Abstract
BackgroundApoptotic neuronal death is known as programmed cell death. Inhibition of this progression might contribute to a new treatment strategy. However, methods for in vivo detection of live apoptotic cells are in need to be developed and established.Context and purposeThe purpose of this study is to develop a new method for in vivo brain imaging for live apoptotic lesions using magnetic resonance imaging (MRI). We focused on the specific accumulation of our recently developed functional magnetic nanoparticles (FMNPs) into apoptotic cells using a rat cerebral ischemia model. Sulphorhodamine B, fluorescent dye was linked to valylalanylaspartic acid fluoromethyl ketone as a pan-caspase inhibitor to form SR-FLIVO. SR-FLIVO was bound with FMNPs to develop SR-FLIVO-FMNP probe. Ischemic rat brains were scanned by 7T MRI before and after intravenous injection of SR-FLIVO-FMNP and the distribution was evaluated by subtraction images of T2* colored mapping. SR-FLIVO, intracellular FMNPs, and T2* reduction area were histologically analyzed. The distribution of SR-FLIVO-FMNP was evaluated by subtracting the T2* signal images and was significantly correlated with the histological findings by TUNEL staining.ResultsOur experimental results revealed several findings where our newly developed probe SR-FLIVO-FMNP was intravenously administered into ischemic rats and FLIVO expression was tracked and found in apoptotic cells in rat brains after cerebral ischemia. A remarkable T2* reduction within the ischemic lesion was recorded using MRI based SR-FLIVO-FMNP probe as a contrasting agent due to the specific probe accumulation in apoptotic cells whereas, no observation of T2* reduction within the non-ischemic lesion due to no probe accumulation in non-apoptotic cells. Histological analysis based on the correlation between FLIVO and TUNEL staining showed that almost all FLIVO-positive cells were positive for TUNEL staining. These findings suggest the possibility for establishment of in vivo targeting delivery methods to live apoptotic cells based on conjugation of magnetic and fluorescent dual functional probes.ConclusionA newly developed probe SR-FLIVO-FMNP might be considered as a useful probe for in vivo apoptotic detection, and FMNPs might be a strong platform for noninvasive imaging and targeting delivery.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-016-0173-1) contains supplementary material, which is available to authorized users.
Highlights
Apoptotic neuronal death is known as programmed cell death
Our experimental results revealed several findings where our newly developed probe SR-FLIVO-functional magnetic nanoparticles (FMNPs) was intravenously administered into ischemic rats and FLIVO expression was tracked and found in apoptotic cells in rat brains after cerebral ischemia
It should be noted that the influence of SR-FLIVO-FMNP on T2* reduction was relatively modest compared with that of a standard or commercially available contrast agent based on Fe3O4 magnetic iron oxide nanoparticles (MNPs) (Fig. 2)
Summary
Apoptotic neuronal death is known as programmed cell death. Inhibition of this progression might contribute to a new treatment strategy. Methods for in vivo detection of live apoptotic cells are in need to be developed and established. Context and purpose: The purpose of this study is to develop a new method for in vivo brain imaging for live apoptotic lesions using magnetic resonance imaging (MRI). We focused on the specific accumulation of our recently developed functional magnetic nanoparticles (FMNPs) into apoptotic cells using a rat cerebral ischemia model. Ischemic rat brains were scanned by 7T MRI before and after intravenous injection of SR-FLIVO-FMNP and the distribution was evaluated by subtraction images of T2* colored mapping. In vivo detection of apoptotic cells can provide the physician with important information to develop further therapeutic strategies in chemotherapy or radiotherapy of tumors, in transplantation of organs, or in rescue of ischemic areas [2]. Yivgi-Ohana et al [8] used fluorescence microscopy to examine the in vivo apoptosis expression of split yellow fluorescence protein (YFP) fragments in liver hepatocytes
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