Glioblastoma multiforme (GBM) is the most lethal primary intracranial malignant neoplasm in adults and most resistant to treatment. Integration of gene therapy and chemotherapy, chemovirotherapy, has the potential to improve treatment. We have introduced an intravenous bacteriophage (phage) vector for dual targeting of therapeutic genes to glioblastoma. It is a hybrid AAV/phage, AAVP, designed to deliver a recombinant adeno‐associated virus genome (rAAV) by the capsid of M13 phage. In this vector, dual tumor targeting is first achieved by phage capsid display of the RGD4C ligand that binds the α v β 3 integrin receptor. Second, genes are expressed from a tumor‐activated and temozolomide (TMZ)‐induced promoter of the glucose‐regulated protein, Grp78 . Here, we investigated systemic combination therapy using TMZ and targeted suicide gene therapy by the RGD4C/AAVP‐ Grp78 . Firstly, in vitro we showed that TMZ increases endogenous Grp78 gene expression and boosts transgene expression from the RGD4C/AAVP‐ Grp78 in human GBM cells. Next, RGD4C/AAVP‐ Grp78 targets intracranial tumors in mice following intravenous administration. Finally, combination of TMZ and RGD4C/AAVP‐ Grp78 targeted gene therapy exerts a synergistic effect to suppress growth of orthotopic glioblastoma.

The availability of catalytic/reducing sites at metallic Cu0 sources during supplemental activator and reducing agent atom transfer radical polymerization (SARA ATRP) is regulated by the components of the polymerization mixture, including ligand (L), alkyl halide initiator (R–X), and CuII-based deactivator. Their contributions were analyzed by quantifying the dissolution of Cu species within a quartz crystal microbalance with dissipation (QCM-D), subjecting a Cu0-coated sensor to different polymerization mixtures. The control of catalyst diffusion from Cu0 was subsequently exploited to fabricate structured polymer brushes with diverse compositions, when ATRP was performed from surface-immobilized initiators in the presence of a Cu0 plate, placed at a determined distance (d) from the substrate. Surface-initiated ATRP in the presence of Cu0 (Cu0-SI-ATRP) is compatible with a broad variety of monomers, including oligo­(ethylene glycol) acrylate (OEGA), methyl acrylate (MA), and acrylamide (AAm). The kinetics of brush growth is finely tuned by the independent variation of d, polymerization time, and concentration of added deactivator. Modulation of these parameters allowed us to generate homopolymer and multiblock copolymer brush gradients featuring a variety of morphologies and controlled interfacial properties, with unprecedented spatial resolution over the brush structure.

The use of zerovalent iron (Fe 0 )-coated plates, which act both as a source of catalyst and as a reducing agent during surface-initiated atom transfer radical polymerization (SI-ATRP), enables the controlled growth of a wide range of polymer brushes under ambient conditions, and utilizing either organic or aqueous reaction media. Thanks to its cytocompatibility, Fe 0 SI-ATRP can be applied within cell cultures, providing a tool that can broadly and dynamically modify the substrate's affinity towards cells, without influencing their viability. Upon systematically assessing the application of Fe-based catalytic systems in the controlled grafting of polymers, Fe 0 SI-ATRP emerges as an extremely versatile technique that could be applied to tune the physicochemical properties of cell's microenvironments on biomaterials or within tissue engineering constructs.Experimental details and further characterization are included in the Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org.

Side population (SP) cells are an enriched source of cancer-initiating cells with stemness characteristics, generated by increased ABC transporter activity, which has served as a unique hallmark for multiple myeloma (MM) stem cell studies. Here we isolated and identified MM SP cells via Hoechst 33342 staining. Furthermore, we demonstrate that SP cells possess abnormal cell cycle, clonogenicity, and high drug efflux characteristics-all of which are features commonly seen in stem cells. Interestingly, we found that bortezomib, As2O3, and melphalan all affected apoptosis and clonogenicity in SP cells. We followed by characterizing the miRNA signature of MM SP cells and validated the specific miR-451 target tuberous sclerosis 1 (TSC1) gene to reveal that it activates the PI3K/Akt/mTOR signaling in MM SP cells. Inhibition of miR-451 enhanced anti-myeloma novel agents' effectiveness, through increasing cells apoptosis, decreasing clonogenicity, and reducing MDR1 mRNA expression. Moreover, the novel specific PI3K/Akt/mTOR signaling inhibitor S14161 displayed its prowess as a potential therapeutic agent by targeting MM SP cells. Our findings offer insights into the mechanisms regulating MM SP cells and provide a novel strategy to overcome resistance to existing therapies against myeloma.

The exceptional features of Cu0-mediated surface-initiated atom transfer radical polymerization (Cu0 SI-ATRP), and its potential for implementation in technologically relevant surface functionalizations are demonstrated thanks to a comprehensive understanding of its mechanism. Cu0 SI-ATRP enables the synthesis of multifunctional polymer brushes with a remarkable degree of control, over extremely large areas and without the need for inert atmosphere or deoxygenation of monomer solutions. When a polymerization mixture is placed between a flat copper plate and an ATRP-initiator-functionalized substrate, the vertical distance between these two overlaying surfaces determines the tolerance of the grafting process toward the oxygen, while the composition of the polymerization solution emerges as the critical parameter regulating polymer-grafting kinetics. At very small distances between the copper plate and the initiating surfaces, the oxygen dissolved in the solution is rapidly consumed via oxidation of the metallic substrate. In the presence of ligand, copper species diffuse to the surface-immobilized initiators and trigger a rapid growth of polymer brushes. Concurrently, the presence and concentration of added CuII regulates the generation of CuI-based activators through comproportionation with Cu0. Hence, under oxygen-tolerant conditions, the extent of comproportionation, together with the solvent-dependent rate constant of activation (k act) of ATRP are the main determinants of the growth rate of polymer brushes.

A hydrogen-bonded organic framework (HOF) was constructed by avoiding potential π-π stacking of building blocks with robust and non-coplanar triptycene-based modules. The tailored-fitting interactions were demonstrated by the adsorption of fullerene with a concentration enrichment of ∼420 times in the pores.

Surface-initiated, photoinduced atom transfer radical polymerization (SI-photoATRP) enables the controlled and rapid synthesis of compositionally diverse polymer brushes over large areas, by employing very small reaction volumes, under ambient conditions and without the need for prior deoxygenation of monomer mixtures. The concentration of copper species, and the type and content of amine-based ligands determine the mechanism of SI-photoATRP, regulate the kinetics of polymer-brush growth, and govern the tolerance of this polymer-grafting method toward oxygen. Despite mechanistic analogies with the corresponding solution processes, the intrinsic, highly confined nature of SI-photoATRP leads to significant differences from polymerizations within homogeneous systems. This is especially important to attain controlled/living polymerization and temporal control over polymer-brush growth using UV light as a trigger. efficient method to fabricate functional coatings from light-sensitive substrates, or from spatially confined supports where just a limited dose of UV light can be applied.

Materials built from multiple constituents have revealed emerging properties that are beyond linear integration of those from single components. We report a mesoporous metal-organic framework made from three geometrically distinct metal-containing secondary building units (SBUs) as a result of topological induction. The combinations of the Cu-based triangular, Zn-based octahedral, and Zn-based square pyramidal SBUs have created four types of cages in the network, despite that only one organic linker pyrazolecarboxylate was used. The longest distance for molecules maneuvering inside the largest cage is 5.2 nm. Furthermore, the complex and diversified pore environments allow the installation of various new functionalities in the framework as well as the expedited Ag nanoparticle formation in the pores. As presented in the molecule movement diagram, the crystal has provided specific arrangements of cages and apertures with distinct chemical features for guests transporting between the pores.