Nanocarriers for transcutaneous delivery of vaccines

大量的努力已经指向开发非胃肠外（无针）替代品， 传统的疫苗接种。与传统的疫苗相比，非肠道疫苗具有许多潜在的优势。 疫苗包括1）赋予粘膜以及全身免疫的潜力，2）增加的稳定性，3） 延长保质期，4）消除针头，需要经过专门培训的医疗保健专家， 5）降低成本。一种这样的方法，经皮免疫（TCI）， 是一种将抗原直接递送到裸露皮肤上的非侵入性安全方法。免疫是通过以下方式实现的： 疫苗抗原的直接局部应用。尽管TCI具有吸引力，但该技术受到以下因素的限制： 大分子量疫苗抗原穿过完整皮肤的转运相对低效。 药物透皮给药的最新创新，包括化学增强剂、电、超声， 和微针，证明了大分子通过皮肤渗透运输的可行性- 屏障，特别是角质层。皮肤的外层由紧密堆积的脂质组成 分子和这些脂质的密集的晶体排列创造了防止 水分流失和病原体进入。最近的证据表明，这一障碍可以通过适当的方法克服。 结构化纳米尺寸的颗粒（纳米载体）。该提案将比较三种不同的纳米载体 （温度响应性中空纳米球、纳米水凝胶和星星共聚物）， 掺入模型疫苗抗原并通过角质层将抗原递送至免疫- 表皮中的反应细胞。每种类型的纳米载体的专门组装赋予了每种独特的 性质和角质层脂质通道内的不同相互作用。使用 用于疫苗递送的纳米载体是一种平台技术，适用于递送各种现有的和 潜在的疫苗出于本提案的目的，我们将利用两种不同的蛋白质：1）牛血清 经荧光标记以监测大分子掺入和渗透的白蛋白 抗原，和2）F1-V，来自鼠疫耶尔森氏菌的疫苗抗原，鼠疫的病原体，我们和 其他的已经显示出对有毒鼠疫耶尔森氏菌气溶胶攻击的保护作用。 拟议的研究将解决应用纳米技术进行疫苗输送的重要问题 通过开发纳米载体的新特性。这些研究的结果将广泛 适用于各种疫苗和治疗剂，并将进一步突出 科学和医学中的纳米技术。

A great deal of effort has been directed towards developing nonparenteral (needle-free) alternatives to traditional vaccine delivery. Nonparenteral vaccines offer a number of potential advantages over traditional vaccines including 1) the potential to confer mucosal as well as systemic immunity, 2) increased stability, 3) increased shelf-life, 4) elimination of needles and the need for specially trained healthcare specialists to administer vaccines, and 5) potentially lower costs. One such approach, transcutaneous immunization (TCI), is a non-invasive, safe method of delivering antigens directly onto bare skin. Immunization is achieved by direct topical application of a vaccine antigen. Despite the attractiveness of TCI, the technology is limited by the relative inefficiency of transport of large molecular weight vaccine antigens across intact skin. Recent innovations in transdermal delivery of drugs, including chemical enhancers, electricity, ultrasound, and microneedles, demonstrate the feasibility of large-molecule transport through the skin's permeation- barrier, specifically the stratum corneum. This outer layer of the skin is composed of tightly packed lipid molecules and the dense, crystalline arrangement of these lipids creates the essential barrier to prevent water loss and pathogen entry. Recent evidence has shown that this barrier can be overcome by properly structured nano-sized particles (nanocarriers). This proposal will compare three different nanocarriers (temperature-responsive hollow nanospheres, nanohydrogels, and star copolymers) for the ability to incorporate a model vaccine antigen and deliver that antigen through the stratum corneum to immune- responsive cells in the epidermis. The specialized assembly of each type of nanocarrier gives each unique properties and different interactions within the lipid channels of the stratum corneum. The use of nanocarriers for vaccine delivery is a platform technology, applicable to delivery of a variety of existing and potential vaccines. For the purposes of this proposal, we will utilize two different proteins: 1) Bovine Serum Albumin that has been fluorescently labeled to monitor incorporation and permeation of a macromolecular antigen, and 2) F1-V, a vaccine antigen from Yersinia pestis, the causative agent of plague, which we and others have shown to protect against aerosol challenge with virulent Y.pestis. The proposed studies will address important questions in vaccine delivery by application of nanotechnology through the exploitation of the novel properties of nanocarriers. The findings of these studies will be broadly applicable to a variety of vaccines and therapeutics and will further highlight the important role of nanotechnology in science and medicine.