MPM non-invasive imaging of biological interactions following drug delivery with micro-nanoprojection patches.

我研究的主要目的是开发和评估有效、实用和可重复的物理方法，将基因和药物输送到皮肤中特定的免疫敏感细胞，最终治疗和预防人类疾病。我最近申请了一项专利，该方法使用贴片上的纳米级投影阵列，准确、高效和安全地将生物分子不仅传递到特定的皮肤细胞，而且传递到它们内部的细胞器。从概念上讲，给药装置是一套涂有药物物质的微型纳米针，以小贴片的形式应用于皮肤上。该装置实用、无针、无痛。本项目的目的是利用微纳投影阵列贴片-被配置为唯一地将生物分子递送到给定层级内的细胞-来发现：1)抗原表达质粒-Toll样受体(Toll Like Receptor，TLR)激动剂的递送位置会在完整的动物中导致强烈的体液免疫反应。2)通过多光子显微镜(MPM)局部观察，不同的TLR激动剂对皮肤中不同专业抗原提呈细胞(APC)的成熟和迁移是否有不同的影响。3)APC成熟和迁移的差异是否与不同的系统抗体反应有关。我们将用MPM确定药物-疫苗到皮肤(层、细胞靶向、递送持续时间)的最佳递送位置，以实现所需的全身免疫反应。这将对利用微纳米投影阵列贴片技术(和其他方法)通过皮肤靶向改善重大疾病的免疫疗法做出重要贡献。

The overarching aim of my research is to develop and evaluate effective, practical and reproducible physical methods for delivering genes and drugs to specific immunologically-sensitive cells in the skin to ultimately treat and vaccinate against human diseases. I recently patented a method using arrays of nano-scale projections on a patch to accurately, efficiently and safely deliver biomolecules not just to specific skin cells, but also to organelles within them. Conceptually, the delivery device is a set of microscopic nanoneedles coated with drug substance and applied to the skin as a small patch. The device is practical, needle-free and pain-free. The aim of this current project is to use the micro-nanoprojection array patches-configured to uniquely deliver biomolecules to cells within given strata-to find: 1) what delivery sites of antigen-expression plasmid- toll like receptor (TLR) agonist lead to strong humoral immune responses in the intact animal. 2) whether delivery of different TLR agonists have different effects on the maturation and migration of the different professional antigen presenting cells (APCs) in the skin, as visualised locally by Multi-Photon Microscopy (MPM). 3) whether differences in APC maturation and migration are associated with different systemic antibody responses. We will identify optimal delivery sites of drugs-vaccines to the skin (layer, cells targeted, duration of delivery) with MPM for desired systemic immune responses. This will have important contributions towards improving immunotherapeutics of major diseases via skin targeting with micro-nanoprojection array patch technologies (and other methods).