Rolipram-loaded PgP nanoparticle reduces secondary injury and enhances motor function recovery in a rat moderate contusion SCI model.

Spinal cord injury (SCI) results in immediate axonal damage and cell death, as well as a prolonged secondary injury consist of a cascade of pathophysiological processes. One important aspect of secondary injury is activation of phosphodiesterase 4 (PDE4) that leads to reduce cAMP levels in the injured spinal cord. We have developed an amphiphilic copolymer, poly (lactide-co-glycolide)-graft-polyethylenimine (PgP) that can deliver Rolipram, the PDE4 inhibitor. The objective of this work was to investigate the effect of rolipram loaded PgP (Rm-PgP) on secondary injury and motor functional recovery in a rat moderate contusion SCI model. We observed that Rm-PgP can increase cAMP level at the lesion site, and reduce secondary injury such as the inflammatory response by macrophages/microglia, astrogliosis by activated astrocytes and apoptosis as well as improve neuronal survival at 4 weeks post-injury (WPI). We also observed that Rm-PgP can improve motor functional recovery after SCI over 4 WPI.

Enhanced Endothelial Cell Delivery for Repairing Injured Endothelium via Pretargeting Approach and Bioorthogonal Chemistry.

Arterial wall injury often leads to endothelium cell activation, endothelial detachment, and atherosclerosis plaque formation. While abundant research efforts have been placed on treating the end stages of the disease, no cure has been developed to repair injured and denude endothelium often occurred at an early stage of atherosclerosis. Here, a pretargeting cell delivery strategy using combined injured endothelial targeting nanoparticles and bioorthogonal click chemistry approach was developed to deliver endothelial cells to replenish the injured endothelium via a two-step process. First, nanoparticles bearing glycoprotein 1b α (Gp1bα) proteins and tetrazine (Tz) were fabricated to provide a homogeneous nanoparticle coating on an injured arterial wall via the interactions between Gp1bα and von Willebrand factor (vWF), a ligand that is present on denuded endothelium. Second, transplanted endothelium cells bearing transcyclooctene (TCO) would be quickly immobilized on the surfaces of nanoparticles via TCO:Tz reactions. In vitro binding studies under both static and flow conditions confirmed that our novel Tz-labeled Gp1bα-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles can successfully pretargeted toward the injured site and support rapid adhesion of endothelial cells from the circulation. Ex vivo results also confirm that such an approach is highly efficient in mediating the local delivery of endothelial cells at the sites of arterial injury. The results support that this pretargeting cell delivery approach may be used for repairing injured endothelium in situ at its early stage.

A pretargeting nanoplatform for imaging and enhancing anti-inflammatory drug delivery.

This work details a newly developed "sandwich" nanoplatform via neutravidin-biotin system for the detection and treatment of inflammation. First, biotinylated- and folate-conjugated optical imaging micelles targeted activated macrophages via folate/folate receptor interactions. Second, multivalent neutravidin proteins in an optimal concentration accumulated on the biotinylated macrophages. Finally, biotinylated anti-inflammatory drug-loaded micelles delivered drugs effectively at the inflammatory sites via a highly specific neutravidin-biotin affinity. Both in vitro and in vivo studies have shown that the "sandwich" pretargeting platform was able to diagnose inflammation by targeting activated macrophages as well as improve the therapeutic efficacy by amplifying the drug delivery to the inflamed tissue. The overall results support that our new pretargeting platform has the potential for inflammatory disease diagnosis and treatment.

Development of a dual-wavelength fluorescent nanoprobe for in vivo and in vitro cell tracking consecutively.

Many imaging probes have been developed for a wide variety of imaging modalities. However, no optical imaging probe could be utilized for both microscopic and whole animal imaging. To fill the gap, the dual-wavelength fluorescent imaging nanoprobe was developed to simultaneously carry both visible-range fluorescent dye and near-infrared (NIR) dye. Emission scan confirms that the nanoprobe exhibits two separate peaks with strong fluorescent intensity in both visible and NIR ranges. Furthermore, the dual-wavelength fluorescent nanoprobe has high photostability and colloidal stability, as well as long shelf-life. In vitro cell culture experiments show that the nanoprobe has the ability to label different types of cells (namely, esophageal, prostate, fibroblast and macrophage cell) for fluorescent microscope imaging. More importantly, cell tracking experiments confirm that cell migration and distribution in various organs can be tracked in real time using in vivo whole-body NIR imaging and in vitro microscopic imaging, respectively.

Preparation of a novel injectable in situ-gelling nanoparticle with applications in controlled protein release and cancer cell entrapment.

Temperature sensitive injectable hydrogels have been used as drug/protein carriers for a variety of pharmaceutical applications. Oligo(ethylene glycol) methacrylate (OEGMA) monomers with varying ethylene oxide chain lengths have been used for the synthesis of in situ forming hydrogel. In this study, a new series of thermally induced gelling hydrogel nanoparticles (PMOA hydrogel nanoparticles) was developed by copolymerization with di(ethylene glycol) methyl ether methacrylate (MEO2MA), poly(ethylene glycol) methyl ether methacrylate (300 g mol-1, OEGMA300), and acrylic acid (AAc). The effects of acrylic acid content on the physical, chemical, and biological properties of the nanoparticle-based hydrogels were investigated. Due to its high electrostatic properties, addition of AAc increases LCST as well as gelation temperature. Further, using Cy5-labelled bovine serum albumin and erythropoietin (Epo) as model drugs, studies have shown that the thermogelling hydrogels have the ability to tune the release rate of these proteins in vitro. Finally, the ability of Epo releasing hydrogels to recruit prostate cancer cells was assessed in vivo. Overall, our results support that this new series of thermally induced gelling systems can be used as protein control releasing vehicles and cancer cell traps.

Correction: Preparation of a novel injectable in situ-gelling nanoparticle with applications in controlled protein release and cancer cell entrapment.

[This corrects the article DOI: 10.1039/C8RA06589F.].