MDI 301, a nonirritating retinoid, improves abrasion wound healing in damaged/atrophic skin

Abstract

MDI 301 is a picolinic acid-substituted ester of 9-cis retinoic acid. It has been shown in the past that MDI 301 increases epidermal thickness, decreases matrix metalloproteinase (MMP) activity, and increases procollagen synthesis in organ-cultured human skin. Unlike all-trans retinoic acid (RA), MDI 301 does not induce expression of proinflammatory cytokines or induce expression of leukocyte adhesion molecules in human skin. In the present study we examined topical MDI 301 treatment for ability to improve the structure and function of skin in three models of skin damage in rodents and for ability to improve abrasion wound healing in these models. MDI 301 was applied daily to the skin of rats treated with the potent corticosteroid, clobetasol propionate, to the skin of diabetic rats (8 weeks posttreatment with streptozotocin) and to the skin of aged (14-16-month-old) rats. In all three models, subsequently induced abrasion wounds healed more rapidly in the retinoid-treated animals than in vehicle-treated controls. Immediately after complete wound closure, tissue from the wound site (as well as from a control site) was put into organ culture and maintained for 3 days. At the end of the incubation period, culture fluids were assessed for soluble type I collagen and for MMPs-2 and -9. In all three models, the level of type I collagen was increased and MMP levels were decreased by MDI 301. In all three models, skin irritation during the retinoid-treatment phase was virtually nonexistent.Minor abrasions that occur in healthy skin are expected to heal without incident. Interventions are designed primarily to prevent infection and to provide support for the body's own regenerative mechanisms. In contrast, wounds in chronically damaged and atrophic skin often go on to form nonhealing ulcers with devastating consequences. Diabetes alone is a contributing factor in up to 70% of the > 55,000 amputations that occur annually. [1][2][3][4] Skin that has become atrophic as a consequence of the aging process also demonstrates impaired wound healing, 5-7 as does skin that has been damaged as a result of extended corticosteroid use. [8][9][10] The majority of wound-healing research is directed toward understanding the pathophysiology of impaired wound healing and identifying interventions that can mitigate the critical patho-physiological events.Several past studies have demonstrated the efficacy of all-trans retinoic acid (RA) and its parent compound all-trans retinol (ROL, vitamin A) in wound healing. Although most studies have focused on wounds in the skin, [11][12][13][14][15][16][17] retinoid efficacy has also been demonstrated in healing of wounds in other tissues (bone, cornea, respiratory tract, upper digestive system, and gut). 27 Likewise, skin irritation is also a complication with synthetic retinoidal agents currently on the market. 28 Irritation is a major cause of non-compliance among retinoid users. In addition, excessive irritation may counteract the beneficial effects of retinoid use or actually predispo...

MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy

“…Rodents treated with MDI 301 showed little evidence of skin irritation during the 14-day treatment regimen. Not unexpectedly (and consistent with past reports), ATRA was highly irritating under the same conditions [30,31]. When the two retinoids were compared in human skin organ culture, ATRA induced elaboration of several proinflammatory cytokines (IL-6, IL-8, MCP-1, and GRO-α, among others).…”

“…Comparison of all-trans retinoic acid and MDI 301 for inhibition of tumor cell proliferation in vitro MDI 301 has shown potential as a nonirritating skinrepair agent [29][30][31][32][33], but its capacity to reduce growth in myeloid leukemia cells has not yet been established. To determine how the experimental retinoid might compare with ATRA as an anticancer agent for this disease, we carried out a series of in-vitro studies in which four different myeloid leukemia cell lines were treated with either ATRA or MDI 301 over a range of concentrations.…”

“…To summarize past studies, hairless rats treated daily with topical MDI 301 for 14 days showed increased collagen deposition and decreased matrix metalloproteinase (MMP) levels in the treated skin [31]. When abrasion wounds were subsequently created in the treated skin, the wounds healed more rapidly than similar wounds in control skin.…”

“…Studies carried out in rodents [30,31], Gottingen minipigs [32], and human skin organ culture [29,33] have shown that MDI 301 is similar to ATRA in terms of skin-repair efficacy, but induces much less skin irritation. In human skin organ culture, MDI 301 does not upregulate proinflammatory cytokines or alter adhesion factor expression, in contrast to what is observed with ATRA [28,29].…”

Cytokeratins 16 and 10 bind to retinoic acid covalently in skin tissue of mice

“…[23][24][25][26][27] To generate RA-treated mice, 0AE1% RA (Sigma Chemical Co., St Louis, MO, U.S.A.) dissolved in DMSO (Sigma) (10 lL cm )2 ) was administered topically to mouse skins dorsally as described previously. 25 The administration of agents was carried out daily for 1 week. Animal experiments were performed according to ethical guidelines established by the University Institutional Animal Care and Use Committee.…”