A thrombus (blood clot), composed mainly of activated platelets and fibrin, obstructs arteries or veins, leading to various life-threatening diseases. Inspired by the distinctive physicochemical characteristics of thrombi such as abundant fibrin and an elevated level of hydrogen peroxide (HO), we developed thrombus-specific theranostic (T-FBM) nanoparticles that could provide HO-triggered photoacoustic signal amplification and serve as an antithrombotic nanomedicine. T-FBM nanoparticles were designed to target fibrin-rich thrombi and be activated by HO to generate CO bubbles to amplify the photoacoustic signal. In the phantom studies, T-FBM nanoparticles showed significant amplification of ultrasound/photoacoustic signals in a HO-triggered manner. T-FBM nanoparticles also exerted HO-activatable antioxidant, anti-inflammatory, and antiplatelet activities on endothelial cells. In mouse models of carotid arterial injury, T-FBM nanoparticles significantly enhanced the photoacoustic contrast specifically in thrombosed vessels and significantly suppressed thrombus formation. We anticipate that T-FBM nanoparticles hold great translational potential as nanotheranostics for HO-associated cardiovascular diseases.
A main
challenge in the development of anticancer drugs that eradicate
cancer cells specifically with minimal toxicity to normal cells is
to identify the cancer-specific properties. Cancer cells sustain a
higher level of reactive oxygen species, owing to metabolic and signaling
aberrations and unrestrained growth. Cancer cells are also furnished
with a powerful reducing environment, owing to the overproduction
of antioxidants such as glutathione (GSH). Therefore, the altered
redox balance is probably the most prevailing property of cancer cells
distinct from normal cells, which could serve as a plausible therapeutic
target. In this work, we developed a GSH-depleting pro-oxidant, benzoyloxy
dibenzyl carbonate, termed B2C, which is capable of rapidly declining
GSH and elevating oxidative stress to a threshold level above which
cancer cells cannot survive. B2C was designed to release quinone methide
(QM) that rapidly depletes GSH through esterase-mediated hydrolysis.
B2C was able to rapidly deplete GSH and induce an overwhelming level
of oxidative stress in cancer cells, leading to mitochondrial disruption,
activation of procaspase-3 and PARP-1, and cleavage of Bcl-2. In the
study of tumor xenograft models, intravenously injected B2C caused
apoptotic cell death in tumors and significantly suppressed tumor
growth. These findings provide a new insight into the design of more
effective anticancer drugs, which exploit altered redox balance in
cancer cells.
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