Pharmaceutical Research

, Volume 28, Issue 12, pp 3105–3115 | Cite as

Enhanced Topical and Transdermal Delivery of Antineoplastic and Antiviral Acyclic Nucleoside Phosphonate cPr-PMEDAP

  • Kateřina Vávrová
  • Petra Kovaříková
  • Barbora Školová
  • Martina Líbalová
  • Jaroslav Roh
  • Robert Čáp
  • Antonín Holý
  • Alexandr Hrabálek
Research Paper

ABSTRACT

Purpose

Acyclic nucleoside phosphonates possess unique antiviral and antineoplastic activities; however, their polar phosphonate moiety is associated with low ability to cross biological membranes. We explored the potential of transdermal and topical delivery of 2,6-diaminopurine derivative cPr-PMEDAP.

Methods

In vitro diffusion of cPr-PMEDAP was investigated using formulations at different pH and concentration and with permeation enhancer through porcine and human skin.

Results

Ability of 0.1–5% cPr-PMEDAP to cross human skin barrier was very low with flux values ~40 ng/cm2/h, the majority of compound found in the stratum corneum. The highest permeation rates were found at pH 6; increased donor concentration had no influence. The permeation enhancer dodecyl 6-dimethylaminohexanoate (DDAK, 1%) increased flux of cPr-PMEDAP (up to 61 times) and its concentration in nucleated epidermis (up to ~0.5 mg of cPr-PMEDAP/g of the tissue). No deamination of cPr-PMEDAP into PMEG occurred during permeation studies, but N-dealkylation into PMEDAP mediated by skin microflora was observed.

Conclusions

Transdermal or topical application of cPr-PMEDAP enabled by the permeation enhancer DDAK may provide an attractive alternative route of administration of this potent antitumor and antiviral compound.

KEY WORDS

acyclic nucleoside phosphonates antineoplastics antivirals permeation enhancer topical skin application transdermal delivery 

ABBREVIATIONS

cPr-PMEDAP

N6-cyclopropyl-2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine

DDAK

dodecyl 6-dimethylaminohexanoate

HBSS

Hanks balanced salt solution

PBS

phosphate-buffered saline

PMEDAP

2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine

PMEG

9-[2-(phosphonomethoxy)ethyl]guanine

REFERENCES

  1. 1.
    Holy A. Phosphonomethoxyalkyl analogs of nucleotides. Curr Pharm Des. 2003;9(31):2567–92.PubMedCrossRefGoogle Scholar
  2. 2.
    Kramata P, Downey KM, Paborsky LR. Incorporation and excision of 9-(2-phosphonylmethoxyethyl)guanine (PMEG) by DNA polymerase delta and epsilon in vitro. J Biol Chem. 1998;273(34):21966–71.PubMedCrossRefGoogle Scholar
  3. 3.
    Kramata P, Votruba I, Otova B, Holy A. Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases alpha, delta and epsilon. Mol Pharmacol. 1996;49(6):1005–11.PubMedGoogle Scholar
  4. 4.
    Rose WC, Crosswell AR, Bronson JJ, Martin JC. In vivo antitumor activity of 9-[(2-phosphonylmethoxy)ethyl]-guanine and related phosphonate nucleotide analogues. J Natl Cancer Inst. 1990;82(6):510–2.PubMedCrossRefGoogle Scholar
  5. 5.
    Kreider JW, Balogh K, Olson RO, Martin JC. Treatment of latent rabbit and human papillomavirus infections with 9-(2-phosphonylmethoxy)ethylguanine (PMEG). Antiviral Res. 1990;14(1):51–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Compton ML, Toole JJ, Paborsky LR. 9-(2-Phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cpr-PMEDAP) as a prodrug of 9-(2-phosphonylmethoxyethyl)guanine (PMEG). Biochem Pharmacol. 1999;58(4):709–14.PubMedCrossRefGoogle Scholar
  7. 7.
    Hatse S, Naesens L, De Clercq E, Balzarini J. N6-cyclopropyl-PMEDAP: a novel derivative of 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) with distinct metabolic, antiproliferative, and differentiation-inducing properties. Biochem Pharmacol. 1999;58(2):311–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Holy A, Votruba I, Tloustova E, Masojidkova M. Synthesis and cytostatic activity of N-[2-(phosphonomethoxy)alkyl] derivatives of N-6-substituted adenines, 2,6-diaminopurines and related compounds. Collect Czech Chem Commun. 2001;66(10):1545–92.CrossRefGoogle Scholar
  9. 9.
    Naesens L, Hatse S, Segers C, Verbeken E, De Clercq E, Waer M, et al. 9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine: a novel prodrug of 9-(2-phosphonylmethoxyethyl)guanine with improved antitumor efficacy and selectivity in choriocarcinoma-bearing rats. Oncol Res. 1999;11(4):195–203.PubMedGoogle Scholar
  10. 10.
    Andrei G, Snoeck R, Piette J, Delvenne P, De Clercq E. Antiproliferative effects of acyclic nucleoside phosphonates on human papillomavirus (HPV)-harboring cell lines compared with HPV-negative cell lines. Oncol Res. 1998;10(10):523–31.PubMedGoogle Scholar
  11. 11.
    Schinkmanova M, Votruba I, Holy A. N6-methyl-AMP aminohydrolase activates N6-substituted purine acyclic nucleoside phosphonates. Biochem Pharmacol. 2006;71(9):1370–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Wolfgang GH, Shibata R, Wang J, Ray AS, Wu S, Doerrfler E, et al. GS-9191 is a novel topical prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl)guanine with antiproliferative activity and possible utility in the treatment of human papillomavirus lesions. Antimicrob Agents Chemother. 2009;53(7):2777–84.PubMedCrossRefGoogle Scholar
  13. 13.
    Vavrova K, Zbytovska J, Hrabalek A. Amphiphilic transdermal permeation enhancers: structure-activity relationships. Curr Med Chem. 2005;12(19):2273–91.PubMedCrossRefGoogle Scholar
  14. 14.
    Vavrova K, Lorencova K, Klimentova J, Novotny J, Holy AN, Hrabalek A. Transdermal and dermal delivery of adefovir: effects of pH and permeation enhancers. Eur J Pharm Biopharm. 2008;69(2):597–604.PubMedCrossRefGoogle Scholar
  15. 15.
    Vavrova K, Lorencova K, Novotny J, Holy A, Hrabalek A. Permeation enhancer dodecyl 6-(dimethylamino)hexanoate increases transdermal and topical delivery of adefovir: influence of pH, ion-pairing and skin species. Eur J Pharm Biopharm. 2008;70(3):901–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Hrabalek A, Dolezal P, Vavrova K, Zbytovska J, Holas T, Klimentova J, et al. Synthesis and enhancing effect of transkarbam 12 on the transdermal delivery of theophylline, clotrimazole, flobufen, and griseofulvin. Pharm Res. 2006;23(5):912–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Novotny M, Hrabalek A, Janusova B, Novotny J, Vavrova K. Transkarbams as transdermal permeation enhancers: effects of ester position and ammonium carbamate formation. Bioorg Med Chem Lett. 2010;20(9):2726–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Novotny M, Klimentova J, Janusova B, Palat K, Hrabalek A, Vavrova K. Ammonium carbamates as highly active transdermal permeation enhancers with a dual mechanism of action. J Control Release. 2011;150(2):164–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Novotny J, Kovarikova P, Novotny M, Janusova B, Hrabalek A, Vavrova K. Dimethylamino acid esters as biodegradable and reversible transdermal permeation enhancers: effects of linking chain length, chirality and polyfluorination. Pharm Res. 2009;26(4):811–21.PubMedCrossRefGoogle Scholar
  20. 20.
    Holy A, Rosenberg I. Acyclic Nucleotide Analogs. 3. Synthesis of 9-(2-Phosphonylmethoxyethyl)Adenine and Related-Compounds. Collect Czech Chem Commun. 1987;52(11):2801–9.CrossRefGoogle Scholar
  21. 21.
    Collier SW, Bronaugh RL. Cutaneous metabolism during percutaneous absorption. In: Muhktar H, editor. Pharmacology of the skin. London: CRC; 1992. p. 111–26.Google Scholar
  22. 22.
    Kiptoo PK, Hamad MO, Crooks PA, Stinchcomb AL. Enhancement of transdermal delivery of 6-beta-naltrexol via a codrug linked to hydroxybupropion. J Control Release. 2006;113(2):137–45.PubMedCrossRefGoogle Scholar
  23. 23.
    Kligman AM, Christophers E. Preparation of isolated sheets of human stratum corneum. Arch Dermatol. 1963;88:709–12.PubMedCrossRefGoogle Scholar
  24. 24.
    Vavrova K, Lorencova K, Klimentova J, Novotny J, Hrabalek A. HPLC method for determination of in vitro delivery through and into porcine skin of adefovir (PMEA). J Chromatogr B. 2007;853(1–2):198–203.CrossRefGoogle Scholar
  25. 25.
    Chen X, Xing J, Zhong D. Rearrangement process occurring in the fragmentation of adefovir derivatives. J Mass Spectrom. 2004;39(2):145–52.PubMedCrossRefGoogle Scholar
  26. 26.
    Janusova B, Zbytovska J, Lorenc P, Vavrysova H, Palat K, Hrabalek A, et al. Effect of ceramide acyl chain length on skin permeability and thermotropic phase behavior of model stratum corneum lipid membranes. Biochim Biophys Acta. 2011;1811(3):129–37.PubMedGoogle Scholar
  27. 27.
    Reiser H, Wang J, Chong L, Watkins WJ, Ray AS, Shibata R, et al. GS-9219—a novel acyclic nucleotide analogue with potent antineoplastic activity in dogs with spontaneous non-Hodgkin’s lymphoma. Clin Cancer Res. 2008;14(9):2824–32.PubMedCrossRefGoogle Scholar
  28. 28.
    Naesens L, Balzarini J, Rosenberg I, Holy A, De Clercq E. 9-(2-Phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP): a novel agent with anti-human immunodeficiency virus activity in vitro and potent anti-Moloney murine sarcoma virus activity in vivo. Eur J Clin Microbiol Infect Dis. 1989;8(12):1043–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Naesens L, Neyts J, Balzarini J, Holy A, Rosenberg I, De Clercq E. Efficacy of oral 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) in the treatment of retrovirus and cytomegalovirus infections in mice. J Med Virol. 1993;39(2):167–72.PubMedCrossRefGoogle Scholar
  30. 30.
    Bobkova K, Otova B, Marinov I, Mandys V, Panczak A, Votruba I, et al. Anticancer effect of PMEDAP—monitoring of apoptosis. Anticancer Res. 2000;20(2A):1041–7.PubMedGoogle Scholar
  31. 31.
    Bobkov K, Gut I, Mandys V, Holy A, Votruba I, Otova B. Antitumour activity of a combined treatment with PMEDAP and docetaxel in the Prague inbred Sprague-Dawley/cub rat strain bearing T-cell lymphoma. Anticancer Res. 2001;21(4A):2725–31.PubMedGoogle Scholar
  32. 32.
    Otova B, Francova K, Franek F, Koutnik P, Votruba I, Holy A, et al. 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP)—a potential drug against hematological malignancies—induces apoptosis. Anticancer Res. 1999;19(4B):3173–82.PubMedGoogle Scholar
  33. 33.
    Christensen ND, Pickel MD, Budgeon LR, Kreider JW. In vivo anti-papillomavirus activity of nucleoside analogues including cidofovir on CRPV-induced rabbit papillomas. Antiviral Res. 2000;48(2):131–42.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Kateřina Vávrová
    • 1
    • 2
    • 6
  • Petra Kovaříková
    • 3
  • Barbora Školová
    • 2
  • Martina Líbalová
    • 2
  • Jaroslav Roh
    • 2
  • Robert Čáp
    • 4
  • Antonín Holý
    • 5
  • Alexandr Hrabálek
    • 1
    • 2
  1. 1.Centre for New Antivirals and Antineoplastics Faculty of Pharmacy in Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic
  2. 2.Department of Inorganic and Organic Chemistry Faculty of Pharmacy in Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic
  3. 3.Department of Pharmaceutical Chemistry and Drug Control Faculty of Pharmacy in Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic
  4. 4.Clinics of Surgery, University HospitalHradec KrálovéCzech Republic
  5. 5.Centre for New Antivirals and AntineoplasticsInstitute of Organic Chemistry & Biochemistry AS CR, v.v.i.PragueCzech Republic
  6. 6.Charles University in Prague, Faculty of Pharmacy Hradec KrálovéHradec KrálovéCzech Republic

Personalised recommendations