Detection of Anticancer Drug-Induced Cardiotoxicity Using VCAM1-Targeted Nanoprobes.

Chemotherapy-induced cardiac toxicity is an undesirable yet very common effect that increases the risk of death and reduce the quality of life of individuals undergoing chemotherapy. However, no feasible methods and techniques are available to monitor and detect the degree of cardiotoxicity at an early stage. Therefore, in this project, we aim to develop a fluorescent nanoprobe to image the toxicity within the cardiac tissue induced by an anticancer drug. We have observed that vascular cell adhesion molecule 1 (VCAM1) protein alone with collagen was overly expressed within the heart, when an animal was treated with doxorubicin (DOX), because of inflammation in the epithelial cells. We hypothesize that developing a VCAM1-targeted peptide-based (VHPKQHRGGSKGC) fluorescent nanoprobe can detect and visualize the affected heart. In this regard, we prepared a poly(lactic-co-glycolic acid) (PLGA) nanoparticle linked with VCAM1 peptide and rhodamine B (PLGA-VCAM1-RhB). Selective binding and higher accumulation of the PLGA-VCAM1-RhB nanoprobes were detected in DOX-treated human cardiomyocyte cells (HCMs) compared to the untreated cells. For in vivo studies, DOX (5 mg/kg) was injected via the tail vein once in two weeks for 6 weeks (3 injection total). PLGA-VCAM1-RhB and PLGA-RhB were injected via the tail vein after 1 week of the last dose of DOX, and images were taken 4 h after administration. A higher fluorescent signal of PLGA-RhB-VCAM-1 (48.62% ± 12.79%) was observed in DOX-treated animals compared to the untreated control PLGA-RhB (10.61% ± 4.90) within the heart, indicating the specificity and targeting ability of PLGA-VCAM1-RhB to the inflamed tissues. The quantified fluorescence intensity of the homogenized cardiac tissue of PLGA-RhB-VCAM1 showed 156% higher intensity than the healthy control group. We conclude that PLGA-VCAM1-RhB has the potential to bind inflamed cardiac cells, thereby detecting DOX-induced cardiotoxicity and damaged heart at an early stage.

Bile acid linked ß-glucan nanoparticles for liver specific oral delivery of biologics.

Oral delivery remains one of the most convenient routes for drug administration compared to intravenous, intramuscular, and via suppositories. However, due to the risk of degradation, and proteolysis of molecules in the acidic gastric medium, as well as the difficulty of transporting large molecules through the intestinal membrane, more than half of the therapeutic molecules are prohibited for oral administration. Moreover, most of the large molecules and biological therapeutics are not available in oral dosage form due to their instability in the stomach and inability of intestinal absorption. To achieve expected bioavailability, an orally administered therapeutic molecule must be protected within the stomach, and transportation facilitated via the small intestine. In this project, we have introduced a hybrid carrier, composed of Taurocholic Acid (TA) and ß-Glucan (TAG), that is shown to be effective for the simultaneous protection of the biologics in acidic buffer and simulated gastric juice as well as facilitate enhanced absorption and transportation via the small intestine. In this project, we have used an eGFP encoded plasmid as a model biologic to prepare particles mediated with TAG. TAG show the potential of enhancing transfection and expression of eGFP as we have observed two fold higher expression in the cell upon coincubation for 4 h. In vivo studies on orally dosed mice showed that eGFP expression in the liver was significantly higher in TAG containing particles compared to particles without TAG. The findings suggest that the TAG carrier is capable of not only preserving biologics but also transporting them more efficiently to the liver. As a result, this strategy can be employed for a variety of liver-targeted therapeutic delivery to treat a variety of liver diseases.

Design of Neutron Microscopes Equipped with Wolter Mirror Condenser and Objective Optics for High-Fidelity Imaging and Beam Transport.

We present and compare the designs of three types of neutron microscopes for high-resolution neutron imaging. Like optical microscopes, and unlike standard neutron imaging instruments, these microscopes have both condenser and image-forming objective optics. The optics are glancing-incidence axisymmetric mirrors and therefore suitable for polychromatic neutron beams. The mirrors are designed to provide a magnification of 10 to achieve a spatial resolution of better than 10 µm. The resolution of the microscopes is determined by the mirrors rather than by the L/Dratio as in conventional pinhole imaging, leading to possible dramatic improvements in the signal rate. We predict the increase in the signal rate by at least two orders of magnitude for very high-resolution imaging, which is always flux limited. Furthermore, in contrast to pinhole imaging, in the microscope, the samples are placed far from the detector to allow for a bulky sample environment without sacrificing spatial resolution.

High-resolution neutron depolarization microscopy of the ferromagnetic transitions in Ni3Al and HgCr2Se4 under pressure.

We performed neutron imaging of ferromagnetic transitions in Ni3Al and HgCr2Se4 crystals. These neutron depolarization measurements revealed bulk magnetic inhomogeneities in the ferromagnetic transition temperature with spatial resolution of about 100 µm. To obtain such spatial resolution, we employed a novel neutron microscope equipped with Wolter mirrors as a neutron image-forming lens and a focusing neutron guide as a neutron condenser lens. The images of Ni3Al show that the sample does not homogeneously go through the ferromagnetic transition; the improved resolution allowed us to identify a distribution of small grains with slightly off-stoichiometric composition. Additionally, neutron depolarization imaging experiments on the chrome spinel, HgCr2Se4, under pressures up to 15 kbar highlight the advantages of the new technique especially for small samples or sample environments with restricted sample space. The improved spatial resolution enables one to observe domain formation in the sample while decreasing the acquisition time despite having a bulky pressure cell in the beam.