title: Development of a novel therapeutic approach using a retinoic acid-loaded microneedle patch for seborrheic keratosis treatment and safety study in humans.
abstract: Seborrheic keratosis is one of the most common skin benign tumors in humans with a high occurrence rate of 80%-100% in people > 50 years of age; however, its pathogenesis is still unclear. The standard treatment includes cryotherapy and laser surgery for physically removing lesions. Drug therapy for this condition has not been well established. We aimed to evaluate the use of all-trans retinoic acid (ATRA)-loaded microneedle (MN) patches as a simple, alternative therapeutic option to traditional surgical treatments. This therapeutic strategy was designed to induce the proliferation of basal keratinocytes and accelerate stratum corneum turnover, leading to the lesion falling off the surface of the skin. The MN patch induced epidermal hyperplasia and marked expression of heparin-binding epidermal growth factor-like growth factor mRNA and protein corresponding to ATRA activity in the skin of HR-1 hairless mice. The acceleration of stratum corneum turnover was also observed by the dansyl chloride method. The skin irritation study in mice and safety study in humans support the safety findings of our study. Overall, MN patches can offer an effective and safe means of ATRA delivery into the skin, and the ATRA-loaded MN patch appears to be an effective pharmaceutical product providing a novel therapeutic option for seborrheic keratosis.
authors.affiliation: Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hiraishi
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirobe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iioka
authors.forename: Ying-Shu
authors.initials: YS
authors.lastname: Quan
authors.forename: Fumio
authors.initials: F
authors.lastname: Kamiyama
authors.forename: Hideo
authors.initials: H
authors.lastname: Asada
authors.forename: Naoki
authors.initials: N
authors.lastname: Okada
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Nakagawa
mesh_terms: D000328:Adult; D000818:Animals; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D003879:Dermatologic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016503:Drug Delivery Systems; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D017492:Keratosis, Seborrheic / Q000188:drug therapy; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008845:Microinjections; D008875:Middle Aged; D009339:Needles; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D023422:Skin Irritancy Tests; D057968:Transdermal Patch; D014212:Tretinoin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D016207:Cytokines; D003879:Dermatologic Agents; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; D003094:Collagen
keywords: ATRA; All-trans retinoic acid; CRABPII; CT; EGFR; EVG; Elastica van Gieson; FGFR3; GAPDH; HB-EGF; HE; HSD; Heparin-binding epidermal growth factor-like growth factor; ICDRG; IL-1β; IL-6; International Contact Dermatitis Research Group; MN; Microneedle; SCT; SK; Seborrheic keratosis; Stratum corneum turnover; TNF-α; UV; all-trans retinoic acid; cellular retinoic acid binding protein II; epidermal growth factor receptor; glyceraldehyde-3-phosphate dehydrogenase; hematoxylin and eosin; heparin-binding epidermal growth factor-like growth factor; honestly significant difference; interleukin-1β; interleukin-6; microneedle; seborrheic keratosis; somatic fibroblast growth factor receptor 3; stratum corneum turnover; threshold cycle number; tumor necrosis factor-α; ultraviolet