The extremely low permeability of the blood-brain barrier (BBB) poses the greatest impediment in the treatment of central nervous system (CNS) diseases. Recent work indicated that BBB permeability can be up-regulated by activating A2A adenosine receptor (AR), which temporarily increases intercellular spaces between the brain capillary endothelial cells. However, due to transient circulation lifetime of adenosine-based agonists, their capability to enhance brain delivery of drugs, especially macromolecular drugs, is limited. In this work, a series of nanoagonists (NAs) were developed by labeling different copies of A2A AR activating ligands on dendrimers. In vitro transendothelial electrical resistance measurements demonstrated that the NAs increased permeability of the endothelial cell monolayer by compromising the tightness of tight junctions, the key structure that restricts the entry of blood-borne molecules into the brain. In vivo imaging studies indicated the remarkably up-regulated brain uptake of a macromolecular model drug (45 kDa) after intravenous injection of NAs. Autoradiographic imaging showed that the BBB opening time-window can be tuned in a range of 0.5-2.0 h by the NAs labeled with different numbers of AR-activating ligands. By choosing a suitable NA, it is possible to maximize brain drug delivery and minimize the uncontrollable BBB leakage by matching the BBB opening time-window with the pharmacokinetics of a therapeutic agent. The NA-mediated brain drug delivery strategy holds promise for the treatment of CNS diseases with improved therapeutic efficiency and reduced side-effects.

A new Pd-catalyzed cyanation reaction has been discovered using ethyl cyanoacetate as the cyanating reagent. A variety of electron-rich and electron-deficient aryl halides were efficiently converted into their corresponding nitriles in good to excellent yields.

Purpose: The efficacy of pro-angiogenic therapy is difficult to evaluate with current diagnostic modalities. The objectives were to develop a non-invasive imaging strategy to define the temporal characteristics of angiogenesis and to evaluate the response to pro-angiogenic therapy in diabetic stroke mouse models.Methods: A home-made ανβ3 integrin-targeted multi-modal nanoprobe was intravenously injected into mouse models at set time points after photothrombotic stroke. Magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging were carried out at 24 h post-injection. Bone marrow-derived endothelial progenitor cells (EPCs) were infused into the mouse models of ischemic stroke to stimulate angiogenesis.Results: The peak signal intensity in the ischemic-angiogenic area of diabetic and wild-type mouse models was achieved on day 10, with significantly lower signal enhancement observed in the diabetic models. Although the signal intensity was significantly higher after EPC treatment in both models, the enhancement was less pronounced in the diabetic animals compared with the wild-type controls. Histological analysis revealed that the microvessel density and expression of β3 integrin were correlated with the signal intensity assessed with MRI and NIRF imaging.Conclusions: The non-invasive imaging method could be used for early and accurate evaluation of the response to pro-angiogenic therapy in diabetic stroke models.

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