Long-Circulating Hyaluronan-Based Nanohydrogels as Carriers of Hydrophobic Drugs

[EN] Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack of toxicity, even at high doses, and their different biodistribution with respect to that of native hyaluronan. They were also exploited as carriers of a hydrophobic model drug, the anti-inflammatory piroxicam, that was physically embedded within the nanohydrogels by an autoclave treatment. The nanoformulation was tested by intravenous administration showing an improvement of the pharmacokinetic parameters of the molecule. The obtained results indicate that hyaluronan-based self-assembled nanohydrogels are suitable systems for low-soluble drug administration, by increasing the dose as well as the circulation time of poorly available therapeutic agents.Financial support from University Sapienza Progetti di Ricerca: grant RP116154C2EF9AC8 and grant RM11715C1743EE89 are acknowledged. Isabel Gonzalez-Alvarez, Marta Gonzalez-Alvarez and Marival Bermejo acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitivity). Mayte Martinez-Martínez received a grant from the Ministry of Education and Science of Spain (FPU13-01105).Di Meo, C.; Martínez Martínez, M.; Coviello, T.; Bermejo, M.; Merino Sanjuán, V.; Gonzalez-Alvarez, I.; Gonzalez-Alvarez, M.... (2018). Long-Circulating Hyaluronan-Based Nanohydrogels as Carriers of Hydrophobic Drugs. Pharmaceutics. 10(4):1-15. https://doi.org/10.3390/pharmaceutics10040213S115104Allison, D. D., & Grande-Allen, K. J. (2006). Review. Hyaluronan: A Powerful Tissue Engineering Tool. Tissue Engineering, 12(8), 2131-2140. doi:10.1089/ten.2006.12.2131Prestwich, G. D. (2008). Engineering a clinically-useful matrix for cell therapy. Organogenesis, 4(1), 42-47. doi:10.4161/org.6152Ossipov, D. A. (2010). Nanostructured hyaluronic acid-based materials for active delivery to cancer. Expert Opinion on Drug Delivery, 7(6), 681-703. doi:10.1517/17425241003730399Rao, N. V., Yoon, H. Y., Han, H. S., Ko, H., Son, S., Lee, M., … Park, J. H. (2015). Recent developments in hyaluronic acid-based nanomedicine for targeted cancer treatment. Expert Opinion on Drug Delivery, 13(2), 239-252. doi:10.1517/17425247.2016.1112374Dosio, F., Arpicco, S., Stella, B., & Fattal, E. (2016). Hyaluronic acid for anticancer drug and nucleic acid delivery. Advanced Drug Delivery Reviews, 97, 204-236. doi:10.1016/j.addr.2015.11.011Montanari, E., D’Arrigo, G., Di Meo, C., Virga, A., Coviello, T., Passariello, C., & Matricardi, P. (2014). Chasing bacteria within the cells using levofloxacin-loaded hyaluronic acid nanohydrogels. European Journal of Pharmaceutics and Biopharmaceutics, 87(3), 518-523. doi:10.1016/j.ejpb.2014.03.003Svanovsky, E., Velebny, V., Laznickova, A., & Laznicek, M. (2008). The effect of molecular weight on the biodistribution of hyaluronic acid radiolabeled with111In after intravenous administration to rats. European Journal of Drug Metabolism and Pharmacokinetics, 33(3), 149-157. doi:10.1007/bf03191112Harris, E. N., Kyosseva, S. V., Weigel, J. A., & Weigel, P. H. (2006). Expression, Processing, and Glycosaminoglycan Binding Activity of the Recombinant Human 315-kDa Hyaluronic Acid Receptor for Endocytosis (HARE). Journal of Biological Chemistry, 282(5), 2785-2797. doi:10.1074/jbc.m607787200Choi, K. Y., Min, K. H., Na, J. H., Choi, K., Kim, K., Park, J. H., … Jeong, S. Y. (2009). Self-assembled hyaluronic acid nanoparticles as a potential drug carrier for cancer therapy: synthesis, characterization, and in vivo biodistribution. Journal of Materials Chemistry, 19(24), 4102. doi:10.1039/b900456dPedrosa, S. S., Pereira, P., Correia, A., & Gama, F. M. (2017). Targetability of hyaluronic acid nanogel to cancer cells : In vitro and in vivo studies. European Journal of Pharmaceutical Sciences, 104, 102-113. doi:10.1016/j.ejps.2017.03.045Yang, C., Li, C., Zhang, P., Wu, W., & Jiang, X. (2017). Redox Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive Cancer, both Primary and Metastatic Tumors. Theranostics, 7(6), 1719-1734. doi:10.7150/thno.18340Rosso, F., Quagliariello, V., Tortora, C., Di Lazzaro, A., Barbarisi, A., & Iaffaioli, R. V. (2013). Cross-linked hyaluronic acid sub-micron particles: in vitro and in vivo biodistribution study in cancer xenograft model. Journal of Materials Science: Materials in Medicine, 24(6), 1473-1481. doi:10.1007/s10856-013-4895-4Nakai, T., Hirakura, T., Sakurai, Y., Shimoboji, T., Ishigai, M., & Akiyoshi, K. (2012). Injectable Hydrogel for Sustained Protein Release by Salt-Induced Association of Hyaluronic Acid Nanogel. Macromolecular Bioscience, 12(4), 475-483. doi:10.1002/mabi.201100352Montanari, E., Capece, S., Di Meo, C., Meringolo, M., Coviello, T., Agostinelli, E., & Matricardi, P. (2013). Hyaluronic Acid Nanohydrogels as a Useful Tool for BSAO Immobilization in the Treatment of Melanoma Cancer Cells. Macromolecular Bioscience, 13(9), 1185-1194. doi:10.1002/mabi.201300114Montanari, E., Di Meo, C., Sennato, S., Francioso, A., Marinelli, A. L., Ranzo, F., … Matricardi, P. (2017). Hyaluronan-cholesterol nanohydrogels: Characterisation and effectiveness in carrying alginate lyase. New Biotechnology, 37, 80-89. doi:10.1016/j.nbt.2016.08.004Montanari, E., De Rugeriis, M. C., Di Meo, C., Censi, R., Coviello, T., Alhaique, F., & Matricardi, P. (2015). One-step formation and sterilization of gellan and hyaluronan nanohydrogels using autoclave. Journal of Materials Science: Materials in Medicine, 26(1). doi:10.1007/s10856-014-5362-6Di Meo, C., Montanari, E., Manzi, L., Villani, C., Coviello, T., & Matricardi, P. (2015). Highly versatile nanohydrogel platform based on riboflavin-polysaccharide derivatives useful in the development of intrinsically fluorescent and cytocompatible drug carriers. Carbohydrate Polymers, 115, 502-509. doi:10.1016/j.carbpol.2014.08.107Manzi, G., Zoratto, N., Matano, S., Sabia, R., Villani, C., Coviello, T., … Di Meo, C. (2017). «Click» hyaluronan based nanohydrogels as multifunctionalizable carriers for hydrophobic drugs. Carbohydrate Polymers, 174, 706-715. doi:10.1016/j.carbpol.2017.07.003Lozoya-Agullo, I., Araújo, F., González-Álvarez, I., Merino-Sanjuán, M., González-Álvarez, M., Bermejo, M., & Sarmento, B. (2018). PLGA nanoparticles are effective to control the colonic release and absorption on ibuprofen. European Journal of Pharmaceutical Sciences, 115, 119-125. doi:10.1016/j.ejps.2017.12.009Samiei, N., Mangas-Sanjuan, V., González-Álvarez, I., Foroutan, M., Shafaati, A., Zarghi, A., & Bermejo, M. (2013). Ion-pair strategy for enabling amifostine oral absorption: Rat in situ and in vivo experiments. European Journal of Pharmaceutical Sciences, 49(4), 499-504. doi:10.1016/j.ejps.2013.04.025Wei, X., Senanayake, T. H., Bohling, A., & Vinogradov, S. V. (2014). Targeted Nanogel Conjugate for Improved Stability and Cellular Permeability of Curcumin: Synthesis, Pharmacokinetics, and Tumor Growth Inhibition. Molecular Pharmaceutics, 11(9), 3112-3122. doi:10.1021/mp500290

Biopharmaceutical optimization in neglected diseases for paediatric patients by applying the provisional paediatric biopharmaceutical classification system

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146268/1/bcp13650.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146268/2/bcp13650_am.pd

Gated Mesoporous Silica Nanocarriers for a "two-Step" Targeted System to Colonic Tissue

[EN] Colon targeted drug delivery is highly relevant not only to treat colonic local diseases but also for systemic therapies. Mesoporous silica nanoparticles (MSNs) have been demonstrated as useful systems for controlled drug release given their biocompatibility and the possibility of designing gated systems able to release cargo only upon the presence of certain stimuli. We report herein the preparation of three gated MSNs able to deliver their cargo triggered by different stimuli (redox ambient (S1), enzymatic hydrolysis (S2), and a surfactant or being in contact with cell membrane (S3)) and their performance in solution and in vitro with Caco-2 cells. Safranin O dye was used as a model drug to track cargo fate. Studies of cargo permeability in Caco-2 monolayers demonstrated that intracellular safranin O levels were significantly higher in Caco-2 monolayers when using MSNs compared to those of free dye. Internalization assays indicated that S2 nanoparticles were taken up by cells via endocytosis. S2 nanoparticles were selected for in vivo tests in rats. For in vivo assays, capsules were filled with S2 nanoparticles and coated with Eudragit FS 30 D to target colon. The enteric coated capsule containing the MSNs was able to deliver S2 nanoparticles in colon tissue (first step), and then nanoparticles were able to deliver safranin O inside the colonic cells after the enzymatic stimuli (second step). This resulted in high levels of safranin O in colonic tissue combined with low dye levels in plasma and body tissues. The results suggested that this combination of enzyme-responsive gated MSNs and enteric coated capsules may improve the absorption of drugs in colon to treat local diseases with a reduction of systemic effects.The authors acknowledge the financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R, SAF2016-78756 and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (Project GVA/2014/13).Gonzalez-Alvarez, M.; Coll Merino, MC.; Gonzalez-Alvarez, I.; Giménez Morales, C.; Aznar, E.; Martínez-Bisbal, M.; Lozoya Agulló, I.... (2017). Gated Mesoporous Silica Nanocarriers for a "two-Step" Targeted System to Colonic Tissue. Molecular Pharmaceutics. 14(12):4442-4453. https://doi.org/10.1021/acs.molpharmaceut.7b00565S44424453141

Ionic Hydrogel Based on Chitosan Cross-Linked with 6-Phosphogluconic Trisodium Salt as a Drug Delivery System

[EN] In this work, 6-phosphogluconic trisodium salt (6-PG(-)Na(+)) is introduced as a new aqueous and nontoxic cross-linking agent to obtain ionic hydrogels. Here, it is shown the formation of hydrogels based on chitosan cross-linked with 6-PG(-)Na(+). This formulation is obtained by ionic interaction of cationic groups of polymer with anionic groups of the cross linker. These hydrogels are nontoxic, do not cause dermal irritation, are easy to extend, and have an adequate adhesion force to be applied as polymeric film over the skin. This AWN formulation exhibits a first order release kinetic and can be applied as drug vehicle for topical administration or as wound dressing for wound healing. The primary goal of this communication is to report the identification and utility of 6-phosphogluconic trisodium salt (6-PG(-)Na(+)) as a nontoxic cross-linker applicable for cationic polymers.The authors acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitiveness). Maria Teresa Martinez Martinez received a grant from the Ministry of Education and Science of Spain (FPU13-01105). The product was patented in Spain in 2016 by authors of this paper. Patent application 201631463.Martínez Martínez, M.; Rodríguez Berna, G.; Gonzalez-Alvarez, I.; Hernández, MJ.; Corma Canós, A.; Bermejo, M.; Merino Sanjuán, V.... (2018). Ionic Hydrogel Based on Chitosan Cross-Linked with 6-Phosphogluconic Trisodium Salt as a Drug Delivery System. Biomacromolecules. 19(4):1294-1304. https://doi.org/10.1021/acs.biomac.8b00108S1294130419

Osteogenic effects of simvastatin-loaded mesoporous titania thin films

The use of statins in the field of bone regeneration is under current investigation due to the existing demand for non-toxic anabolic agents capable of enhancing bone formation in cases of substantial loss. Simvastatin, a coenzyme currently prescribed in clinics to inhibit cholesterol biosynthesis, has been proven to promote osteogenic differentiation by stimulating bone formation and inhibiting osteoclasts activity. We present the loading of simvastatin in mesoporous TiO2 thin films toward combining the pro-osteogenic properties of this molecule with the demonstrated bioactivity of titania. TiO2 thin films processing and characterization were carried out, as well as evaluation of MC3T3-E1 pre-osteoblasts viability when directly incubated with different concentrations of simvastatin, followed by the analysis of osteogenic activity promoted by simvastatin upon loading in the thin films. The accessible porosity of 36% quantified on the 95 ± 5 nm thick mesoporous thin films, together with pore diameters of 5.5 nm, necks between pores of 2.8 nm and interpore distances of 12 ± 2 nm allow the loading of the simvastatin molecule, as confirmed by FTIR spectroscopy. Simvastatin was found to promote MC3T3-E1 pre-osteoblasts viability at concentrations ≤0.01 g l−1, with a cytotoxicity threshold of 0.05 g l−1. We additionally found that film loadings with 0.001 g l−1 simvastatin promotes statistically higher MC3T3-E1 pre-osteoblast proliferation whereas a higher concentration of 0.01 g l−1 leads to statistically higher osteogenic activity (ALP synthesis), after 21 days of incubation, as compared to unloaded films. These results demonstrate the potential of simvastatin local administration based on bioactive mesoporous thin films to promote pro-osteogenic properties. By focusing this strategy on the coating of metallic prostheses, the supply of simvastatin to the target tissue can be favored and risks of systemic side effects will be reduced while enhancing the osteointegration of the implants.Fil: Lopez Alvarez, Miriam. Universidad de Vigo; EspañaFil: López Puente, Vanesa. Universidad de Vigo; EspañaFil: Rodriguez Valencia, Cosme. Universidad de Vigo; EspañaFil: Angelome, Paula Cecilia. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Liz Marzan, Luis M. Ikerbasque; EspañaFil: Serra, Julia. Universidad de Vigo; EspañaFil: Pastoriza Santos, Isabel. Universidad de Vigo; EspañaFil: Gonzalez, Pio. Universidad de Vigo; Españ

New Insights of Oral Colonic Drug Delivery Systems for Inflammatory Bowel Disease Therapy

[EN] Colonic Drug Delivery Systems (CDDS) are especially advantageous for local treatment of inflammatory bowel diseases (IBD). Site-targeted drug release allows to obtain a high drug concentration in injured tissues and less systemic adverse effects, as consequence of less/null drug absorption in small intestine. This review focused on the reported contributions in the last four years to improve the effectiveness of treatments of inflammatory bowel diseases. The work concludes that there has been an increase in the development of CDDS in which pH, specific enzymes, reactive oxygen species (ROS), or a combination of all of these triggers the release. These delivery systems demonstrated a therapeutic improvement with fewer adverse effects. Future perspectives to the treatment of this disease include the elucidation of molecular basis of IBD diseases in order to design more specific treatments, and the performance of more in vivo assays to validate the specificity and stability of the obtained systems.The authors want to thank the Spanish Government (project RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE)) and the Generalitat Valenciana (project PROMETEO/2018/024) for support. This work was also supported by the project "MODELOS IN VITRO DE EVALUACION BIOFARMACEUTICA" SAF2016-78756(AEI/FEDER, EU) funded by Agencia Estatal Investigacion and European Union, through FEDER (Fondo Europeo de Desarrollo Regional).Hernández Teruel, A.; Gonzalez-Alvarez, I.; Bermejo, M.; Merino Sanjuán, V.; Marcos Martínez, MD.; Sancenón Galarza, F.; Gonzalez-Alvarez, M.... (2020). New Insights of Oral Colonic Drug Delivery Systems for Inflammatory Bowel Disease Therapy. 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IgG4-Related Disease Affecting Testicle and Myelodysplastic Syndrome: Just a Coincidence?

Immunoglobulin G4-related disease (IgG4-RD) is progressive immune-mediated fibrotic condition characterised by a tendency to form tumefactive lesions in different organs and by elevated IgG4 serum concentrations. Urological manifestations are rare and normally occur together with other systemic affections. Myelodysplastic syndromes (MDS) are hematopoietic stem cell neoplasms, with different subtypes based on the type of blood cells involved. MDS can be associated with other pathologies or medical treatments. We present an uncommon case of testicular manifestation associated with myelodysplastic syndrome here

First lunar outpost

Design and research efforts at the University of Puerto Rico have focused on the evaluation and refinement of the Habitability Criteria for a prolonged human presence in space during the last four years. Living quarters for a Mars mission and a third generation lunar base concept were proposed. This academic year, 1991-92, work on further refinement of the habitability criteria and design of partial gravity furniture was carried on. During the first semester, design alternatives for furniture necessary in a habitat design optimized for lunar and Martian environments were developed. Designs are based on recent research data from lunar and Mars gravity simulations, and current NASA standards. Artifacts will be submitted to NASA architects to be tested in KC-135 flights. Test findings will be submitted for incorporation in future updates to NASA habitat design standards. Second semester work was aimed at integrating these findings into the First Lunar Outpost (FLO), a mission scenario currently being considered by NASA. The mission consists of a manned return to the moon by crews of four astronauts for periods of 45 days. The major hardware components of the mission are as follows: (1) a Crew Module for the delivery of the crew and their supplies, and (2) the Habitat Module, which will arrive on the Moon unmanned. Our design efforts concentrated on this Habitat Module and on application of habitability criteria. Different geometries for the pressure vessel and their impact on the interior architecture were studied. Upon the selection of a geometry, a more detailed analysis of the interior design was performed, taking into consideration the reduced gravity, and the protection against radiation, micrometeorites, and the extreme temperature variation. A proposal for a FLO was submitted by the students, consisting essentially of a 24-feet (7.3 m.) by 35-feet (10.67 m) high vertical cylinder with work areas, crew quarters, galley, wardroom, leisure facilities, health maintenance, waste management, EVA operations facilities, and safe havens

Linfoma cutáneo de células B tipo centro folicular con infiltración a médula ósea reporte de un caso

Los linfomas cutáneos primarios de células B constituyen cerca del 20-25% de todos los linfomas. Ellinfoma cutáneo primario de células B tipo centro folicular es el subtipo más frecuente y se manifiesta principalmente en pacientes adultos con una edad media de 58 años (1), la diseminación extra-cutánea es muy rara y se presenta con nódulos, tumores o placas solitarios o en grupo usualmente localizados en cabeza o tronco. Presentamos el caso de una paciente con un linfoma primario cutáneo tipo centro folicular con infiltración a médula ósea