Nanocarriers for transcutaneous delivery of vaccines

已经做出了大量的努力来开发非肠外(无针)替代方案 传统的疫苗投放方式。与传统疫苗相比，非肠外疫苗具有许多潜在的优势 疫苗包括1)潜在的粘膜免疫和系统免疫，2)增强稳定性，3) 延长保质期，4)消除针头，以及需要经过专门培训的医疗专家来 管理疫苗，以及5)潜在的更低成本。其中一种方法是经皮免疫(TCI)， 是一种将抗原直接输送到裸露皮肤的非侵入性、安全的方法。免疫接种通过以下方式实现 疫苗抗原的直接局部应用。尽管TCI很有吸引力，但这项技术受到以下限制 大分子疫苗抗原在完整皮肤上运输的相对低效。 药物经皮给药方面的最新创新，包括化学增强剂、电、超声波、 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类组成 分子和这些脂类致密的晶体排列形成了基本的屏障，以防止 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式克服 结构化纳米颗粒(纳米载体)。这项提案将比较三种不同的纳米载体 (温度敏感型中空纳米球、纳米水凝胶和星形共聚物) 加入一种模型疫苗抗原，并通过角质层传递该抗原以免疫- 表皮中有反应的细胞。每种类型的纳米载体的专门组装使每个 角质层脂质通道的性质和不同的相互作用。对.的使用 纳米载体用于疫苗递送是一种平台技术，适用于各种现有和 潜在的疫苗。在这项提议中，我们将使用两种不同的蛋白质：1)牛血清 已被荧光标记以监测大分子的掺入和渗透的白蛋白 和2)F1-V，一种来自鼠疫耶尔森氏菌的疫苗抗原，鼠疫的病原体，我们和 其他人已经显示出可以抵御强毒力的鼠疫杆菌对气溶胶的挑战。 拟议的研究将解决通过应用纳米技术提供疫苗的重要问题。 通过开发纳米载体的新特性。这些研究的结果将广泛地 适用于各种疫苗和治疗方法，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.