ENLARGED PATHWAYS FOR TRANSDERMAL PROTEIN DELIVERY

描述：（改编自申请人摘要）-本提案的目标是建立大分子（如肽、蛋白质和核酸）的经皮递送方法，具有良好控制和低成本的潜力。申请人将研究通过皮肤角质层（SC）的扩大透皮水通路，这是在“高压”（HV）脉冲（Uskin大于或等于50V）产生初级水后发生的二次过程所产生的。目标。由于涉及的参数很多，我们的目标是在体外广泛研究和优化途径扩展，然后进行体内动物研究，包括途径创建、大分子运输和副作用的初步评估。的意义。Aims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。设想的技术将提供电子控制的水溶性分子的快速递送，从传统药物到大分子，具有短的体内半衰期。因此，注射器的许多用途可以被取代。以前的工作。非优化方案表明：(1)纯粹的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，以潜在的治疗水平（每平方厘米每小时100微克）运输蛋白质。根据未来设备的要求，传输似乎集中在小的皮肤部位（局部传输区；“ltr”），其占1平方厘米皮肤面积的10%以下。使用微电极和微孔的原型电极/储层装置在体内提供无痛脉冲。（申请者和其他人的）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，抗体分子（每摩尔150,000 g的IGG）被运输。方法。申请人将强调多参数扩大通路创建方案的体外优化，使用人皮、无毛大鼠和猪皮，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含有扩大通路的ltr。将对局部场、加热、路径创建和运输进行理论分析，这对优化扩大的路径至关重要。

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.