Purpose: The aim of our study was to assess if the sodium salt of cobaltabis(dicarbollide) and its di-iodinated derivative (Na[o-COSAN] and Na[8,8′-I2-o-COSAN]) could be promising agents for dual anti-cancer treatment (chemotherapy + BNCT) for GBM. Methods: The biological activities of the small molecules were evaluated in vitro with glioblastoma cells lines U87 and T98G in 2D and 3D cell models and in vivo in the small model animal Caenorhabditis elegans (C. elegans) at the L4-stage and using the eggs. Results: Our studies indicated that only spheroids from the U87 cell line have impaired growth after treatment with both compounds, suggesting an increased resistance from T98G spheroids, contrary to what was observed in the monolayer culture, which highlights the need to employ 3D models for future GBM studies. In vitro tests in U87 and T98G cells conclude that the amount of 10B inside the cells is enough for BNCT irradiation. BNCT becomes more effective on T98G after their incubation with Na[8,8′-I2-o-COSAN], whereas no apparent cell-killing effect was observed for untreated cells. Conclusions: These small molecules, particularly [8,8′-I2-o-COSAN]−, are serious candidates for BNCT now that the facilities of accelerator-based neutron sources are more accessible, providing an alternative treatment for resistant glioblastoma.
The use of smart drug delivery systems (DDSs) is one of the most promising approaches to overcome some of the drawbacks of drug-based therapies, such as improper biodistribution and lack of specific targeting. Some of the most attractive candidates as DDSs are naturally occurring, self-assembling protein nanoparticles, such as viruses, virus-like particles, ferritin cages, bacterial microcompartments, or eukaryotic vaults. Vaults are large ribonucleoprotein nanoparticles present in almost all eukaryotic cells. Expression in different cell factories of recombinant versions of the “major vault protein” (MVP) results in the production of recombinant vaults indistinguishable from native counterparts. Such recombinant vaults can encapsulate virtually any cargo protein, and they can be specifically targeted by engineering the C-terminus of MVP monomer. These properties, together with nanometric size, a lumen large enough to accommodate cargo molecules, biodegradability, biocompatibility and no immunogenicity, has raised the interest in vaults as smart DDSs. In this work we provide an overview of eukaryotic vaults as a new, self-assembling protein-based DDS, focusing in the latest advances in the production and purification of this platform, its application in nanomedicine, and the current preclinical and clinical assays going on based on this nanovehicle.
Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, highly resistant to conventional radiotherapy and chemotherapy. Therefore, the development of multidrug resistance and tumor recurrence are frequent....
A new carbon-based hybrid nanocomposite, which consists of monoiodinated boron-cluster derivatives covalently attached to graphene oxide, is hereby introduced. This GO-I-COSAN has been synthesized using a novel boron-rich cobaltabisdicarbollide precursor with one iodide group attached to one of the boron atoms of the cluster (I-COSAN), and designed to be subsequently labeled with radioactive 124 I for its use in Positron Emission Tomography (PET).In-vitro cytotoxicity studies of GO-I-COSAN with HeLa cells at different concentrations up to 48 h proved that the cell mortality was lower than 10 %, indicating minimal cytotoxicity of the nanomaterial. Remarkably, the internalization of the nanomaterial by cells was confirmed by Transmission Electron Microscopy (TEM), which indicated its accumulation in the cytoplasm, without causing changes neither in the size nor in the morphology of cells.Additionally, in vivo tests using C. elegans confirmed that GO-I-COSAN could be ingested by the worms, showing no significant damage and very low toxicity, which supports the results observed in the in-vitro studies. Radioisotopic labeling of I-COSAN using a Pd-catalyzed isotopic exchange reaction with Na[ 124 I]I and its subsequent functionalization onto GO was performed successfully, leading to the formation of a new radioactive nanocomposite GO-[ 124 I]I-COSAN, which was quickly injected in mice. PET images at different times revealed excellent in-vivo stability of the developed nanomaterial. No activity in thyroid and stomach was observed even at long times, proving that iodide did not detach from the material. GO-[ 124 I]I-COSAN presented a favourable biodistribution profile, being mainly accumulated in the liver and slightly in the lung, with long residence time on blood and progressive elimination via gastrointestinal tract. Noteworthy, the high boron content of this material paves the way towards theranostics, since benefits of a traceable boron delivery for boron neutron cancer therapy (BNCT). I-COSAN, 1, was characterized by 1 H, 11 B and 13 C nuclear magnetic resonance (NMR,
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