ENLARGED PATHWAYS FOR TRANSDERMAL PROTEIN DELIVERY

产品说明：（改编自申请人的摘要）-本提案的目标是建立用于大分子（例如，肽、蛋白质和核酸），具有优异的控制和低成本的潜力。申请人将研究通过皮肤角质层（SC）的扩大的经皮水通道，其由在通过“高压”（HV）脉冲（Uskin大于或等于50 V）电产生初级水通道之后发生的次级过程产生。目标。由于涉及许多参数，目的是广泛研究和优化体外途径扩大，然后进行体内动物研究，包括途径创建，大分子转运和副作用的初步评估。意义该目标的成功实现将为基于紧凑、低成本电化学技术的经皮给药奠定基础。所设想的技术将提供电子控制的水溶性分子的快速递送，范围从常规药物到体内半衰期短的大分子。因此，注射器的许多用途可以被取代。以前的工作。非优化的方案表明：（1）纯物理刺激可能会产生扩大的通路，（2）无毒的通路扩大分子产生扩大的通路，这些通路以潜在的治疗水平（每平方厘米每小时100微克）转运蛋白质。如未来装置所要求的，转运似乎集中在小的皮肤部位（局部转运区域;“LTR”），其占据小于1平方厘米皮肤面积的10%。使用微电极和微孔的原型电极/储液器装置在体内提供无痛脉冲。（申请人和其他人的）实验和局部电场的理论建模都表明副作用应该是最小的。在一种情况下，转运抗体分子（150，000 g/摩尔的IGG）。方法.申请人将强调使用人、无毛大鼠和猪皮肤体外优化多参数扩大通路创建方案，然后进行体内评估。他们将使用皮肤电阻和荧光分子通量测量以及图像分析来表征包含扩大通路的LTR。局部领域，加热，路径创建和运输的理论分析将进行，是必不可少的优化扩大的途径。

DESCRIPTION: (Adapted from the applicant's abstract) - The goal of this proposal is to establish methods for transdermal delivery of macromolecules, (e.g., peptides, proteins, and nucleic acids), with the potential for excellent control and low cost. The applicants will study enlarged transdermal aqueous pathways through the skin's stratum corneum (SC), that are created by secondary processes occurring after electrical creation of primary aqueous by "high- voltage" (HV) pulses (Uskin greater than or equal to 50V). Aims. Because of the many parameters involved, the aims are to study extensively and optimize pathway enlargement in vitro, followed by in vivo animal studies involving pathway creation, macromolecule transport, and initial evaluation of side effects. Significance. Successful pursuit of the Aims will establish a basis for transdermal drug delivery based on a compact, low-cost electrochemical technology. The envisioned technology will provide electronically controlled rapid delivery of water-soluble molecules ranging from conventional pharmaceuticals to macromolecules with short in vivo half lives. Thus, many of the uses of syringes could be replaced. Previous Work. Nonoptimized protocols show that (1) purely physical stimuli may create enlarged pathways, and (2) a nontoxic pathway-enlarging molecule created enlarged pathways which transported proteins at potentially therapeutic levels (100 micrograms per hour per centimeter squared). As required for future devices, transport appears to be concentrated at small skin sites (local transport regions; "LTRs") which occupy less than 10% of a 1 square centimeter area of skin. Prototype electrode/reservoir devices using microelectrodes and microholes provide painless pulsing in vivo. Both experiments (of the applicants and others) and theoretical modeling of localized electric fields show that side effects should be minimal. In one case, antibody molecules (IGG at 150,000 g per mole) were transported. Methods. The applicants will emphasize in vitro optimization of multiparametric enlarged pathway-creation protocols, using human, hairless rat, and pig skin, followed by in vivo assessment. They will use skin electrical resistance and fluorescent molecule flux measurements with image analysis to characterize the LTRs containing enlarged pathways. Theoretical analysis of localized fields, heating, pathway creation, and transport will be carried out, and is essential to optimizing enlarged pathways.