Effect of surface properties in protein corona development on mesoporous silica nanoparticles

[EN] The composition of the protein corona formed on mesoporous silica nanoparticles with several surface modifications was characterized. Low MW serum proteins were preferentially adsorbed, and PEGylated nanoparticles did not adsorb protein regardless of PEG chain length.The authors are thankful for financial support by the Spanish Ministry of Economy and Competiveness (projects SEV-2012-0267, MAT2012-39290-C02-02 and IPT-2012-0574-300000) and by the University of Vermont.Clemments, AM.; Muniesa Lajara, C.; Landry, CC.; Botella Asuncion, P. (2014). Effect of surface properties in protein corona development on mesoporous silica nanoparticles. RSC Advances. 4(55):29134-29138. https://doi.org/10.1039/c4ra03277bS291342913845

Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin

[EN] We report the design, synthesis, characterization and in vitro testing of a novel nanodrug based on a covalent linking model that allows intracellular controlled release of the pharmaceutical payload. A new synthetic strategy is implemented by direct coupling of as-synthesized (pyridin-2-yldisulfanyl)alkyl carbonate derivatives of camptothecin (CPT) with thiol groups of silica hybrid nanoparticles containing a non-porous core and a mesoporous shell. Upon reaction with thiols in physiological conditions, disulfide bridge cleavage occurs, releasing the naked drug after an intramolecular cyclization mechanism. Additional incorporation of a fluorophore into particles core facilitates imaging at the subcellular level for the monitoring of uptake and delivery. Confocal microscopy experiments in HeLa cervix cancer cells confirms that nanoparticles enter the cells by endocytosis but are able to escape from endo-lysosomes and enter the cytosolic compartment to release their cargo. The incorporation to cells of L-buthionine-sulfoximine, a glutathione inhibitor allows concluding that the intracellular releasing mechanism is mainly driven by the reducing activity of this tripeptide. This camptothecin nanoplatform shows the same cytotoxic activity than the free drug and is clearly superior to those release systems depending on enzymatic hydrolysis (as determined by calculation of the IC50 ratios).This work was financially supported by "Comision Interministerial de Ciencia y Tecnologia" of Spain (projects CSD2009-00050 and MAT2012-39290-C02-02), and grants from CIBER-BBN (NanoMets Intramural Grant) "Fondo de Investigaciones Sanitarias - Instituto de Salud Carlos III" (PI080771) y "Universidad Catolica de Valencia San Vicente Martir" (PI2011-011-010). CM thanks the Spanish "Ministerio de Economia y Competitividad" for a FPU Ph.D. studentship (AP2008-02851). SSA thanks the "Universidad Catolica de Valencia San Vicente Martir" for a Ph.D. studentship.Muniesa Lajara, C.; Vicente Vilas, V.; Quesada Vilar, M.; Saez-Atienzar, S.; Blesa-Blesa, JR.; Abasolo, I.; Fernández, Y.... (2013). Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin. RSC Advances. 3(35):15121-15131. https://doi.org/10.1039/c3ra41404cS151211513133

Hybrid PLGA-Organosilica Nanoparticles with Redox-Sensitive Molecular Gates

[EN] A novel type of hybrid material based on a PLGA nanoparticle core and a redox-responsive amorphous organosilica shell have been successfully synthesized. The outer layer is obtained by self-assembly of silicate ions with a silsesquioxane containing a disulfide bridge. These organic linkers work as molecular gates that can be selectively cleaved by reducing agents. This system is particularly suitable for storage and release of hydrophobic molecules, as the treatment with dithiothreitol leaves open doors that allow for the discharge of encapsulated molecules in the organic matrix. Using pyrene as a probe molecule, it has been shown that after partial disruption of the organic−inorganic coating, the release mechanism from PLGA particles fits pretty well into Higuchi s model, corresponding to a diffusion-mediated process. These nanohybrids impose a better control and slower release of encapsulated molecules than bare PLGA nanoparticles, are reasonably stable in a physiological medium, and show great potential as stimuli-responsive vehicles for drug delivery.The authors are thankful for financial support by "CICYT" of Spain (projects CSD2009-00050 and MAT2012-39290-C02-02). C.M. thanks the Spanish "Ministerio de Economia y Competitividad" for an FPU Ph.D. studentship (AP2008-02851). We kindly appreciate the technical support of the Electronic Microscopy Service of UPV.Quesada Vilar, M.; Muniesa Lajara, C.; Botella Asuncion, P. (2013). Hybrid PLGA-Organosilica Nanoparticles with Redox-Sensitive Molecular Gates. Chemistry of Materials. 25(13):2597-2602. doi:10.1021/cm400700gS25972602251

Surface-modified silica nanoparticles for tumor-targeted delivery of camptothecin and its biological evaluation

[EN] Here we report the design, synthesis and biological evaluation of surface-modified silica nanoparticles (SNP) for the delivery of camptothecin (CPT). Drug has been covalently linked to the nanoparticle through an ester bond with the 20-hydroxy moiety, in order to stabilize its lactone ring and to avoid unspecific release of the drug. The obtained material is highly stable in plasma, with low release of the cargo at physiological pH. Cell internalization and in vitro efficacy assays demonstrated that nanoparticles carrying CPT (SNP-CPT) entered cells via endocytosis and the intracellular release of the cargo induced cell death with half maximal inhibitory concentration (IC(50)) values and cell cycle distribution profiles similar to those observed for the naked drug. Further, in vivo biodistribution, therapeutic efficacy and biocompatibility of the SNP-CPT were evaluated in human colorectal cancer xenografts using in vivo fluorescence or bioluminescence optical imaging. In vivo tumor-accumulation and whole-body tissue distribution were carried out based on the acquisition of fluorescence emission of a fluorophore (Cy5.5) conjugated to the SNP-CPT, as well as by HPLC quantification of tissue CPT levels. The results showed that, although SNP-CPT tended to accumulate in organs of the reticuloendothelial system, nanoparticles boost CPT concentration in tumor vs administration of the free drug. Accordingly, SNP-CPT treatment delayed the growth of subcutaneous tumors while significantly reducing the systemic toxicity associated with CPT administration. These results indicate that the SNP-CPT could be used as a robust drug delivery system for antitumoral treatments based on CPT. (C) 2011 Elsevier B. V. All rights reserved.This work was financially supported by "Comision Interministerial de Ciencia y Tecnologia" of Spain (project MAT2006-14274-C02-01 to A. C.), Spanish National Research Council (project 200880I092 to P. B.) and grants from CIBER-BBN (NanoMets Intramural Grant) and "Fondo de Investigaciones Sanitarias - Instituto de Salud Carlos III" (PI080771) to S. S. CM thanks the Spanish "Ministerio de Ciencia e Innovacion" for a FPU Ph D studentship (AP2008-02851).Botella Asuncion, P.; Abasolo, I.; Fernández, Y.; Muniesa Lajara, C.; Miranda, S.; Quesada Vilar, M.; Ruiz Carrascal, J.... (2011). Surface-modified silica nanoparticles for tumor-targeted delivery of camptothecin and its biological evaluation. Journal of Controlled Release. 156(2):246-257. https://doi.org/10.1016/j.jconrel.2011.06.039S246257156

Multifunctional hybrid materials for combined photo and chemotherapyof cancer

[EN] Combined chemo and photothermal therapy in in vitro testing has been achieved by means of multifunctional nanoparticles formed by plasmonic gold nanoclusters with a protecting shell of porous silica that contains an antitumor drug. We propose a therapeutic nanoplatform that associates the optical activity of small gold nanoparticles aggregates with the cytotoxic activity of 20(S)-camptothecin simultaneously released for the efficient destruction of cancer cells. For this purpose, a method was used for the controlled assembly of gold nanoparticles into stable clusters with a tailored absorption crosssection in the vis/NIR spectrum, which involves aggregation in alkaline medium of 15 nm diameter gold colloids protected with a thin silica layer. Clusters were further encapsulated in an ordered homogeneous mesoporous silica coating that provides biocompatibility and stability in physiological fluids. After internalization in 42-MG-BA human glioma cells, these protected gold nanoclusters were able to produce effective photothermolysis under femtosecond pulse laser irradiation of 790 nm. Cell death occurred by combination of a thermal mechanism and mechanical disruption of the membrane cell due to induced generation of micrometer-scale bubbles by vaporizing the water inside the channels of the mesoporous silica coating. Moreover, the incorporation of 20(S)-camptothecin within the pores of the external shell, which was released during the process, provoked significant cell death increase. This therapeutic model could be of interest for application in the treatment and suppression of non-solid tumors.This work was financially supported by Comision Interministerial de Ciencia y Tecnologia of Spain through the projects FIS2006-09319, SAF2008-03694, MAT2006-14274-C02-01 and MULTICAT (Consolider-Ingenio 2010). CM thanks the Spanish "Ministerio de Economia y Competitividad" for a FDU Ph D studentship (AP2008-02851).Botella Asuncion, P.; Ortega, I.; Quesada Vilar, M.; Madrigal Madrigal, RF.; Muniesa Lajara, C.; Fimia Gil, A.; Fernandez Jover, E.... (2012). Multifunctional hybrid materials for combined photo and chemotherapyof cancer. Dalton Transactions. 41(31):9243-9554. https://doi.org/10.1039/c2dt30381gS92439554413

Feasibility and potential advantages using VMAT in SRS metastasis treatments

Background: Utilization of stereotactic radiosurgery (SRS) for brain metastases (BM) has become the technique of choice as opposed to whole brain radiation therapy (WBRT). The aim of this work is to evaluate the feasibility and potential benefits in terms of normal tissue (NT) and dose escalation of volumetric modulated arc therapy (VMAT) in SRS metastasis treatment. A VMAT optimization procedure has therefore been developed for internal dose scaling which minimizes planner dependence. Materials and methods: Five patient-plans incorporating treatment with frame-based SRS with dynamic conformal arc technique (DA) were re-planned for VMAT. The lesions selected were between 4–6 cm3. The same geometry used in the DA plans was maintained for the VMAT cases. A VMAT planning procedure was performed attempting to scale the dose in inner auxiliary volumes, and to explore the potential for dose scaling with this technique. Comparison of dose-volume histogram (DVH) parameters were obtained. Results: VMAT allows a superior NT sparing plus conformity and dose scaling using the auxiliary volumes. The VMAT results were significantly superior in NT sparing, improving both the V10 and V12 values in all cases, with a 2–3 cm3 saving. In addition, VMAT improves the dose coverage D95 by about 0.5 Gy. The objective of dose escalation was achieved with VMAT with an increment of the Dmean and the Dmedian of about 2 Gy. Conclusions: This work shows a benefit of VMAT in SRS treatment with significant NT sparing. A VMAT optimization procedure, based on auxiliary inner volumes, has been developed, enabling internal dose escalation