvio Gutkind

Authors
  1. Zakhar Nudelman
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  2. Mordechai Findler
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  3. Dinorah Barasch
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  4. Alina Nemirovski
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  5. Anna Pikovsky
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  6. David Kirmayer
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  7. Maamoun Basheer
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  8. J. Silvio Gutkind
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  9. Michael Friedman
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  10. Rakefet Czerninski
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Corresponding author

Correspondence to Rakefet Czerninski.

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Nudelman, Z., Findler, M., Barasch, D. et al. Levels of sirolimus in saliva and blood following oral topical sustained-release varnish delivery system application. Cancer Chemother Pharmacol 75, 969–974 (2015). https://doi.org/10.1007/s00280-015-2721-z

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  • DOI: https://doi.org/10.1007/s00280-015-2721-z

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