carbocyanines and Brain-Injuries--Traumatic

More than 2.8 million annually in the United States are afflicted with some form of traumatic brain injury (TBI), where 75% of victims have a mild form of TBI (MTBI). TBI risk is higher for individuals engaging in physical activities or involved in accidents. Although MTBI may not be initially life-threatening, a large number of these victims can develop cognitive and physical dysfunctions. These late clinical sequelae have been attributed to the development of secondary injuries that can occur minutes to days after the initial impact. To minimize brain damage from TBI, it is critical to diagnose and treat patients within the first or "golden" hour after TBI. Although it would be very helpful to quickly determine the TBI locations in the brain and direct the treatment selectively to the affected sites, this remains a challenge. Herein, we disclose our novel strategy to target cyclosporine A (CsA) into TBI sites, without the need to locate the exact location of the TBI lesion. Our approach is based on TBI treatment with a cyanine dye nanocage attached to CsA, a known therapeutic agent for TBI that is associated with unacceptable toxicities. In its caged form, CsA remains inactive, while after near-IR light photoactivation, the resulting fragmentation of the cyanine nanocage leads to the selective release of CsA at the TBI sites.

Topics: Animals; Brain Injuries, Traumatic; Carbocyanines; Cyclosporine; Disease Models, Animal; Drug Carriers; Drug Liberation; Humans; Infrared Rays; Nanoparticles; Neuroprotective Agents; Photochemotherapy; Rats

Neural stem cells (NSCs) have been attractive donor sources for cell therapy in traumatic brain injuries (TBI). Monitoring the fate of transplanted cells, including the survival and differentiation, will provide vital information to assess the outcome during the therapy time course. However, the current labeling methods are based on the principles of cell endocytosis, demanding relatively high fluorescent probes concentration and long incubation time, which may affect the proliferation and differentiation of transplanted cells. In our study, an efficient and relatively fast labeling strategy for NSCs with Cy3 based on DNA hybridization was proposed for monitoring the fate of transplanted cells. The oligo[dA]

Topics: Animals; Brain Injuries, Traumatic; Carbocyanines; Cell Differentiation; Cell Survival; Disease Models, Animal; DNA; Mice; Neural Stem Cells; Nucleic Acid Hybridization; Stem Cell Transplantation

Traumatic brain injury (TBI) is a serious public health problem, often with devastating consequences for patients and their families. Affordable and timely therapies can have a substantial impact on outcomes in severe TBI. Despite the common use of sedatives and anesthetics in the acute phase of TBI management, their effect on glial cells is not well understood. We investigated the effect of a commonly used sedative, pentobarbital, on glial cells and their uptake of nanoparticles. First, we studied how pentobarbital affects BV2 mouse microglial cells in culture. The cell morphology was imaged by confocal microscopy and analyzed. Our results suggest that microglia change to a more swollen, 'activated' shape with pentobarbital (cell area increased by approximately 20%, p<0.001). Such glial activation may have negative implications for the ability of the injured brain to clear edema. Second, we investigated how pentobarbital treatment affected nanoparticle uptake. BV-2 mouse microglial cells in the presence and absence of pentobarbital were treated with fluorescently-labeled, hydroxyl-functionalized poly(amidoamine) dendrimer nanoparticles (Dendrimer-Cy5). We demonstrated that the presence of pentobarbital increased the dendrimer nanoparticle uptake significantly (~2-fold both 2 and 6h following treatment). This semi-quantitative fluorescence assessment was broadly consistent among confocal image analysis, flow cytometry, and fluorescence quantification of cell-extracted dendrimer-Cy5. Although anesthetics appear to activate microglia, the increased uptake of dendrimer nanoparticles in their presence can be exploited to deliver drug-loaded nanoparticles directly to microglia after TBI. These drugs could restore glial and glymphatic function, enabling efficient drainage of waste and fluid from the brain and effectively improving recovery after TBI. A key future direction is to validate these findings in TBI models.

Topics: Anesthetics; Animals; Brain Injuries, Traumatic; Carbocyanines; Cell Line; Dendrimers; Drug Delivery Systems; Fluorescent Dyes; Mice; Microglia; Pentobarbital