Dermal delivery of topically applied oligonucleotides via follicular transport in mouse skin
Dermal delivery of topically applied oligonucleotides via follicular transport in mouse skin
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DOI：
10.1111/j.0022-202x.2005.23672.x
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发表时间：
2005-05-01
影响因子：
6.5
通讯作者：
Karras, JG
中科院分区：
文献类型：
--
作者：
Dokka, S;Cooper, SR;Karras, JG
在乳膏制剂配制反义寡脱氧核苷酸正在检查在临床上作为局部治疗银屑病。为了产生预期的抗炎作用，这些大的阴离子分子必须穿透角质层，到达活的表皮和真皮层。一种靶向细胞间粘附分子-1的硫代反义寡核苷酸最近被证明可以调节细胞因子诱导的靶基因在移植皮肤中的表达。在这项研究中，我们研究了荧光染料标记的或裸的第二代2'- o -甲氧基乙基修饰的寡核苷酸进入小鼠皮肤的途径，这些寡核苷酸与抗体特异性反应，使用外用乳膏为基础的配方。在无毛小鼠皮肤中，局部应用后，免疫组织化学分析和荧光显微镜无法检测到表皮或真皮中寡核苷酸的存在，尽管免疫染色与角质层相关，并且在毛囊中观察到异硫氰酸荧光素标记的寡核苷酸。局部应用于剪毛BALB/c小鼠皮肤的寡核苷酸动力学分析显示，早期毛囊定位，寡核苷酸从中毛囊扩散，随后皮肤积聚。生理盐水配方导致寡核苷酸留在毛囊内。这些结果表明，寡核苷酸在皮肤中的渗透涉及毛囊途径，进一步说，局部寡核苷酸治疗可能特别适合于改变毛囊和相关结构内的生理机能。
Antisense oligodeoxynucleotides formulated in cream preparations are being examined in the clinic as topical therapy for psoriasis. To produce their intended anti-inflammatory effects, these large anionic molecules must penetrate the stratum corneum and reach the living epidermis and dermis. A topically applied phosphorothioate antisense oligonucleotide targeted to intercellular adhesion molecule-1 recently was shown to modulate cytokine-inducible target gene expression in engrafted human skin. In this study, we examined the route of entry into mouse skin of fluorochrome-tagged or naked second-generation 2'-O-methoxyethyl-modified oligonucleotides that react specifically with an antibody, using topical cream-based formulations. In hairless mouse skin, immunohistochemical analysis and fluorescence microscopy were unable to detect the presence of oligonucleotide in the epidermis or dermis following topical application although immunostaining was associated with the stratum corneum and fluorescein isothiocyanate-labeled oligonucleotide was observed in hair follicles. Kinetic analysis of oligonucleotide topically applied to hair-clipped BALB/c mouse skin showed early follicular localization, diffusion of oligonucleotide from the mid-follicle, and subsequent dermal accumulation. Saline formulation resulted in oligonucleotide remaining within the hair follicle. These results suggest that oligonucleotide penetration in skin involves a follicular route and further, that topical oligonucleotide therapy may be particularly well suited for altering physiology within the hair follicle and related structures.