1-2-dioleoyloxy-3-(trimethylammonium)propane and Psoriasis

Cyclosporine (CYC), a calcineurin inhibitor acts specifically on T-cells and is one of the most effective treatment options for psoriasis. Systemic administration of the drug has been associated with dose-dependent toxic effects, while its topical delivery is a challenging task due to unfavourable physicochemical properties of drug. The aim of the present study is to develop and evaluate the efficacy of topical liposomal gel containing CYC loaded cationic liposomal nanocarriers in imiquimod induced psoriatic plaque model. Liposomes composed of DOTAP and cholesterol was formulated by different liposomal preparation techniques. Optimized liposomal carriers prepared by ethanol injection method were characterized with respect to size, zeta potential, entrapment efficiency, stability,

Topics: Administration, Cutaneous; Animals; Cations; Cholesterol; Cyclosporine; Cytokines; Dermatologic Agents; Drug Compounding; Drug Liberation; Fatty Acids, Monounsaturated; Humans; Hydrogels; Liposomes; Male; Mice, Inbred BALB C; Nanocapsules; Psoriasis; Quaternary Ammonium Compounds; Skin; Skin Absorption; Treatment Outcome

Topical delivery of siRNA is challenging task due to complex barrier property of stratum corneum and cationic lipid based carriers have been widely explored for this purpose due to improved permeation through skin. For gene delivery application, dendrimers are considered as efficient carrier due to their cationic nature and well-defined surface groups. However, they are not well explored for topical delivery. This work compares the suitability of PAMAM dendrimer with DOTAP liposome for topical delivery of siRNA against TNF-α. The particle size, zeta potential and entrapment efficiency of dendriplex were 99.80 ± 1.80 nm, 13.40 ± 4.84 mV and 98.72 ± 2.02% whereas for lipoplex were 174.80 ± 0.80 nm, 29.96 ± 0.51 mV and 94.99 ± 5.01% respectively. Both the formulations were stable in serum and in the presence of RNAse. TNF-α is inflammatory cytokine, hence the in vivo efficacy of developed formulations was determined using psoriatic plaque model. Results suggested improved phenotypic and histopathological features and reduced levels of IL-6, TNF-α, IL-17 and IL-22 for dendriplex and lipoplex treated groups in comparison to Imiquimod treated group. These findings suggest that dendrimer can be a potential carrier for topical gene delivery.

Topics: Animals; Cytokines; Dendrimers; Fatty Acids, Monounsaturated; Gene Transfer Techniques; Imiquimod; Liposomes; Mice, Inbred BALB C; Psoriasis; Quaternary Ammonium Compounds; RNA, Small Interfering; Skin

RNA interference (RNAi) is a rapidly emerging approach for targeted gene silencing to alleviate disease pathology. However, lack of efficient carriers for targeted delivery delays the clinical translation of RNAi. An interesting target for local RNAi therapeutics is the skin as it allows direct access to target cells. Still, applications are limited due to the effective skin barrier which hinders penetration. Herein, a description is given of a liposomal carrier, called 'DDC642', capable of delivering RNAi molecules to the epidermis of impaired and intact human skin, without targeting the dermis or circulatory system. In a psoriasis tissue model, down-regulation of the psoriasis marker human beta-defensin 2 by DDC642-delivered siRNA was confirmed, providing proof-of-concept. These liposomes thus hold great potential as topical delivery system for RNAi therapeutics in the treatment of numerous skin diseases.

Topics: Administration, Topical; beta-Defensins; Cholesterol; Elasticity; Ethanol; Fatty Acids, Monounsaturated; Gene Transfer Techniques; Humans; Keratinocytes; Liposomes; Melanocytes; MicroRNAs; Phosphatidylethanolamines; Psoriasis; Quaternary Ammonium Compounds; RNA Interference; RNA, Small Interfering