How particles enter the body: investigating particle-barrier interactions in the digestive tract (PARENTRY)

在第一个资助期内，我们（i）成功开发了具有高度定义的发射光谱和特定化学表面特性的量身定制的量子点（QD），（ii）通过活体双光子显微镜建立了用于纳米颗粒（NP）组织内跟踪的新型多维成像模式，（iii）表征了NP与粘液和肠液的相互作用，和（iii）确定NP进入肠粘膜的沿着途径。在第二个资助期，我们将把这些知识和仪器应用于整个消化道。因为大多数NP被证明在与胃肠道物质接触时改变尺寸和表面特征，NP的“摄入史”可能严重影响其粘膜吸收。因此，我们将我们独特的成像方法扩展到消化道的其他部分（口腔，食道，胃，大肠），包括细菌定植和入侵的影响，并研究粘膜炎症的影响。随着在第一个资助期内开发的新一代强发射量子点/量子棒（QD/QR），将提高复杂组织中NP的检测灵敏度。单粒子成像也将通过将非线性成像扩展到近红外来实现，这避免了背景荧光。我们将覆盖NP尺寸范围从20-100纳米均匀的表面化学。通过将我们的成像方法与新型肠外植模型和NP摄取的全身定量相结合，我们试图确定在消化道的不同部分中摄取的NP的绝对量和百分比。NP属性的受控变化，将使我们能够预测最可能的入口位置和吸收程度作为NP大小，形状和表面性质的函数。

In the first funding period, we (i) successfully developed tailor-made quantum dots (QDs) with highly defined emission spectra and specific chemical surface properties, (ii) built-up novel multi-dimensional imaging modes for in-tissue tracking of nanoparticles (NPs) by intravital 2-photon microscopy, (iii) characterized the interaction of NPs with mucus and intestinal fluids, and (iiii) identified pathways along which NPs enter the gut mucosa. In the second funding period, we will apply this knowledge and instrumentation to the whole digestive tract. Because most NPs proved to alter size and surface characteristics upon contact with gastrointestinal matter, the “ingestion history” of an NP might critically affect its mucosal uptake. We therefore will extend our unique imaging approach to other sections of the digestive tract (oral cavity, esophagus, stomach, large intestine), include the effect of bacterial colonization and invasion, and study the implications of mucosal inflammation. With the new generation of strongly emitting quantum dot/quantum rods (QD/QRs) developed in the first funding period, the NP detection sensitivity in complex tissues will be increased. Single particle imaging will also be achieved by extending the non-linear imaging to the near IR which avoids background fluorescence. We will cover the NP size range from 20–100 nm with uniform surface chemistry. By combining our imaging approach with a novel intestinal explant model and total body quantitation of NP uptake, we attempt to determine the absolute amount and percentage of NPs taken up in the different sections of the digestive tract. Controlled variation of NP properties, will allow us to predict the most probable site of entry and extent of uptake as a function of NP size, shape and surface properties.