Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Eur J Pharm Biopharm. 2013 Jan;83(1):16-24. doi: 10.1016/j.ejpb.2012.08.011. Epub 2012 Sep 23.
The ability of small interfering RNAs (siRNAs) to potently but reversibly silence genes in vivo has made them particularly well suited as a new class of drugs that interfere with disease-causing or disease-promoting genes. However, the largest remaining hurdle for the widespread use of this technology in skin is the lack of an effective delivery system. The aim of the present study was to evaluate nanodispersed systems in liquid crystalline phases that deliver siRNA into the skin. The proposed systems present important properties for the delivery of macromolecules in a biological medium, as they are formed by substances that have absorption-enhancing and fusogenic effects; additionally, they facilitate entrapment by cellular membranes due to their nano-scale structure. The cationic polymer polyethylenimine (PEI) or the cationic lipid oleylamine (OAM) were added to monoolein (MO)-based systems in different concentrations, and after dispersion in aqueous medium, liquid crystalline phase nanodispersions were obtained and characterized by their physicochemical properties. Then, in vitro penetration studies using diffusion cell and pig ear skin were carried out to evaluate the effect of the nanodispersions on the skin penetration of siRNA; based on these results, the nanodispersions containing MO/OA/PEI/aqueous phase (8:2:5:85, w/w/w/w) and MO/OA/OAM/aqueous phase (8:2:2:88, w/w/w/w) were selected. These systems were investigated in vivo for skin penetration, skin irritation, and the ability to knockdown glyceraldehyde 3-phosphate dehydrogenase (GAPDH) protein levels in animal models. The results showed that the studied nanodispersions may represent a promising new non-viral vehicle and can be considered highly advantageous in the treatment of skin disorders; they were effective in optimizing the skin penetration of siRNA and reducing the levels of the model protein GAPDH without causing skin irritation.
小干扰 RNA（siRNA）能够有效地、可逆地使体内基因沉默，这使得它们特别适合作为一种新的药物类别，干扰致病或促进疾病的基因。然而，这项技术在皮肤中广泛应用的最大剩余障碍是缺乏有效的传递系统。本研究的目的是评估纳米分散体系在液晶相中递送至皮肤的能力。所提出的系统具有在生物介质中递送大分子的重要特性，因为它们由具有增强吸收和融合作用的物质形成；此外，由于其纳米级结构，它们有利于被细胞膜捕获。将阳离子聚合物聚乙烯亚胺（PEI）或阳离子脂质油胺（OAM）以不同浓度添加到单油酸甘油酯（MO）基系统中，并在水性介质中分散后，得到液晶相纳米分散体，并通过其物理化学性质进行表征。然后，使用扩散池和猪耳皮肤进行体外渗透研究，以评估纳米分散体对 siRNA 皮肤渗透的影响；基于这些结果，选择含有 MO/OA/PEI/水相（8:2:5:85，w/w/w/w）和 MO/OA/OAM/水相（8:2:2:88，w/w/w/w）的纳米分散体。这些系统在体内进行了皮肤渗透、皮肤刺激性和在动物模型中降低甘油醛 3-磷酸脱氢酶（GAPDH）蛋白水平的能力的研究。结果表明，所研究的纳米分散体可能代表一种有前途的新型非病毒载体，并可被认为在治疗皮肤疾病方面具有高度优势；它们能够有效地优化 siRNA 的皮肤渗透，降低模型蛋白 GAPDH 的水平，而不会引起皮肤刺激。
