ABSTRACT
Purpose
To evaluate skin permeation enhancement mediated by fractional laser for different permeants, including hydroquinone, imiquimod, fluorescein isothiocyanate-labeled dextran (FD), and quantum dots.
Methods
Skin received a single irradiation of a fractional CO2 laser, using fluence of 2 or 4 mJ with densities of 100 ∼ 400 spots/cm2. In vitro and in vivo skin penetration experiments were performed. Fluorescence and confocal microscopies for imaging delivery pathways were used.
Results
The laser enhanced flux of small-molecule drugs 2 ∼ 5-fold compared to intact skin. A laser fluence of 4 mJ with a 400-spot/cm2 density promoted FD flux at 20 and 40 kDa from 0 (passive transport) to 0.72 and 0.43 nmol/cm2/h, respectively. Microscopic images demonstrated a significant increase in fluorescence accumulation and penetration depth of macromolecules and nanoparticles after laser exposure. Predominant routes for laser-assisted delivery may be intercellular and follicular transport. CO2 laser irradiation produced 13-fold enhancement in follicular deposition of imiquimod. Laser-mediated follicular transport could deliver permeants to deeper strata. Skin barrier function as determined by transepidermal water loss completely recovered by 12 h after irradiation, much faster than conventional laser treatment (4 days).
Conclusions
Fractional laser could selectively enhance permeant targeting to follicles such as imiquimod and FD but not hydroquinone, indicating the importance of selecting feasible drugs for laser-assisted follicle delivery.
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REFERENCES
Davidson A, Al-Qallaf B, Das DB. Transdermal drug delivery by coated microneedles: geometry effects on effective skin thickness and drug permeability. Chem Eng Res Des. 2008;86:1196–206.
Lee WR, Shen SC, Fang CL, Zhuo RZ, Fang JY. Topical delivery of methotrexate via skin pretreated with physical enhancement techniques: low-fluence erbium:YAG laser and electroporation. Lasers Surg Med. 2008;40:468–76.
Gómez C, Costela Á, Garćia-Moreno I, Llanes F, Teijón JM, Blance D. Laser treatments on skin enhancing and controlling transdermal delivery of 5-fluorouracil. Lasers Surg Med. 2008;40:6–12.
Pan TL, Wang PW, Lee WR, Fang CL, Chen CC, Huang CM, et al. Systematic evaluations of skin damage irradiated by an erbium:YAG laser: histopathologic analysis, proteomic profiles, and cellular response. J Dermatol Sci. 2010;58:8–18.
Tsai TH, Jee SH, Chan JY, Lee JN, Lee WR, Dong CY, et al. Visualizing laser-skin interaction in vivo by multiphoton microscopy. J Biomed Opt. 2009;14:024034.
Lee WR, Shen SC, Wang KH, Hu CH, Fang JY. The Effect of laser treatment on skin to enhance and control transdermal delivery of 5-fluorouracil. J Pharm Sci. 2002;91:1613–26.
Haak CS, Illes M, Paasch U, Hædersdal M. Histological evaluation of vertical laser channels from ablative fractional resurfacing: an ex vivo pig skin model. Lasers Med Sci. 2011;26:465–71.
Allemann IB, Kaufman J. Fractional photothermolysis – an update. Lasers Med Sci. 2010;25:137–44.
Carniol PJ, Harirchian S, Kelly E. Fractional CO2 laser resurfacing. Facial Plast Surg Clin N Am. 2011;19:247–51.
Rendon MI, Gaviria JI. Review of skin-lightening agents. Dermatol Surg. 2005;31:886–9.
Metcalf S, Crowson AN, Naylor M, Haque R, Cornelison R. Imiquimod as an antiaging agent. J Am Acad Dermatol. 2007;56:422–5.
Kalluri H, Banga AK. Transdermal delivery of proteins. AAPS PharmSciTech. 2011;12:431–41.
Chiu TM, Huang CC, Lin TJ, Fang JY, Wu NL, Hung CF. In vitro and in vivo anti-photoaging effects of an isoflavone extract from soybean cake. J Ethnopharmacol. 2009;126:108–13.
Lee WR, Shen SC, Al-Suwayeh SA, Yang HH, Yuan CY, Fang JY. Laser-assisted topical drug delivery by using a low-fluence fractional laser: imiquimod and macromolecules. J Control Release. 2011;153:240–8.
Hsieh PW, Al-Suwayeh SA, Fang CL, Lin CF, Chen CC, Fang JY. The co-drug of conjugated hydroquinone and azelaic acid to enhance topical skin targeting and decrease penetration through the skin. Eur J Pharm Biopharm. 2012;81:369–78.
Teichmann A, Jacobi U, Ossadnik M, Richter H, Koch S, Sterry W, et al. Differential stripping: determination of the amount of topically applied substances penetrated into the hair follicles. J Invest Dermatol. 2005;125:264–9.
Chen X, Shah D, Kositratna G, Manstein D, Anderson RR, Wu MX. Facilitation of transcutaneous drug delivery and vaccine immunization by a safe laser technology. J Control Release. 2012;159:43–51.
Lee S, McAuliffe DJ, Flotte TJ, Kollias N, Doukas AG. Photomechanical transdermal delivery: the effect of laser confinement. Lasers Surg Med. 2001;28:344–7.
Donnelly RF, Morrow DIJ, McCarron PA, Woolfson AD, Morrissey A, Juzenas P, et al. Microneedle-mediated intradermal delivery of 5-aminolevulinic acid: potential for enhanced topical photodynamic therapy. J Control Release. 2008;129:154–62.
Lee WR, Shen SC, Lai HH, Hu CH, Fang JY. Transdermal drug delivery enhanced and controlled by erbium:YAG laser: a comparative study of lipophilic and hydrophilic drugs. J Control Release. 2001;75:155–66.
Cao D, Kitamura T, Todo H, Yoo SD, Sugibayashi K. Pretreatment effects of maxibustion on the skin permeation of FITC-dextran. Int J Pharm. 2008;354:117–25.
Maeba S, Otake S, Namikoshi J, Shibata Y, Hayakawa M, Abiko Y, et al. Transcutaneous immunization with a 40-kDa outer membrane protein of Porphyromonas gingivalis induces specific antibodies which inhibit coaggregation by P. gingivalis. Vaccine. 2005;23:2513–21.
Lanke SSS, Kolli CS, Strom JG, Banga AK. Enhanced transdermal delivery of low molecular weight heparin by barrier perturbation. Int J Pharm. 2009;365:26–33.
Lee WR, Shen SC, Pai MH, Yang HH, Yuan CY, Fang JY. Fractional laser as a tool to enhance the skin permeation of 5-aminolevulinic acid with minimal skin disruption: a comparison with conventional erbium:YAG laser. J Control Release. 2010;145:124–33.
Lombry C, Dujardin N, Préat V. Transdermal delivery of macromolecules using skin electroporation. Pharm Res. 2000;17:32–7.
Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26:1261–8.
Yoo KH, Lee JW, Li K, Kim BJ, Kim MN. Photodynamic therapy with methyl 5-aminolevulinate acid might be ineffective in recalcitrant alopecia totalis regardless of using a microneedle roller to increase skin penetration. Dermatol Surg. 2010;36:618–22.
Schön MP, Schön M. Imiquimod: mode of action. Br J Dermatol. 2007;157 Suppl 2:8–13.
Swanson N, Abramovits W, Berman B, Kulp J, Rigel DS, Levy S. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol. 2010;62:582–90.
Bachhav YG, Heinrich A, Kalia YN. Using laser microporation to improve transdermal delivery of diclofenac: increasing bioavailability and the range of therapeutic applications. Eur J Pharm Biopharm. 2011;78:408–14.
Imura Y, Choda N, Matsuzaki K. Magainin 2 in action: distinct modes of membrane permeabilization in living bacterial and mammalian cells. Biophys J. 2008;95:5757–65.
Otberg N, Richter H, Schaefer H, Blume-Peytavi U, Sterry W, Lademann J. Variations of hair follicle size and distribution in different body sites. J Invest Dermatol. 2004;122:14–9.
Lademann J, Otberg N, Richter H, Weigmann HJ, Lindemann U, Schaefer H, et al. Investigation of follicular penetration of topically applied substances. Skin Pharmacol Physiol. 2001;14 Suppl 1:17–22.
Fang JY, Lee WR, Shen SC, Wang HY, Fang CL, Hu CH. Transdermal delivery of macromolecules by erbium:YAG laser. J Control Release. 2004;100:75–85.
Shim J, Kang HS, Park WS, Han SH, Kim J, Chang IS. Transdermal delivery of minoxidil with block copolymer nanoparticles. J Control Release. 2004;97:477–84.
Otberg N, Petzelt A, Rasulev U, Hagemeister T, Linscheid M, Sinkgraven R, et al. The role of hair follicles in the percutaneous absorption of caffeine. Br J Clin Pharmacol. 2007;65:488–92.
Jeong SH, Kim JH, Yi SM, Lee JP, Kim JH, Sohn KH, et al. Assessment of penetration of quantum dots through in vitro and in vivo human skin using the human skin equivalent model and the tape stripping method. Biochem Biophys Res Comm. 2010;394:612–5.
Gratieri T, Schaefer UF, Jing L, Gao M, Kostka KH, Lopez RFV, et al. Penetration of quantum dot particles through human skin. J Biomed Nanotechnol. 2010;6:586–95.
Zhang LW, Monteiro-Riviere NA. Assessment of quantum dot penetration into intact, tape-stripped, abraded and flexed rat skin. Skin Pharmacol Physiol. 2008;21:166–80.
Lademann J, Richter H, Teichmann A, Otberg N, Blume-Peytavi U, Luengo J, et al. Nanoparticles – an efficient carrier for drug delivery into the hair follicles. Eur J Pharm Biopharm. 2007;66:159–64.
Honma Y, Arai I, Sakurai T, Futaki N, Hashimoto Y, Sugimoto M, et al. Effects of indomethacin and dexamethasone on mechanical scratching-induced cutaneous barrier disruption in mice. Exp Dermatol. 2006;15:501–8.
Goldberg DJ, Berlin AL, Phelps R. Histologic and ultrastructural analysis of melasma after fractional resurfacing. Lasers Surg Med. 2008;40:134–8.
ACKNOWLEDGMENTS AND DISCLOSURES
This project was supported by the National Plan for Science and Technology in the Kingdom of Saudi Arabia (grant number: 10-NAN1030-02).
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Lee, WR., Shen, SC., Al-Suwayeh, S.A. et al. Skin Permeation of Small-Molecule Drugs, Macromolecules, and Nanoparticles Mediated by a Fractional Carbon Dioxide Laser: The Role of Hair Follicles. Pharm Res 30, 792–802 (2013). https://doi.org/10.1007/s11095-012-0920-4
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DOI: https://doi.org/10.1007/s11095-012-0920-4