Nanocarriers for transcutaneous delivery of vaccines

描述(由申请人提供)：为开发传统疫苗交付的非静脉(无针头)替代方法，已经做出了大量努力。与传统疫苗相比，非肠外疫苗具有许多潜在的优势，包括1)赋予粘膜和系统免疫力的潜力，2)提高稳定性，3)延长保质期，4)消除针头，需要受过专门培训的医疗专家来管理疫苗，以及5)潜在的较低成本。其中一种方法，经皮免疫(TCI)，是一种将抗原直接传递到裸露皮肤的非侵入性、安全的方法。免疫是通过直接局部应用疫苗抗原来实现的。尽管TCI很有吸引力，但由于大分子疫苗抗原在完整皮肤上的传输相对低效，该技术受到了限制。最近药物经皮给药的创新，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屏障，特别是角质层的可行性。皮肤的外层由紧密堆积的脂类分子组成，这些脂类的致密、结晶排列形成了防止水分流失和病原体进入的基本屏障。最近的证据表明，这一障碍可以通过结构合理的纳米颗粒(纳米载体)来克服。这项提案将比较三种不同的纳米载体(温度敏感型空心纳米球、纳米水凝胶和星形共聚物)结合模型疫苗抗原并通过角质层将该抗原输送到表皮中的免疫反应细胞的能力。每种类型的纳米载体的专门组装使每种载体具有独特的性质，并在角质层的脂质通道内具有不同的相互作用。利用纳米载体进行疫苗输送是一种平台技术，适用于各种现有的和潜在的疫苗的输送。在这项建议中，我们将使用两种不同的蛋白质：1)被荧光标记的牛血清白蛋白，用于监测大分子抗原的掺入和渗透；2)F1-V，来自鼠疫耶尔森氏菌的疫苗抗原，我们和其他人已经证明，它可以保护动物免受强毒鼠疫杆菌的气溶胶攻击。拟议的研究将通过开发纳米载体的新特性来解决通过应用纳米技术提供疫苗的重要问题。这些研究的结果将广泛适用于各种疫苗和疗法，并将进一步突出纳米技术在科学和医学中的重要作用。

DESCRIPTION (provided by applicant): 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 immunoresponsive 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.