The development of targeted nanocarriers able to be selectively internalized within tumor cells, and therefore to deliver anti-tumor drugs specifically to diseased cells, constitutes one of the most important goals in nano-oncology. Herein, the development of Janus mesoporous silica particles asymmetrically decorated with two targeting moieties, one of them selective for folate membrane cell receptors (folic acid) and the other one able to bind to mitochondria membrane (triphenylphosphine, TPP), is described in order to achieve sequential cell to organelle vectorization. The asymmetric decoration of each side of the particle allows fine control in the targeting attachment process in comparison with the use of symmetric nanocarriers. The presence of folic acid induces a higher increase in particle accumulation inside tumor cells, and once there, these nanocarriers are guided close to mitochondria by the action of the TPP moiety. This strategy can be applied for improving the therapeutic efficacy of current nanomedicines.
A series of gold complexes were tested as catalysts in
the synthesis
of propargylamines by the three component coupling reaction of amines,
aldehydes, and alkynes. These complexes are efficient catalysts for
the three-component coupling reaction (yields up to 97%). In homogeneous
solution, the conversions to the respective propargylamine were higher
than under heterogeneous conditions. Heterogenized complexes were
stable and recoverable for at least six cycles. Ligands, gold(I) or
gold(III), homogeneous or heterogenized systems have pronounced effects
on the catalytic activity of the corresponding gold complexes.
The poor delivery of nanoparticles to target cancer cells hinders their success in the clinical setting. In this work, an alternative target readily available for circulating nanoparticles has been selected to eliminate the need for nanoparticle penetration in the tissue: the tumor blood vessels. A tumor endothelium-targeted nanoparticle (employing an RGD-containing peptide) capable of co-delivering two anti-vascular drugs (one anti-angiogenic drug and one vascular disruption agent) is here presented. Furthermore, the nanodevice presents two additional anti-vascular capabilities upon activation by Near-Infrared light: provoking local hyperthermia (by gold nanorods in the system) and generating toxic reactive oxygen species (by the presence of a photosensitizer). RGD-targeting is shown to increase uptake by HUVEC cells, and while the nanoparticles are shown not to be toxic for these cells, upon Near-Infrared irradiation their almost complete killing is achieved. The combination of all four therapeutic modalities is then evaluated in an ex ovo fibrosarcoma xenograft model, which shows a significant reduction in the number of blood vessels irrigating the xenografts when the nanoparticles are present, as well as the destruction of the existing blood vessels 2 upon irradiation. These results suggest that the combination of different anti-vascular therapeutic strategies in a single nanocarrier appears promising and should be further explored in the future.
Novel targeting agents based on meta-Iodobenzylguanidine (MIBG) moiety against neuroblastoma were synthetized and biologically evaluated for nanocarrier vectorization. These compounds have been anchored on the surface of drug loaded mesoporous silica nanocarriers causing improved cellular uptake in tumoral cells. Neuroblastoma (NB) is the most frequent extracranial pediatric tumor. Advanced forms of the disease (metastatic and/or refractory) have a dismal prognosis despite the combination of chemotherapy, radiotherapy, surgery and bone narrow transplant. These treatments carry severe side effects and, in some cases, compromise the patient life. MIBG has been widely applied in medical diagnosis of NB due to its affinity for the tumor cells through the norepinephrine transporter (NET), which is expressed in 90 % of NB. The exclusive accumulation of MIBG in neuroblastoma has been widely studied; however, its properties have been never exploited as targeting agent in nanocarrier drug delivery systems. Several structural analogues of MIBG have been prepared and attached on the nanocarrier surface. Their selective internalization has been tested against human neuroblastoma cells showing, in the best case, four times higher cellular uptake versus the naked nanosystem. Furthermore, in vivo experiments showed preferential and selective accumulation and retention of targeted nanosystem comparing with the naked and the just PEGylated counterpart systems. This novel nanosystem could be easily applicable for all kind of drug delivery nanocarriers, allowing a universal tool for neuroblastoma chemotherapies in the way to step down the classical approaches providing a newfangled nanosystem exclusively designed against this terrible malignancy.
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