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000278048 1001_ $$00000-0003-1041-5747$$aKhalin, Igor$$b0
000278048 245__ $$aNanocarrier Drug Release and Blood-Brain Barrier Penetration at Post-Stroke Microthrombi Monitored by Real-Time Förster Resonance Energy Transfer.
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000278048 520__ $$aNanotechnology holds great promise for improving the delivery of therapeutics to the brain. However, current approaches often operate at the organ or tissue level and are limited by the lack of tools to dynamically monitor cargo delivery in vivo. We have developed highly fluorescent lipid nanodroplets (LNDs) that enable tracking of nanocarrier behavior at the subcellular level while also carrying a Förster resonance energy transfer (FRET)-based drug delivery detection system (FedEcs) capable of monitoring cargo release in vivo. Using two-photon microscopy, we demonstrate that circulating LNDs in naïve mouse brain vasculature exhibit 3D real-time FRET changes, showing size-dependent stability over 2 h in blood circulation. Further, in the Nanostroke model, dynamic intravital two-photon imaging revealed that LNDs accumulated within cerebral postischemic microthrombi, where they released their cargo significantly faster than in normal blood circulation. Furthermore, the blood-brain barrier (BBB) became permeable at the microclot sites thereby allowing accumulated FedEcs-LNDs to cross the BBB and deliver their cargo to the brain parenchyma. This microthrombi-associated translocation was confirmed at the ultrastructural level via volume-correlative light-electron microscopy. Consequently, FedEcs represents an advanced tool to quantitatively study the biodistribution and cargo release of nanocarriers at high resolution in real-time. By enabling us to resolve passive targeting mechanisms poststroke, specifically, accumulation, degradation, and extravasation via poststroke microthrombi, this system could significantly enhance the translational validation of nanocarriers for future treatments of brain diseases.
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000278048 650_7 $$2Other$$ablood-brain barrier
000278048 650_7 $$2Other$$acorrelative light-electron microscopy
000278048 650_7 $$2Other$$amicrothrombosis
000278048 650_7 $$2Other$$ananocarriers
000278048 650_7 $$2Other$$astroke
000278048 650_7 $$2NLM Chemicals$$aDrug Carriers
000278048 650_7 $$2NLM Chemicals$$aLipids
000278048 650_2 $$2MeSH$$aBlood-Brain Barrier: metabolism
000278048 650_2 $$2MeSH$$aBlood-Brain Barrier: drug effects
000278048 650_2 $$2MeSH$$aAnimals
000278048 650_2 $$2MeSH$$aFluorescence Resonance Energy Transfer
000278048 650_2 $$2MeSH$$aMice
000278048 650_2 $$2MeSH$$aDrug Carriers: chemistry
000278048 650_2 $$2MeSH$$aStroke: drug therapy
000278048 650_2 $$2MeSH$$aStroke: metabolism
000278048 650_2 $$2MeSH$$aDrug Liberation
000278048 650_2 $$2MeSH$$aNanoparticles: chemistry
000278048 650_2 $$2MeSH$$aLipids: chemistry
000278048 650_2 $$2MeSH$$aThrombosis: drug therapy
000278048 650_2 $$2MeSH$$aThrombosis: metabolism
000278048 650_2 $$2MeSH$$aMice, Inbred C57BL
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000278048 7001_ $$aAdarsh, Nagappanpillai$$b1
000278048 7001_ $$0P:(DE-2719)2812260$$aSchifferer, Martina$$b2$$udzne
000278048 7001_ $$aWehn, Antonia$$b3
000278048 7001_ $$aBoide-Trujillo, Valeria J$$b4
000278048 7001_ $$aMamrak, Uta$$b5
000278048 7001_ $$aShrouder, Joshua$$b6
000278048 7001_ $$0P:(DE-2719)2810727$$aMisgeld, Thomas$$b7$$udzne
000278048 7001_ $$0P:(DE-2719)2810523$$aFilser, Severin$$b8$$eLast author$$udzne
000278048 7001_ $$00000-0002-2423-830X$$aKlymchenko, Andrey S$$b9
000278048 7001_ $$aPlesnila, Nikolaus$$b10
000278048 773__ $$0PERI:(DE-600)2383064-5$$a10.1021/acsnano.4c17011$$gVol. 19, no. 15, p. 14780 - 14794$$n15$$p14780 - 14794$$tACS nano$$v19$$x1936-0851$$y2025
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