Tranexamic acid in a mouse model of cerebral amyloid angiopathy: setting the stage for a novel stroke treatment approach.

Background: Symptomatic intracerebral hemorrhage (sICH) commonly occurs in patients with cerebral amyloid angiopathy (CAA). Amyloid also initiates plasminogen activation and might promote sICH. Objectives: As amyloid-driven plasmin formation can be blocked by tranexamic acid (TXA), we aimed to evaluate the biodistribution and long-term consequences of TXA on brain amyloid-beta (Aß) levels, inflammation, and neurologic function in APP/PS1 mice. Methods: APP/PS1 mice overexpressing the mutant human amyloid precursor protein and wild-type littermates were randomized to TXA (20 mg/mL) or placebo in the drinking water for 6 months. TXA in plasma and various organs was determined by liquid chromatography-mass spectrometry. Plasmin activity assays were performed to evaluate changes in fibrinolytic activity. Neurologic function was evaluated by Y-maze and parallel rod floor testing. Proximity ligation-based immunoassays were used to quantitate changes of 92 biomarkers of inflammation. Brain Aß levels were assessed by immunohistochemistry. Results: Long-term oral TXA administration inhibited fibrinolysis. TXA accumulated in the kidney (19.4 ± 11.2 µg/g) with 2- to 5-fold lower levels seen in the lung, spleen, and liver. TXA levels were lowest in the brain (0.28 ± 0.01 µg/g). Over 6 months, TXA had no discernible effect on motor coordination, novelty preference, or brain Aß levels. TXA reduced plasma levels of epithelial cell adhesion molecule and increased CCL20. Conclusion: Long-term TXA treatment does not alter brain Aß levels or impact neurologic behavior in mice predisposed to amyloid deposition and had minor effects on the levels of inflammatory mediators. This finding supports the safety of TXA and lays the foundation for TXA as a novel treatment to reduce sICH in patients with CAA.

Lipid-based lyotropic liquid crystalline phase transitions as a novel assay platform using birefringence as the visual signal output.

Amphiphilic lipids can often form various lipid-based lyotropic liquid crystalline phases when they are exposed to aqueous environments, which includes the inverse hexagonal (H2), inverse cubic (V2), inverse discontinuous cubic (I2) and lamellar (Lα) phases. Their different interactions with crossed-polarised light make some phases appear bright and some dark, which offers great potential in developing a novel universal assay platform using birefringence as the visual signal output. Here, we have developed a novel strategy for constructing an assay platform using lyotropic liquid crystalline phases as the signal transducer and using changes in their birefringence upon exposure to lipase as the signal output. The hydrolysis of the ester group of glyceryl monooleate (GMO) by lipase induced a phase transition from cubic phase to hexagonal phase and consequently "turned on" the birefringence as the signal output. The change in the intensity of the birefringence depended on both the exposure time and concentration of lipase. The streptavidin-biotin affinity was utilised to demonstrate the potential of the birefringence assay platform, using free biotin as the model analyte, biotinylated lipase and streptavidin-coated magnetic beads in the competitive format. A semi-quantitative assay with a detection limit of 5 µg mL-1 to free biotin as the model analyte was achieved in the visual birefringence mode. This study demonstrated a proof-of-concept lyotropic assay platform with birefringence as the visual signal output that could be deployed as an electronics- and colour-free diagnostic device for a wide range of applications, for example to indicate the presence of toxins in water.

PEGylation and surface functionalization of liposomes containing drug nanocrystals for cell-targeted delivery.

Liposomal formulations have important therapeutic applications in anti-cancer treatments but current formulations suffer from serious side effects, high dosage requirements and prolonged treatment. In this study, PEGylated azide-functionalized liposomes containing drug nanocrystals were investigated with the aim of increasing the drug payload and achieving functionalization for targeted delivery. Liposomes were characterized using cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS), small and ultra-small angle neutron scattering (SANS/USANS) and small and wide angle X-ray scattering (SAXS/WAXS). Cryo-TEM experiments revealed the dimensions of the nanocrystal-loaded liposomes and the change of shape from spherical to elongated after the formation of nanocrystals. Results from SANS/USANS experiments confirmed the asymmetric particle shape. SAXS/WAXS experiments confirmed that the crystalline drug only occurred in freeze-thawed samples and correlated with a new unidentified polymorphic form of ciprofloxacin. Using a small molecule dye, dibenzocyclooctyne (DBCO)-cy5, specific conjugation between DBCO groups and surface azide groups on the liposomes was confirmed; this indicates the promise of this system for tumour-targeted delivery.