Transdermal Delivery and Cutaneous Targeting of Antivirals using a Penetration Enhancer and Lysolipid Prodrugs
In this work, we investigate prodrug and enhancer approaches for transdermal and topical delivery of antiviral drugs belonging to the 2,6-diaminopurine acyclic nucleoside phosphonate (ANP) group. Our question was whether we can differentiate between transdermal and topical delivery, i.e., to control the delivery of a given drug towards either systemic absorption or retention in the skin.
The in vitro transdermal delivery and skin concentrations of seven antivirals, including (R)- and (S)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine ((S)-HPMPDAP), its 8-aza analog, and their cyclic and hexadecyloxypropyl (HDP) prodrugs, was investigated with and without the penetration enhancer dodecyl-6-(dimethylamino)hexanoate (DDAK) using human skin.
The ability of ANPs to cross the human skin barrier was very low (0.5–1.4 nmol/cm2/h), and the majority of the compounds were found in the stratum corneum, the uppermost skin layer. The combination of antivirals and the penetration enhancer DDAK proved to be a viable approach for transdermal delivery, especially in case of (R)-PMPDAP, an anti-HIV effective drug (30.2 ± 2.3 nmol/cm2/h). On the other hand, lysophospholipid-like HDP prodrugs, e.g., HDP-(S)-HPMPDAP, reached high concentrations in viable epidermis without significant systemic absorption.
By using penetration enhancers or lysolipid prodrugs, it is possible to effectively target systemic diseases by the transdermal route or to target cutaneous pathologies by topical delivery.
KEY WORDSacyclic nucleoside phosphonate antivirals lysolipid prodrug penetration enhancer skin absorption transdermal drug delivery
acyclic nucleoside phosphonate
dodecyl ester of 6-(dimethylamino)hexanoic acid
hydrophilic interaction liquid chromatography
human immunodeficiency virus
hexadecyloxypropyl ester of (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine
hexadecyloxypropyl ester of (R)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine
high-performance liquid chromatography
herpes simplex virus
- 18.Balzarini J, Aquaro S, Perno CF, Witvrouw M, Holy A, De Clercq E. Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)-adenine and 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine against human immunodeficiency virus in different human cell systems. Biochem Biophys Res Commun. 1996;219:337–41.PubMedCrossRefGoogle Scholar
- 19.Balzarini J, Holy A, Jindrich J, Naesens L, Snoeck R, Schols D, et al. Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine. Antimicrob Agents Chemother. 1993;37:332–8.PubMedCentralPubMedCrossRefGoogle Scholar
- 22.Krecmerova M, Jansa P, Dracinsky M, Sazelova P, Kasicka V, Neyts J, et al. 9-[2-(R)-(Phosphonomethoxy)propyl]-2,6-diaminopurine (R)-PMPDAP and its prodrugs: Optimized preparation, including identification of by-products formed, and antiviral evaluation in vitro. Bioorg Med Chem. 2013;21:1199–208.PubMedCrossRefGoogle Scholar
- 33.Dal Pozzo F, Andrei G, Holy A, Van Den Oord J, Scagliarini A, De Clercq E, et al. Activities of acyclic nucleoside phosphonates against Orf virus in human and ovine cell monolayers and organotypic ovine raft cultures. Antimicrob Agents Chemother. 2005;49:4843–52.PubMedCentralPubMedCrossRefGoogle Scholar