title: Non-ablative fractional laser assists cutaneous delivery of small- and macro-molecules with minimal bacterial infection risk.
abstract: Use of the ablative laser has been approved to enhance topical drug penetration. Investigation into the usefulness of the non-ablative laser for assisting drug delivery is very limited. In this study, we explored the safety and efficacy of the non-ablative fractional erbium:glass (Er:glass) laser as an enhancement approach to promote drug permeation. Both pig and nude mouse skins were employed as transport barriers. We histologically examined the skin structure after laser exposure. The permeants of 5-aminolevulinic acid (ALA), imiquimod, tretinoin, peptide, dextrans and quantum dots (QD) were used to evaluate in vitro and in vivo skin passage. The fractional laser selectively created an array of photothermal dots deep into the dermis with the preservation of the stratum corneum and epidermis. The barrier function of the skin could be recovered 8-60h post-irradiation depending on the laser spot densities. The application of the laser caused no local infection of Staphylococcus aureus and Pseudomonas aeruginosa. Compared to intact skin, ALA flux was enhanced up to 1200-fold after laser exposure. The penetration enhancement level by the laser was decreased following the increase of permeant lipophilicity. The skin accumulation of tretinoin, an extremely lipophilic drug, showed only a 2-fold elevation by laser irradiation. The laser promoted peptide penetration 10-fold compared to the control skin. Skin delivery of dextrans with a molecular weight (MW) of at least 40kDa could be achieved with the Er:glass laser. QD with a diameter of 20nm penetrated into the skin with the assistance of the non-ablative laser. The confocal microscopic images indicated the perpendicular and lateral diffusions of dextrans and nanoparticles via laser-created microscopic thermal zones. Controlled Er:glass laser irradiation offers a valid enhancement strategy to topically administer the permeants with a wide MW and lipophilicity range.
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Department of Dermatology, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan.
authors.forename: Woan-Ruoh
authors.initials: WR
authors.lastname: Lee
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shing-Chuan
authors.initials: SC
authors.lastname: Shen
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Aljuffali
authors.affiliation: School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan.
authors.forename: Yin-Ku
authors.initials: YK
authors.lastname: Lin
authors.affiliation: Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Chang-Wei
authors.initials: CW
authors.lastname: Huang
authors.affiliation: Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan. Electronic address: fajy@mail.cgu.edu.tw.
authors.forename: Jia-You
authors.initials: JY
authors.lastname: Fang
mesh_terms: D000279:Administration, Cutaneous; D000622:Aminolevulinic Acid / Q000493:pharmacokinetics; D000634:Aminoquinolines / Q000493:pharmacokinetics; D000818:Animals; D003911:Dextrans / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D019793:Fluorescein / Q000737:chemistry; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000077271:Imiquimod; D053844:Lasers, Solid-State; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010455:Peptides / Q000493:pharmacokinetics; D011552:Pseudomonas Infections / Q000517:prevention & control; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D045663:Quantum Dots; D012867:Skin / Q000378:metabolism / Q000382:microbiology; D012869:Skin Absorption; D013203:Staphylococcal Infections / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000302:isolation & purification; D013552:Swine; D014212:Tretinoin / Q000493:pharmacokinetics
chemical_list: D000634:Aminoquinolines; D003911:Dextrans; D010455:Peptides; C015219:fluorescein isothiocyanate dextran; D014212:Tretinoin; D000622:Aminolevulinic Acid; D016650:Fluorescein-5-isothiocyanate; D000077271:Imiquimod; D019793:Fluorescein
keywords: Cutaneous delivery; Macromolecule; Nanoparticle; Non-ablative fractional laser; Small-molecule drug