The skin is the largest organ in the human body and can be affected by a wide variety of diseases. For the treatment of these diseases, a topical administration becomes very interesting because of easy accessibility of the affected regions, reduced systemic effects, possible loss of therapeutic efficacy due to first pass metabolism and, as a therapeutic non-invasive and easy to application, improves patient's adherence to treatment (PRAUZNITZ, 2004).
But for the viability of this route of administration for delivery of drugs, some obstacles must be overcome such as the barrier function of stratum corneum (SC), outermost layer of skin that due to its composition and cellular distribution, represent the main obstacle to skin penetration of drugs (MADISON, 2003; CEVC; VIERL, 2010).
A tool to resolve this issue is the development of delivery systems effective, safe and clinically acceptable, allowing the penetration of drugs by the EC and with it, feasible this attractive route of administration. With the development of delivery systems also becomes possible deployment of new therapeutic classes as in the case of gene therapy by RNA interference (RNAi) with the placement of small interfering RNA (siRNA) against specific molecular targets.
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The clinical use of siRNAs in the treatment of chronic and severe diseases has some limitations, such as hard cellular uptake, low rate of cell transfection, rapid degradation by endogenous enzymes resulting in a short half-life, negative charge that prevents it from crossing the cell membranes and insufficient bioavailability. Therefore, the development of delivery systems is the greatest challenge to provide the clinical use of siRNAs (NIMESH; CHANDRA, 2009; REISCHL; ZIMMER, 2009).
The use of siRNAs for the treatment of various diseases has been reported and the results have been quite promising.
Pachyonychia congenita (PC)
It is a dominant negative genetic disease of the skin caused by mutations in the genes encoding keratin. The gene most frequently mutaded is KRT6A. It presents as a thickened nails and palmoplantar hyperkeratosis.
Due the location of the lesions, non-invasive treatment topic becomes a great advantage and the RNAi technology that allows a very selective way of eliminating the functionality of this mutant allele provides an effective treatment for this pathology.
It is worth noting that among the 18 ongoing clinical trials with the use of siRNA, one is concerning the treatment of PC with a specific siRNA against the gene KRT6A and it is the first use siRNA in human skin (LEACHMAN et al., 2008; LEACHMAN et al., 2010).
Allergic Skin Disease
Ritprajak and colleagues (2008) proposed the topical administration of a cream-emulsified with CD86 siRNA against dendritic cells (DC) for the treatment of contact hypersensitive (CH) and atopic dermatitis (AD).
Increased expression of CD86 in inflammatory skin diseases has been reported in humans and animals. The blocking of its expression by siRNA influences the T cell response specific antigen in animal models of allergic diseases.
The cream used as a delivery system allowed the increased penetration of the siRNA and its accumulation in the epidermis and dermis. The animals were treated with the cream daily for 6 weeks. 1 week after initiation of treatment showed that mean skin score and the production of IL-4, IgE, Df specific IgG1 were reduced. It was also observed reduction of edema, cellular infiltration and migration of skin DC to regional lymph nodes.
The results obtained by the group suggest that topical use of CD86 siRNA against cutaneous dendritic cells may be a promising strategy for the treatment of allergic skin diseases (RITPRAJAK; HASHIGUCHI; AZUMA, 2008).
Among the variety of diseases that can have the local expression of genes modulated strategically have a wound that represent a substantial biomedical burden and is a candidate gene manipulation by RNAi.
Thanik and colleagues (2007) developed a delivery system based in agarose to deliver siRNA-liposomal transfection complex for the treatment of nondelimited wounds. MAPK-1 and lamin A/C were the molecular targets selected because of their high levels of expression.
Animal models of wounds were created by removing the dorsal skin of animals. The formulation with siRNA and control were applied topically on the wounds 24 hours after its creation.
The results showed reduced expression of MAPK-1 and lamin A/C 14 and 21 days after initiation of treatment compared with control groups demonstrating the potential application of gene silencing for the treatment of wounds (THANIK et al., 2007).
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Rheumatoid arthritis (RA)
Takanashi et al (2006) demonstrated the use of a topical delivery system for serving siRNA against to osteopontin (OPN), a cytokine extracellular transcribed by activated T lymphocytes and target in many inflammatory diseases such as RA , autoimmune disease characterized by chronic inflammation and joint destruction.
The cream formulation proposed, GeneCream, was able to penetrate the stratum corneum and deposit the siRNA in the epidermis, dermis and to a lesser extent in the subcutaneous tissue.
An animal model of RA was developed with the use of type II collagen antibody to prove if the cream with siRNA against OPN could suppress the development of RA. The animals were treated daily with the cream one week before the induction of arthritis.
The results showed that the topical cream improved symptoms of RA in an animal model and also reduced the expression of OPN in the skin and subcutaneous tissue (TAKANASHI et al., 2009)
Psoriasis is a chronic inflammatory disease characterized by demarcated erythematous scaly plaques. The abnormal and accelerated proliferation of keratinocytes leads to epidermal hyperplasia.
The molecular target for the treatment of this skin disorder is TNF-α which is high expression.
An animal model for the study of psoriasis was developed by performing a transplanted human psoriatic lesional skin onto immunodeficient mice.
We applied a treatment with intradermal injections of lentiviral shRNA-encoging vectors against TNF-α leading to reduced levels of expression of this pro-inflammatory cytokine. We also observed phenotypic improvements which demonstrate this potential molecular target for the treatment of psoriasis (JAKOBSEN; STENDERUP; ROSADA, 2009).
It is an autoimmune disease that affects the hair follicles resulting in hair loss. Around hair follicles found infiltrated with CD4 which suggests an important role of Th1 cells in the occurrence of alopecic lesions.
As a treatment for this disease, Nakamura and colleagues (2008) developed a system for controlled release of siRNA using biodegradable cationized gelatin microspheres and studied its application in animal models of disease (C3H/HeJ mice).
Demonstrated that subcutaneous injections of siRNA against the target Tbox21 three times for seven days inhibited the expression of the gene TBox 21 that has an important role in the differentiation and function of Th1 cells and also promoted the reestablishment of the hair shaft elongation (NAKAMURA et al., 2008).
It is a cancer of pigmented skin cells called melanocytes and are located in the epidermal-dermal junction. The genetic mechanisms of promoters of this cancer are not well understood, however, the mutation of T1799A B-Raf and Akt3 increased activity are frequent changes in this disease.
Tran and colleagues (2008) developed a nanoliposomal cationic to delivery siRNA against the targets V600EB-Raf and Akt3 within the tumors on the skin. The formulation was applied topically and is associated with a low-frequency ultrasound to enhance the penetration of the formulation through the skin.
Observed a reduced expression of both proteins inhibits the development or growth of melanoma, representing a promising alternative to treat this pathology (TRAN et al., 2008).