Topical Proretinal Nanoparticles: Biological Activities, Epidermal Proliferation and Differentiation, Follicular Penetration, and Skin Tolerability.

Proretinal nanoparticles, the retinilidene-chitosan nanoparticles, have been developed to overcome the physicochemical instability of retinal and to lessen the dose-dependent cutaneous irritation, through sustaining the release of retinoid. Compared to conventional retinal at the same concentration, proretinal nanoparticles had no cytotoxicity and could induce a spontaneously immortalized human keratinocyte line to express more cellular retinoic acid binding protein-2. Compared to rats topically applied with conventional retinal which showed clear skin irritation and inflammation, daily topical application of proretinal nanoparticles to rats for 28 consecutive days produced neither irritation nor inflammation but significantly increased epidermal proliferation, epidermal thickness, cellular retinoic acid binding protein- 2 expression, and up-regulation of various differentiation markers including keratin 5, keratin 10, keratin 14, cellular retinoic acid binding protein-2, and proliferating cell nuclear antigen. Through the use of confocal laser scanning microscopy, we observed the in vivo follicular penetration of proretinal nanoparticles with the depth of penetration independent of postapplication time. Proretinal nanoparticles provide better biological activities of retinoids on epidermis and could eliminate the side effect of retinoid dermatitis.

Proretinal nanoparticles: stability, release, efficacy, and irritation.

Despite many potent biological activities, retinoids such as retinoic acid (RA) and retinal possess dose-related broad side effects. In this study, we show that this problem, which has been unsolvable for a long time, can be tackled through a controlled release strategy in which retinal is continuously delivered to the skin via sustained release from proretinal nanoparticles. The water dispersible proretinal nanoparticles are stable when kept in water at neutral pH and at room temperature for 8 months under light-proof conditions, and show sustained release of retinal into human synthetic sebum at a pH of 5. In the daily topical application tests performed for 4 weeks on rats' skin, the nanoparticles showed superior ability to increase epidermal thickness compared to RA and retinal, with no skin irritation observed for the proretinal particles, but severe skin irritation observed for RA and free retinal. When tested under occlusion conditions in human volunteers, insignificant skin irritation was observed for the proretinal nanoparticles. The 12-week, double-blind, split-face study on human volunteers indicates better antiaging efficacy of the particles as compared to the free RA.