In accordance with the two-step hypothesis of T cell activation and the observation that stimulation through the T cell receptor (TCR) alone may lead to anergy, we focused on the introduction of co-stimulatory signaling to this type of receptors to achieve optimal activation. Enhanced mRNA and cell surface receptor expression via the co-stimulatory gene fragment (OX40) was confirmed by RT-PCR and flow cytometry. Inclusion of the OX40 co-stimulatory signaling region in series with the TCR led to enhanced antigen-induced IL-2 production after stimulation by MUC1-expressing cancer cell lines as compared to the chimeric receptor without OX40. Moreover, with the aim of maintaining high efficiency, while providing a means of controlling any possible unwanted proliferation in vivo, a regulation system was used. This controls the dimerization of a membrane-bound caspase 8 protein. Toward that goal, pFKC8 and CAR constructs were co-transfected into Jurkat cells, and the level of apoptosis was measured. 24 h after addition of the dimerizer, a 91% decrease in transfected cells was observed.
The combination of liposomes with magnetic nanoparticles, because of their strong effect on T2 relaxation can open new ways in the innovative cancer therapy and diagnosis. In order to design an intelligent contrast agent in MRI, we chose anti-HER2 nanobody the smallest fully functional antigen-binding fragments evolved from the variable domain, the VHH, of a camel heavy chain-only antibody. These targeted magnetoliposomes bind to the HER2 antigen which is highly expressed on breast and ovarian cancer cells so reducing the side effects as well as increasing image contrast and effectiveness. Cellular iron uptake analysis and in vitro MRI of HER2 positive cells incubated with targeted nanoparticles show specific cell targeting. In vitro MRI shows even at the lowest density (200 Cells/ll), dark spots corresponding to labeled cells which were still detectable. These results suggest that this new type of nanoparticles could be effective antigen-targeted contrast agents for molecular imaging.
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