Biocompatible Red Fluorescent Organic Nanoparticles with Tunable Size and Aggregation‐Induced Emission for Evaluation of Blood–Brain Barrier Damage

Abstract

present safety challenges. Evans blue (EB) assay remains the most commonly used method for the evaluation of BBB damage in the experimental studies of brain injury. [ 7 ] The EB dye works, as widely claimed, based on its ability to bind to serum albumin immediately following its intravenous injection. [ 8,9 ] Although this assay is widely used in numerous studies, EB dye has several limitations as a biomarker, such as its lethal toxicity in vivo and confounding problems in quantitative assessments via various spectroscopic methods. [10][11][12] Therefore, a sensitive, selective, and nontoxic method for evaluating BBB damage and vascular leakage is highly desirable.Fluorogens with aggregation-induced emission characteristics (AIEgens) have been developed for various biological applications in recent years. [13][14][15][16][17][18][19][20][21][22][23][24][25][26] Compared to traditional fl uorogens, which suffer from aggregation-caused quenching phenomenon at high concentrations, AIEgens show very weak fl uorescence in molecularly dissolved state but bright emission in aggregate state due to the inhibition of energy dissipation and restriction of intramolecular motion. [ 13,15,27,28 ] This unique property makes AIEgens great candidates for the design of light-up probes [29][30][31][32][33] and ultrabright organic nanoparticles (NPs) [ 26,27,34,35 ] for sensing and imaging applications. Recently, our group and others have reported several AIEgen NPs for cell tracing [36][37][38] and vascular imaging [ 34,39 ] with high brightness, good contrast, and nonobservable leakage, which provide the opportunity to further explore their potentials for practical biological problems, such as the evaluation of BBB damage and the resulted vascular leakage.To develop a sensitive and selective optical imaging method based on AIEgen NPs that can precisely test BBB integrity and map vascular leakage in animal models, in this work, we utilized 2,3-bis(4-(phenyl(4-(1,2,2-triphenylvinyl)phenyl)amino)phenyl)fumaronitrile (TPETPAFN), an AIEgen with bright red emission in the solid state and developed a strategy to fabricate NPs with controlled sizes of 60, 30, and 10 nm. [ 40 ] The good photostability and biocompatibility of these NPs guarantee the in vivo investigation of BBB. A rat model of photothrombotic ischemia (PTI) was selected to induce the BBB damage. Compared to the widely used ischemia models (middle cerebral artery occlusion), our model could produce ischemic stroke at a targeted single blood vessel with precise location, controlled size, and well-delimited boundary, which could ensure the precise evaluation of BBB integrity. [ 41,42 ] Using this model, we evaluated the integrity of the BBB during the hyperacute phase of ischemia using the TPETPAFN NPs. The extent of NP leakage in various brain locations in response to BBB disruption post The blood-brain barrier (BBB) is a specialized cerebral vascular system which is responsible for strict regulation of paracellular permeability and mediates entry of blood-borne substances in...

Drug Delivery to the Brain across the Blood–Brain Barrier Using Nanomaterials

“…Similarly, it has been demonstrated that 60 nm PS‐PEG particles combined with ultrasound techniques to disturb BBB, can be more diffusive in the normal rat brain than the 110 nm NPs . Furthermore, one study used 10, 30, and 60 nm biocompatible NIR NP; the 10 nm NPs showed poor selectivity, the 30 nm NPs were the most sensitive and selective for BBB damage evaluation, and the 60 nm NPs barely crossed the BBB . In this particular BBB damage imaging/evaluation case, both the 10 and 30 nm NPs can cross the BBB.…”

“…B) In vivo fluorescent imaging of PBI mice injected with vehicle alone (PBS) or PSiNPs conjugated with CAQK or CGGK . C) The in vivo images of the brain at 3 h post PTI (a) without NPs administration (b) with 60 nm NPs (c) 30 nm NPs, and (d) 10 nm NPs . D) Bioluminescent images of mice without Dir, with Dir emulsion or DLPAH nanoclusters via tail vein at 12 min after administration .…”

Organic Spherical Nucleic Acids for the Transport of a NIR‐II‐Emitting Dye Across the Blood–Brain Barrier

“…When the SR expressed on the bEnd.3 cell monolayer was blocked by poly I, the efficient transcytosis of NR@PS‐ b ‐DNA and NR@PS‐ b ‐DNA/Apt was inhibited, resulting in a significantly reduced accumulation in U87MG cells (Figure c and Supporting Information, Figure S6). To study the BBB penetration in vivo, the coronal slices of brains were collected from healthy mice at 3 h post‐injection of NR@PS‐ b ‐DNA and NR@PS‐ b ‐PEG. The CLSM images showed that prominent fluorescence was observed for the NR@PS‐ b ‐DNA group but no fluorescence for the NR@PS‐ b ‐PEG group, resulting in a significant difference in fluorescence intensity (Figure d).…”

Aggregation‐Induced Emission for Visualization in Materials Science

“…In addition, the proposed method was also adapted for the inspection of microdefects in the bone during the repair process, which required a nondestructive method. The fluorescent signals for both the cracks and defects can be clearly identified in the fluorescence images, which made this method a promising visualization probe for damage detection on the microscale …”

“…The fluorescent signals for both the cracks and defects can be clearly identified in the fluorescencei mages, which made this method ap romising visualizationp robe for damage detection on the microscale. [75]…”