Targeting reactive astrocytes by pH-responsive ligand-bonded polymeric nanoparticles in spinal cord injury.

In spinal cord injuries, axonal regeneration decreases with the activation of astrocytes followed by glial scar formation. Targeting reactive astrocytes has been recently performed by unsafe viral vectors to inhibit gliosis. In the current study, biocompatible polymeric nanoparticles were selected as an alternative for viruses to target reactive astrocytes for further drug/gene delivery applications. Lipopolysaccharide-bonded chitosan-quantum dots/poly acrylic acid nanoparticles were prepared by ionic gelation method to target reactive astrocytes both in vitro and in spinal cord-injured rats. Owing to their biocompatibility and pH-responsive behavior, chitosan and poly acrylic acid were the main components of nanoparticles. Nanoparticles were then chemically labeled with quantum dots to track the cell uptake and electrostatically interacted with lipopolysaccharide as a targeting ligand. In vitro and in vivo studies were performed in triplicate and all data were expressed as the mean ± the standard error of the mean. Smart nanoparticles with optimum size (61.9 nm) and surface charge (+ 12.5 mV) successfully targeted primary reactive astrocytes extracted from the rat cerebral cortex. In vitro studies represented high cell viability (96%) in the exposure of biocompatible nanoparticles. The pH-responsive behavior of nanoparticles was proved by their internalization into the cell's nuclei due to the swelling and endosomal escape of nanoparticles in acidic pH. In vivo studies demonstrated higher transfection of nanoparticles into reactive astrocytes compared to the neurons. pH-responsive ligand-bonded chitosan-based nanoparticles are good alternatives for viral vectors in targeted delivery applications for the treatment of spinal cord injuries.

Co-delivery of minocycline and paclitaxel from injectable hydrogel for treatment of spinal cord injury.

Spinal cord injury (SCI) induces pathological and inflammatory responses that create an inhibitory environment at the site of trauma, resulting in axonal degeneration and functional disability. Combination therapies targeting multiple aspects of the injury, will likely be more effective than single therapies to facilitate tissue regeneration after SCI. In this study, we designed a dual-delivery system consisting of a neuroprotective drug, minocycline hydrochloride (MH), and a neuroregenerative drug, paclitaxel (PTX), to enhance tissue regeneration in a rat hemisection model of SCI. For this purpose, PTX-encapsulated poly (lactic-co-glycolic acid) PLGA microspheres along with MH were incorporated into the alginate hydrogel. A prolonged and sustained release of MH and PTX from the alginate hydrogel was obtained over eight weeks. The obtained hydrogels loaded with a combination of both drugs or each of them alone, along with the blank hydrogel (devoid of any drugs) were injected into the lesion site after SCI (at the acute phase). Histological assessments showed that the dual-drug treatment reduced inflammation after seven days. Moreover, a decrease in the scar tissue, as well as an increase in neuronal regeneration was observed after 28 days in rats treated with dual-drug delivery system. Over time, a fast and sustained functional improvement was achieved in animals that received dual-drug treatment compared with other experimental groups. This study provides a novel dual-drug delivery system that can be developed to test for a variety of SCI models or neurological disorders.

Neuropathological and genomic characterization of glioblastoma-induced rat model: How similar is it to humans for targeted therapy?

Glioblastoma multiforme (GBM) is a unique aggressive tumor and mostly develops in the brain, while rarely spreading out of the central nervous system. It is associated with a high mortality rate; despite tremendous efforts having been made for effective therapy, tumor recurrence occurs with high prevalence. To elucidate the mechanisms that lead to new drug discovery, animal models of tumor progression is one of the oldest and most beneficial approaches to not only investigating the aggressive nature of the tumor, but also improving preclinical research. It is also a useful tool for predicting novel therapies' effectiveness as well as side effects. However, there are concerns that must be considered, such as the heterogeneity of tumor, biological properties, pharma dynamic, and anatomic shapes of the models, which have to be similar to humans as much as possible. Although several methods and various species have been used for this approach, the real recapitulation of the human tumor has been left under discussion. The GBM model, which has been verified in this study, has been established by using the Rat C6 cell line. By exploiting bioinformatic tools, the similarities between aberrant gene expression and pathways have been predicted. In this regard, 610 common genes and a number of pathways have been detected. Moreover, while magnetic resonance imaging analysis enables us to compare tumor features between these two specious, pathological findings provides most of the human GBM characteristics. Therefore, the present study provides genomics, pathologic, and imaging evidence for showing the similarities between human and rat GBM models.