Enhancing cell therapies from the outside in: Cell surface engineering using synthetic nanomaterials

Therapeutic treatments based on the injection of living cells are in clinical use and preclinical development for diseases ranging from cancer to cardiovascular disease to diabetes. To enhance the function of therapeutic cells, a variety of chemical and materials science strategies are being developed that engineer the surface of therapeutic cells with new molecules, artificial receptors, and multifunctional nanomaterials, synthetically endowing donor cells with new properties and functions. These approaches offer a powerful complement to traditional genetic engineering strategies for enhancing the function of living cells.Massachusetts Institute of Technology. Center for Materials Science and Engineering (National Science Foundation (U.S.) DMR-0819762)United States. Dept. of Defense. Prostate Cancer Research Program (W81XWH-10-1-0290)National Institutes of Health (U.S.) (CA140476)National Institutes of Health (U.S.) (EB012352

Spectroscopy of mechanical dissipation in micro-mechanical membranes

We measure the frequency dependence of the mechanical quality factor (Q) of SiN membrane oscillators and observe a resonant variation of Q by more than two orders of magnitude. The frequency of the fundamental mechanical mode is tuned reversibly by up to 40% through local heating with a laser. Several distinct resonances in Q are observed that can be explained by coupling to membrane frame modes. Away from the resonances, the background Q is independent of frequency and temperature in the measured range.Comment: 4 pages, 5 figure

Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles

Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T-cell membrane proteins enables efficient delivery of compounds into the T-cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T-cell/APC contact zone during antigen recognition. To translate these findings into a therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T-cell receptor activation in the synapse, in the context of adoptive T cell therapy of cancer. Conjugating NSC-87877-loaded NPs to the surface of tumor-specific T cells just prior to adoptive transfer into mice with advanced prostate cancer promoted a much greater T-cell expansion at the tumor site, relative to co-infusing the same drug dose systemically, leading to enhanced survival of treated animals. In summary, our studies support the application of T-cell-linked synthetic NPs as efficient drug delivery vehicles into the IS, as well as the broad applicability of this new paradigm for therapeutically modulating signaling events at the T-cell/APC interface.National Institutes of Health (U.S.) (CA140476)National Institutes of Health (U.S.) (EB123622)United States. Dept. of Defense. Prostate Cancer Research Program (W81XWH-10-1-0290)National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051)National Cancer Institute (U.S.)American Cancer Society (Postdoctoral Fellowship 12109-PF-11-025-01-LIB

Spin Hall magnetoresistance in antiferromagnet/heavy-metal heterostructures

We investigate the spin Hall magnetoresistance in thin film bilayer heterostructures of the heavy metal Pt and the antiferromagnetic insulator NiO. While rotating an external magnetic field in the easy plane of NiO, we record the longitudinal and the transverse resistivity of the Pt layer and observe an amplitude modulation consistent with the spin Hall magnetoresistance. In comparison to Pt on collinear ferrimagnets, the modulation is phase shifted by 90{\deg} and its amplitude strongly increases with the magnitude of the magnetic field. We explain the observed magnetic field-dependence of the spin Hall magnetoresistance in a comprehensive model taking into account magnetic field induced modifications of the domain structure in antiferromagnets. With this generic model we are further able to estimate the strength of the magnetoelastic coupling in antiferromagnets. Our detailed study shows that the spin Hall magnetoresistance is a versatile tool to investigate the magnetic spin structure as well as magnetoelastic effects, even in antiferromagnetic multidomain materials