A gain of function paradox: Targeted therapy for glioblastoma associated with abnormal NHE9 expression

Glioblastoma (GBM) is the most frequent and inevitably lethal primary brain cancer in adults. It is recognized that the overexpression of the endosomal Na+/H+ exchanger NHE9 is a potent driver of GBM progression. Patients with NHE9 overexpression have a threefold lower median survival relative to GBM patients with normal NHE9 expression, using available treatment options. New treatment strategies tailored for this GBM subset are much needed. According to the prevailing model, NHE9 overexpression leads to an increase in plasma membrane density of epidermal growth factor receptors (EGFRs) which consequently enhances GBM cell proliferation and migration. However, this increase is not specific to EGFRs. In fact, the hallmark of NHE9 overexpression is a pan‐specific increase in plasma membrane receptors. Paradoxically, we report that this gain of function in NHE9 can be exploited to effectively target GBM cells for destruction. When exposed to gold nanoparticles, NHE9 overexpressing GBM cells accumulated drastically high amounts of gold via receptor‐mediated endocytosis, relative to control. Irradiation of these cells with near‐infrared light led to apoptotic tumour cell death. A major limitation for delivering therapeutics to GBM cells is the blood‐brain barrier (BBB). Here, we demonstrate that macrophages loaded with gold nanoparticles can cross the BBB, deliver the gold nanoparticles and effect the demise of GBM cells. In combination with receptor tyrosine kinase inhibition, we show this approach holds great promise for a new GBM‐targeted therapy.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152030/1/jcmm14665.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152030/2/jcmm14665_am.pd

Self-assembled monolayers of small aromatic disulfide and diselenide molecules on polycrystalline gold films: a comparative study of the geometrical constraint using temperature-dependent surface-enhanced raman spectroscopy, X-ray photoelectron spectroscopy, and electrochemistry

A detailed investigation of the self-assembled monolayers of diphenyl disulfide (DDS), diphenyl diselenide (DDSe), and naphthalene disulfide (NDS) on polycrystalline gold films using surface-enhanced Raman spectroscopy (SERS), X-ray photoelectron spectroscopy (XPS), and electrochemistry is presented. Whereas DDS dissociatively chemisorbs on Au, in both DDSe and NDS, the Se-Se and S-S bonds, respectively, are preserved upon adsorption. All of the molecules adsorb with the molecular plane perpendicular to the surface. Temperature-dependent SERS studies suggest that the DDS monolayer is by far the most stable one and is stable up to a temperature of 423 K. Both DDSe and NDS desorb without breaking the diselenide and disulfide bonds. None of the monolayers show any structural change upon heating. XPS investigations show the presence of beam-induced damage upon X-ray exposure to DDS and NDS monolayers, and the damage is greater in the latter. Electrochemical investigations support the SERS and XPS data. Number of pinholes and defects are much less in the DDS monolayer than in NDS and DDSe. The impedance parameters such as double-layer capacitance, charge-transfer resistance, and diffusion coefficients measured at different frequencies support the above conclusion. It is suggested that the geometric constraint imposed by the rigid naphthalene ring inhibits the cleavage of the S-S bond, and consequently, the adsorption sites for sulfurs are not strongly bonded. For DDSe, it appears that the Se-Se distance is such that appropriate binding sites are available, thus leading to a more ordered monolayer. For DDS, the facile cleavage of the S-S bond leads to strong binding of the adsorbate molecules at the preferred surface sites, resulting in a rather well-ordered self-assembled structure

Formation of microcrystalline zirconia using the functionalized interface of a self-assembled monolayer of dithiol on polycrystalline gold at room temperature

A self-assembled monolayer of dithiol, namely 1,4-benzenedimethanethiol (BDT), on a polycrystalline gold surface was effectively used to carry out a two-dimensional reaction between pendent -SH and zirconium ion in solution to produce oriented monoclinic zirconia at room temperature on potentiodynamic cycling. Cyclic voltammetry (CV), X-ray diffraction (XRD), and scanning electron microscopy (SEM) were used to follow the monolayer formation, Zr-attachment on the SAM surface, and the subsequent formation of ZrO2 phase. The XRD analysis shows the growth of the crystal as monoclinic form with a size ranging from 5 to 15 μ m. A tentative reaction scheme and also a mechanism are proposed to understand the role of SAM in changing the size and habit during the crystallization of ZrO2 at room temperature

Formation of a self-assembled monolayer of diphenyl diselenide on polycrystalline gold

Results of cyclic voltammetric and impedance measurements demonstrate that small aromatic diselenides like diphenyl diselenide can form a self-assembled monolayer with 99% surface coverage on polycrystalline gold. The redox response of a solution species like Fe(CN)4-/3- is partially blocked as a result of SAM formation, and the double layer capacitance is also observed to decrease (i.e., 9.4 μ F/cm2 as compared to 21 μ F/cm2 for bare gold) due to the increased separation between the electrode surface and the plane of closest approach for ionic charges. Impedance analysis suggests that pinholes tend to distribute as isolated patches over the monolayer surface. Furthermore, quartz crystal microbalance measurement shows a steady-state mass loading of about 292 ng, indicating the monolayer formation

Novel room-temperature synthesis of microcrystalline zirconia

A novel room-temperature method is described for the preparation of microcrystalline zirconia (ZrO2) in monoclinic form via a simple electrochemical technique. Almost-epitaxial growth is observed, with crystal sizes in the range of 5-15 μm. A tentative reaction scheme also is suggested, to elucidate the underlying process that leads to the formation of the ZrO2 phase

In Situ Generation of Two-Dimensional Au–Pt Core–Shell Nanoparticle Assemblies

Abstract Two-dimensional assemblies of Au&#8211;Pt bimetallic nanoparticles are generated in situ on polyethyleneimmine (PEI) silane functionalized silicon and indium tin oxide (ITO) coated glass surfaces. Atomic force microscopy (AFM), UV&#8211;Visible spectroscopy, and electrochemical measurements reveal the formation of core&#8211;shell structure with Au as core and Pt as shell. The core&#8211;shell structure is further supported by comparing with the corresponding data of Au nanoparticle assemblies. Static contact angle measurements with water show an increase in hydrophilic character due to bimetallic nanoparticle generation on different surfaces. It is further observed that these Au&#8211;Pt core&#8211;shell bimetallic nanoparticle assemblies are catalytically active towards methanol electro-oxidation, which is the key reaction for direct methanol fuel cells (DMFCs).</p

Self-assembled monolayers of small aromatic disulfide and diselenide molecules on polycrystalline gold films: a comparative study of the geometrical constraint using temperature-dependent surface-enhanced raman spectroscopy, X-ray photoelectron spectroscopy, and electrochemistry

A detailed investigation of the self-assembled monolayers of diphenyl disulfide (DDS), diphenyl diselenide (DDSe), and naphthalene disulfide (NDS) on polycrystalline gold films using surface-enhanced Raman spectroscopy (SERS), X-ray photoelectron spectroscopy (XPS), and electrochemistry is presented. Whereas DDS dissociatively chemisorbs on Au, in both DDSe and NDS, the Se-Se and S-S bonds, respectively, are preserved upon adsorption. All of the molecules adsorb with the molecular plane perpendicular to the surface. Temperature-dependent SERS studies suggest that the DDS monolayer is by far the most stable one and is stable up to a temperature of 423 K. Both DDSe and NDS desorb without breaking the diselenide and disulfide bonds. None of the monolayers show any structural change upon heating. XPS investigations show the presence of beam-induced damage upon X-ray exposure to DDS and NDS monolayers, and the damage is greater in the latter. Electrochemical investigations support the SERS and XPS data. Number of pinholes and defects are much less in the DDS monolayer than in NDS and DDSe. The impedance parameters such as double-layer capacitance, charge-transfer resistance, and diffusion coefficients measured at different frequencies support the above conclusion. It is suggested that the geometric constraint imposed by the rigid naphthalene ring inhibits the cleavage of the S-S bond, and consequently, the adsorption sites for sulfurs are not strongly bonded. For DDSe, it appears that the Se-Se distance is such that appropriate binding sites are available, thus leading to a more ordered monolayer. For DDS, the facile cleavage of the S-S bond leads to strong binding of the adsorbate molecules at the preferred surface sites, resulting in a rather well-ordered self-assembled structure

Comparative behavior of aromatic disulfide and diselenide monolayers on polycrystalline gold films using cyclic voltammetry, STM, and quartz crystal microbalance

A comparative investigation of the self-assembled monolayers of diphenyl disulfide (DDS), diphenyl diselenide (DDSe), and naphthalene disulfide (NDS) on polycrystalline gold films using STM, QCM, and electrochemical techniques is presented. The geometric constraint imposed by the rigid naphthalene ring for NDS inhibits the cleavage of the S-S bond, thus adversely affecting the monolayer organization and stability relative to the monolayers formed with DDS and DDSe. A comparative analysis using techniques like cyclic voltammetry and quartz-crystal microbalance indicates that, for DDS, the facile cleavage of the S-S bond leads to strong binding of the adsorbate molecules at the preferred surface sites, resulting in a rather well-organized self-assembled structure. The STM pattern of NDS reveals a periodic domain (i.e., less than 10 nm in size) while no such small domains are seen in the case of DDS and DDSe due to the orientational flexibility of the rings