Enhanced Topical and Transdermal Delivery of Antineoplastic and Antiviral Acyclic Nucleoside Phosphonate cPr-PMEDAP
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.
In vitro diffusion of cPr-PMEDAP was investigated using formulations at different pH and concentration and with permeation enhancer through porcine and human skin.
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.
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 WORDSacyclic nucleoside phosphonates antineoplastics antivirals permeation enhancer topical skin application transdermal delivery
Hanks balanced salt solution
- 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
- 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
- 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
- 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