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1.
Proc Natl Acad Sci U S A ; 119(46): e2210562119, 2022 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-36343224

RESUMEN

The development of chimeric antigen receptor (CAR) T cell therapy has become a critical milestone in modern oncotherapy. Despite the remarkable in vitro effectiveness, the problem of safety and efficacy of CAR T cell therapy against solid tumors is challenged by the lack of tumor-specific antigens required to avoid on-target off-tumor effects. Spatially separating the cytotoxic function of CAR T cells from tumor antigen recognition provided by protein mediators allows for the precise control of CAR T cell cytotoxicity. Here, the high affinity and capability of the bacterial toxin-antitoxin barnase-barstar system were adopted to guide CAR T cells to solid tumors. The complementary modules based on (1) ankyrin repeat (DARPin)-barnase proteins and (2) barstar-based CAR (BsCAR) were designed to provide switchable targeting to tumor cells. The alteration of the DARPin-barnase switches enabled the targeting of different tumor antigens with a single BsCAR. A gradual increase in cytokine release and tunable BsCAR T cell cytotoxicity was achieved by varying DARPin-barnase loads. Switchable BsCAR T cell therapy was able to eradicate the HER2+ ductal carcinoma in vivo. Guiding BsCAR T cells by DARPin-barnase switches provides a universal approach for a controlled multitargeted adoptive immunotherapy.


Asunto(s)
Neoplasias , Linfocitos T , Humanos , Receptores de Antígenos de Linfocitos T , Inmunoterapia Adoptiva , Neoplasias/metabolismo , Antígenos de Neoplasias
2.
ACS Appl Bio Mater ; 5(6): 2976-2989, 2022 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-35616387

RESUMEN

We present a targeted drug delivery system for therapy and diagnostics that is based on a combination of contrasting, cytotoxic, and cancer-cell-targeting properties of multifunctional carriers. The system uses multilayered polymer microcapsules loaded with magnetite and doxorubicin. Loading of magnetite nanoparticles into the polymer shell by freezing-induced loading (FIL) allowed the loading efficiency to be increased 5-fold, compared with the widely used layer-by-layer (LBL) assembly. FIL also improved the photoacoustic signal and particle mobility in a magnetic field gradient, a result unachievable by the LBL alone. For targeted delivery of the carriers to cancer cells, the carrier surface was modified with a designed ankyrin repeat protein (DARPin) directed toward the epithelial cell adhesion molecule (EpCAM). Flow cytometry measurements showed that the DARPin-coated capsules specifically interacted with the surface of EpCAM-overexpressing human cancer cells such as MCF7. In vivo and ex vivo biodistribution studies in FvB mice showed that the carrier surface modification with DARPin changed the biodistribution of the capsules toward epithelial cells. In particular, the capsules accumulated substantially in the lungs─a result that can be effectively used in targeted lung cancer therapy. The results of this work may aid in the further development of the "magic bullet" concept and may bring the quality of personalized medicine to another level.


Asunto(s)
Portadores de Fármacos , Nanocompuestos , Animales , Cápsulas , Proteínas de Repetición de Anquirina Diseñadas , Sistemas de Liberación de Medicamentos/métodos , Molécula de Adhesión Celular Epitelial , Ratones , Polímeros , Distribución Tisular
3.
J Mater Chem B ; 9(42): 8823-8831, 2021 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-34633027

RESUMEN

The present study focuses on the immobilization of the bacterial ribonuclease barnase (Bn) into submicron porous calcium carbonate (CaCO3) particles. For encapsulation, we apply adsorption, freezing-induced loading and co-precipitation methods and study the effects of adsorption time, enzyme concentration and anionic polyelectrolytes on the encapsulation efficiency of Bn. We show that the use of negatively charged dextran sulfate (DS) and ribonucleic acid from yeast (RNA) increases the loading capacity (LC) of the enzyme on CaCO3 particles by about 3-fold as compared to the particles with Bn itself. The ribonuclease (RNase) activity of encapsulated enzyme depends on the LC of the particles and transformation of metastable vaterite to stable calcite, as studied by the assessment of enzyme activities in particles.


Asunto(s)
Proteínas Bacterianas/química , Carbonato de Calcio/química , Polielectrolitos/química , Ribonucleasas/química , Adsorción , Proteínas Bacterianas/biosíntesis , Proteínas Bacterianas/metabolismo , Carbonato de Calcio/metabolismo , Sulfato de Dextran/química , Sulfato de Dextran/metabolismo , Escherichia coli/enzimología , Tamaño de la Partícula , Polielectrolitos/metabolismo , Porosidad , ARN/química , ARN/metabolismo , Ribonucleasas/biosíntesis , Ribonucleasas/metabolismo , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo , Propiedades de Superficie
4.
Molecules ; 25(18)2020 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-32961731

RESUMEN

Theranostic approach is currently among the fastest growing trends in cancer treatment. It implies the creation of multifunctional agents for simultaneous precise diagnosis and targeted impact on tumor cells. A new type of theranostic complexes was created based on NaYF4: Yb,Tm upconversion nanoparticles coated with polyethylene glycol and functionalized with the HER2-specific recombinant targeted toxin DARPin-LoPE. The obtained agents bind to HER2-overexpressing human breast adenocarcinoma cells and demonstrate selective cytotoxicity against this type of cancer cells. Using fluorescent human breast adenocarcinoma xenograft models, the possibility of intravital visualization of the UCNP-based complexes biodistribution and accumulation in tumor was demonstrated.


Asunto(s)
Nanopartículas del Metal/química , Nanomedicina Teranóstica , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Colorantes Fluorescentes/química , Fluoruros/química , Humanos , Nanopartículas del Metal/uso terapéutico , Nanopartículas del Metal/toxicidad , Ratones , Ratones Desnudos , Polietilenglicoles/química , Receptor ErbB-2/metabolismo , Tulio/química , Trasplante Heterólogo , Iterbio/química , Itrio/química
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