In Situ-Forming Gels Loaded with Stimuli-Responsive Gated Mesoporous Silica Nanoparticles for Local Sustained Drug Delivery.

A novel combination of in situ-forming hydrogels of hyaluronic acid with gated mesoporous materials was developed to design depots for local sustained release of chemotherapeutics. The depot consists of a hyaluronic-based gel loaded with redox-responsive mesoporous silica nanoparticles loaded with safranin O or doxorubicin and capped with polyethylene glycol chains containing a disulfide bond. The nanoparticles are able to deliver the payload in the presence of the reducing agent, glutathione (GSH), that promotes the cleavage of the disulfide bonds and the consequent pore opening and cargo delivery. Release studies and cellular assays demonstrated that the depot can successfully liberate the nanoparticles to the media and, subsequently, that the nanoparticles are internalized into the cells where the high concentration of GSH induces cargo delivery. When the nanoparticles were loaded with doxorubicin, a significant reduction in cell viability was observed. Our research opens the way to the development of new depots that enhance the local controlled release of chemotherapeutics by combining the tunable properties of hyaluronic gels with a wide range of gated materials.

Oftalmía nodosa en el trópico / Ophthalmia nodosa in the tropics

Antecedentes: La oftalmía nodosa (ON) fue descrita por primera vez por Schön en 1861, y desde entonces ha recibido múltiples nombres, ampliando la identificación de los agentes causales. En Colombia no se tienen referencias precisas sobre dichos agentes. Objetivo: Realizar revisión de tema sobre una enfermedad subdiagnosticada como la ON. Material y métodos: Análisis retrospectivo y narrativo de la literatura, a propósito de la publicación de cinco casos diagnosticados con ON en la Clínica Barraquer, Bogotá, Colombia, de enero de 1983 a diciembre de 2020. Resultados: Los pacientes valorados en nuestra institución presentaron resolución completa de los síntomas una vez que se realizó tratamiento descrito de manera oportuna. Conclusiones: La ON es una enfermedad conocida que requiere alta sospecha clínica para ser diagnosticada. Los corticoesteroides tópicos son la primera línea de tratamiento y se recomienda la retirada del cuerpo extraño siempre que sea posible.

Background: Ophthalmia nodosa (ON) was first described by Schön in 1861, and since then it has received multiple names, broadening the identification of the causal agents. In Colombia there are no precise references to these agents. Objective: To perform a review of an underdiagnosed entity such us ON. Material and methods: To report of five patients diagnosed with ON in Clinica Barraquer, Bogotá, Colombia from January 1983 to December 2020. Retrospective and narrative literature analysis. Results: Patients presented complete resolution once the described treatment was carried out on time. Conclusions: ON is a well-known disease that requires a high clinical suspicion to be diagnosed. Topical corticosteroids are the first line of treatment and removal of the foreign body is recommended.

pH-Dependent Molecular Gate Mesoporous Microparticles for Biological Control of Giardia intestinalis.

Giardiasis is a parasitism produced by the protozoa Giardia intestinalis that lives as trophozoite in the small intestine (mainly in the duodenum) attached to the intestinal villus by means of billed discs. The first line treatment is metronidazole, a drug with high bioavailability, which is why to obtain therapeutic concentrations in duodenum, it is necessary to administer high doses of drug to patients with the consequent occurrence of side effects. It is necessary to developed new therapeutical approaches to achieve a local delivery of the drug. In this sense, we have developed gated mesoporous silica microparticles loaded with metronidazole and with a molecular gate pH dependent. In vitro assays demonstrated that the metronidazole release is practically insignificant at acidic pHs, but in duodenum conditions, the metronidazole delivery from the microparticles is effective enough to produce an important parasite destruction. In vivo assays indicate that this microparticulate system allows to increase the concentration of the drug in duodenum and reduce the concentration in plasma avoiding systemic effects. This system could be useful for other intestinal local treatments in order to reduce doses and increase drug availability in target tissues.

Nanoparticle-cell-nanoparticle communication by stigmergy to enhance poly(I:C) induced apoptosis in cancer cells.

Nanoparticle-cell-nanoparticle communication by stigmergy was demonstrated using two capped nanodevices. The first community of nanoparticles (i.e.S(RA)IFN) is loaded with 9-cis-retinoic acid and capped with interferon-γ, whereas the second community of nanoparticles (i.e.S(sulf)PIC) is loaded with sulforhodamine B and capped with poly(I:C). The uptake of S(RA)IFN by SK-BR-3 breast cancer cells enhanced the expression of TLR3 receptor facilitating the subsequent uptake of S(sulf)PIC and cell killing.

Prevalencia de pacientes con queratocono en la Clínica Barraquer en Bogotá, Colombia / Prevalence of keratoconus patients at the Barraquer Clinic in Bogotá, Colombia

Introducción: Queratocono es un término clínico amplio, que describe un estado de la córnea derivado de su adelgazamiento focal y protrusión secundaria central, paracentral y/o periférica. Los reportes epidemiológicos globales revelan un amplio rango en cifras de prevalencia e incidencia que se podría explicar por las diferencias geográficas, factores de riesgo, tipo de población, métodos y criterios diagnósticos utilizados. En Colombia no hay estudios epidemiológicos que evalúen esta enfermedad de manera integral por lo que su frecuencia aún no ha podido ser determinada. Objetivo: identificar la prevalencia de Queratocono y Degeneración Marginal Pelucida (DMP) en el centro oftalmológico privado Clínica Barraquer, durante el periodo de tiempo comprendido entre enero de 2014 y enero de 2019. Diseño del estudio: estudio transversal de fuentes secundarias. Método: revisión de los registros médicos electrónicos de todos los pacientes que consultaron por primera vez; posteriormente, se filtraron por el diagnóstico de Ectasia Corneal y/o Queratocono. Cada una de las historias clínicas fue analizada por un oftalmólogo teniendo en cuenta los diagnósticos preestablecidos. Resultados: del grupo de 91.426 pacientes, 2.647 tenían Queratocono o DMP. Se estableció una prevalencia de Queratocono y DMP del 2.84%. La edad promedio al momento del diagnóstico fue de 29.7±12 años. El 42.8% eran mujeres y el 57.2% hombres. Conclusión: la ectasias corneales de tipo Queratocono y DMP, son enfermedades con una prevalencia significativa en la población colombiana evaluada en la clínica Barraquer; consideramos se requiere de programas de tamizaje visual para su detección y tratamiento oportunos.

Background: Keratoconus is a wide clinical term used to describe a corneal disease characterized by thinning and secondary central, paracentral or peripheral protrusion of the cornea. The global epidemiological reports reveal a wide range of prevalence and incidence, that may be explained by geographical differences, risk factors, kind of population, and methods and diagnostic criteria employed. There are no epidemiological studies to evaluate globally this disease in Colombia, therefore, its frequency has not been determined yet. Objective: to identify the prevalence of Keratoconus and Pellucid Marginal Degeneration (PMD) from January 2014 to January 2019 at the private ophthalmological center Clínica Barraquer. Study Design: cross-sectional study using secondary data. Method: a review of the electronic medical records of all patients who consulted for the first time was performed, and then, filtered by the initial diagnosis of Corneal Ectasia or Keratoconus. Each one of the medical records was analyzed by an ophthalmologist taking into account a series of pre-established diagnostic criteria. Results: of 91.426 patients, 2.647 had Keratoconus or PMD within the time interval of the study. A prevalence of 2.84% was determined in first time patients. The average age at the time of diagnosis was 29.7±12 years. 42.8% were female patients and 57.2% male patients. Conclusion: Keratoconus and PMD are diseases with significant prevalence in the Colombian population evaluated at the Barraquer clinic, thus, visual screening programs are required for accurate detection and treatment.

Indicaciones y técnicas de trasplante de córnea en una clínica oftalmológica privada en Colombia / Indications and techniques of corneal transplantation in a private ophthalmologic clinic in Colombia

Introducción: el trasplante de córnea es el injerto mas frecuente en el campo de la medicina; las técnicas para realizarlo han evolucionado permitiendo hacer procedimientos menos invasivos, con menor riesgo de rechazo del injerto y con una recuperación más rápida. La escasez de donantes para realizar trasplantes de córnea, genera una limitación terapéutica muy importante en el campo de la patología corneal. Objetivo: Reportar las Indicaciones y Técnicas empleadas en los Trasplantes de Córnea, en una institución privada con atención terciaria en Oftalmología en Bogotá, Colombia. Diseño del Estudio: Estudio transversal de fuentes secundarias. Método: Se hizo un estudio transversal, con las historias clínicas electrónicas de los pacientes operados con algún tipo de trasplante de córnea, en la Clínica Barraquer de América en el periodo comprendido desde Enero del 2010 a Diciembre del 2018 Resultados: Las cuatro primeras Indicaciones para Trasplantes de córnea fueron: 1) Ectasias Corneales 38.27% 2) Descompensación corneal 20.88% 3) Reposición de Injerto 17.72% 4) Leucomas Cicatriciales 16.22%. Las técnicas empleadas fueron Injerto Penetrante el 54.11% - Injertos Laminares (43.52%) con un 17.25% de Injertos Endoteliales. Conclusión: Existen diferencias en la frecuencia de las Indicaciones para trasplante de córnea según la región del país y también respecto a las publicaciones internacionales. El Queratocono fue la indicación mas frecuente. La Queratoplastia Penetrante la técnica más frecuente como procedimiento primario, pero también como técnica alternativa debido a la falta de oportunidad para realizar el trasplante.

Background: corneal transplant is the most frequent graft in the fi eld of medicine; the techniques to carry it out have evolved allowing to make less invasive procedures, with less risk of rejection of the graft and with a faster recovery. The shortage of donors to perform corneal transplants generates a very important therapeutic limitation in the field of corneal pathology.. Objective: To report the Indications and surgical techniques in Corneal Transplants in a tertiary referral center and private Ophthalmological clinic in Bogotá-ColombiaStudy Design: Cross sectional study using secondary data. Method: A cross sectional study was performed with the electronic clinical records of the patients that had a corneal graft of any kind during the period between January 2010 and December 2018 at the Barraquer Clinic in América. Results: The top four indications for corneal transplantation were: 1) Corneal Ectasias 38.27% - 2) Bullous Keratopathy 20.88% ­ 3) Re-Graft 17.72% and 4) Leucomas 16.22%. Penetrating Keratoplasty was the most common indication (54.11%) followed by Lamellar Techniques 43.52% of which Endothelial keratoplasty was performed in 17.25%. Conclusion: Corneal transplant indications and its frequency, are different between country regions in Colombia and towards international reviews. For us, Keratoconus was the most frequent indication. and Penetrating Keratoplasty, the most frequent technique as a primary procedure, but also as an alternative technique due to the lack of opportunity to perform the transplant.

Functional Magnetic Mesoporous Silica Microparticles Capped with an Azo-Derivative: A Promising Colon Drug Delivery Device.

Magnetic micro-sized mesoporous silica particles were used for the preparation of a gated material able to release an entrapped cargo in the presence of an azo-reducing agent and, to some extent, at acidic pH. The magnetic mesoporous microparticles were loaded with safranin O and the external surface was functionalized with an azo derivative 1 (bearing a carbamate linkage) yielding solid S1. Aqueous suspensions of S1 at pH 7.4 showed negligible safranin O release due to the presence of the bulky azo derivative attached onto the external surface of the inorganic scaffold. However, in the presence of sodium dithionite (azoreductive agent), a remarkable safranin O delivery was observed. At acidic pH, a certain safranin O release from S1 was also found. The pH-triggered safranin O delivery was ascribed to the acid-induced hydrolysis of the carbamate moiety that linked the bulky azo derivatives onto the mesoporous inorganic magnetic support. The controlled release behavior of S1 was also tested using a model that simulated the gastro intestinal tract.

Full inhibition of enzymatic browning in the presence of thiol-functionalised silica nanomaterial.

Darkening processed fruits and vegetables is caused mainly by enzymatic browning through polyphenol oxidase (PPO) action. Accordingly, we explored the potential of four silica-based materials (MCM-41 nanometric size, MCM-41 micrometric size, UVM-7 and aerosil), non-functionalised and functionalised with thiol groups, to inhibit PPO activity in the model system and apple juice. All materials showed relevant performance when immobilising and inhibiting PPO in model systems, and support topology is a main factor for enzyme immobilisation and inhibition. Thiol-containing silica UVM7-SH showed the greatest inactivation, and similar browning values to those obtained by acidification. The enzyme's kinetic parameters in the presence of UVM-7-SH suggested non-competitive inhibition, which indicated that the material interacted with the enzyme, but beyond the active centre. In real systems, UVM-7-SH completely inhibited enzymatic browning in apple juice (cv. Granny Smith and cv. Golden Delicious) up to 9days after 5min of contact.

Can Appropriate Systemic Treatment Help Protect the Cornea in Patients With Rheumatoid Arthritis? A Multidisciplinary Approach to Autoimmune Ocular Involvement.

PURPOSE: To correlate rheumatologic with ophthalmic and laboratory findings in patients with rheumatoid arthritis (RA) to identify what effect these have on development of ocular disease. METHODS: This is a cross-sectional study of 172 eyes of 86 patients with RA. Patients were examined by a group of rheumatologists. Sociodemographic, clinical, and laboratory data were collected. All patients underwent complete ophthalmologic examination including corneal topography and endothelial cell count. RESULTS: There was no significant correlation between RA-negative prognostic indicators (NPIs) and pathologic corneal findings. Patients using disease-modifying antirheumatic drugs (DMARDs) and antimalarial drugs had greater corneal volumes (mean difference 8.51 mm, 90% confidence interval [CI], 3.98-13.04, P = 0.004; and 2.24, 90% CI, 0.32-4.54, P = 0.048, respectively). Patients using azathioprine had lower endothelial cell counts compared with those using other drugs (mean difference 180 cells/mm, 90% CI, 69-291, P = 0.008). Patients using biologic DMARDs had better tear osmolarity values (between 280 and 300 mOsm/L) than patients not using them (mean difference 14.3 mOsm/L, P = 0.022). There was no correlation between NPIs of RA and positive keratoconus screening indices (Spearman correlation OD -0.013, P = 0.91; OS -0.033, P = 0.76). CONCLUSIONS: There was no clear correlation between RA-NPIs and pathologic corneal findings in our study. DMARDs treatment may help maintain corneal integrity in our patients and prevented collagenolytic manifestations of RA. Other medications such as azathioprine should be used carefully, as endothelial damage may potentially occur.

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

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.

Selective Fluorogenic Sensing of As(III) Using Aptamer-Capped Nanomaterials.

Organic-inorganic hybrid nanomaterials offer extremely valuable tools for monitoring many types of analytes in solution. Within this framework, aptamer-based nanomaterials for heavy metal detection are still very scarce. Herein, a novel sensing nanoprobe for the selective and sensitive detection of As(III) based on the combination of aptamers with mesoporous silica nanoparticles has been developed. The efficiency of the sensor is demonstrated in environmental conditions, showing a great potential in As(III) monitoring assays.

Self-Regulated Glucose-Sensitive Neoglycoenzyme-Capped Mesoporous Silica Nanoparticles for Insulin Delivery.

We describe herein the preparation of glucose-sensitive capped mesoporous silica nanoparticles for insulin delivery. The new material consists of an expanded-pore nanometric silica support grafted with 1-propyl-1-H-benzimidazole groups, loaded with fluorescein isothiocyanate-labeled insulin (FITC-Ins) and capped by the formation of inclusion complexes between cyclodextrin-modified glucose oxidase (CD-GOx) and the benzimidazole groups grafted on the mesoporous support. Insulin delivery from the gated material in simulated blood plasma was assessed upon addition of glucose. Glucose is transformed by GOx into gluconic acid, which promoted the dethreading of the benzimidazole-CD-GOx inclusion complexes, allowing cargo release. Small quantities of this support would be needed to release the amount of insulin necessary to decrease diabetic blood glucose concentrations to regular levels.

Surface Enhanced Raman Scattering and Gated Materials for Sensing Applications: The Ultrasensitive Detection of Mycoplasma and Cocaine.

We present herein a novel combination of gated mesoporous silica nanoparticles (MSNs) and surface-enhanced Raman scattering (SERS) for sensing applications. As a proof-of-concept, we show the design of a system comprising MSNs loaded with crystal violet (CV), a molecule with high Raman cross section acting as SERS reporter, and capped with either a suitable DNA sequence for the detection of Mycoplasma genomic DNA or with an aptamer that selectively coordinates cocaine. In both cases the presence of the corresponding target analyte in solution (i.e., genomic DNA or cocaine) resulted in the release of CV. CV delivery was detected by SERS upon adsorption on gold nanotriangles (AuNTs), which display an efficient electromagnetic field enhancement and a high colloidal stability. By using this novel procedure a limit of detection of at least 30 copies DNA per µL was determined for the detection of Mycoplasma genomic DNA, whereas cocaine was detected at concentrations as low as 10 nm.

Caspase 3 Targeted Cargo Delivery in Apoptotic Cells Using Capped Mesoporous Silica Nanoparticles.

Excessive apoptotic cell death is at the origin of several pathologies, such as degenerative disorders, stroke or ischemia-reperfusion damage. In this context, strategies to improve inhibition of apoptosis and other types of cell death are of interest and may represent a pharmacological opportunity for the treatment of cell-death-related disorders. In this scenario new peptide-containing delivery systems (solids S1 -P1 and S1 -P2 ) are described based on mesoporous silica nanoparticles (MSNs) loaded with a dye and capped with the KKGDEVDKKARDEVDK (P1 ) peptide that contains two repeats of the DEVD target sequence that are selectively hydrolyzed by caspase 3 (C3). This enzyme plays a central role in the execution-phase of apoptosis. HeLa cells electroporated with S1 -P1 are able to deliver the cargo in the presence of staurosporin (STS), which induces apoptosis with the consequent activation of the cytoplasmic C3 enzyme. Moreover, the nanoparticles S1 -P2 , containing both a cell-penetrating TAT peptide and P1 also entered in HeLa cells and delivered the cargo preferentially in cells treated with the apoptosis inducer cisplatin.

Cathepsin-B induced controlled release from peptide-capped mesoporous silica nanoparticles.

New capped silica mesoporous nanoparticles for intracellular controlled cargo release within cathepsin B expressing cells are described. Nanometric mesoporous MCM-41 supports loaded with safranin O (S1-P) or doxorubicin (S2-P) containing a molecular gate based on a cathepsin B target peptidic sequence were synthesized. Solids were designed to show "zero delivery" and to display cargo release in the presence of cathepsin B enzyme, which selectively hydrolyzed in vitro the capping peptide sequence. Controlled delivery in HeLa, MEFs WT, and MEFs lacking cathepsin B cell lines were also tested. Release of safranin O and doxorubicin in these cells took place when cathepsin B was active or present. Cells treated with S2-P showed a fall in cell viability due to nanoparticles internalization, cathepsin B hydrolysis of the capping peptide, and cytotoxic agent delivery, proving the possible use of these nanodevices as new therapeutic tools for cancer treatment.

An aptamer-gated silica mesoporous material for thrombin detection.

An aptamer-capped mesoporous material for the selective and sensitive detection of α-thrombin in human plasma and serum has been prepared and characterised.

Gated silica mesoporous supports for controlled release and signaling applications.

Blending molecular and supramolecular advances with materials science has resulted in recent years in the development of new organic-inorganic hybrid materials displaying innovative functionalities. One appealing concept in this field is the development of gated nanodevices. These materials are prepared by grafting molecular or supramolecular caps onto the external surface of mesoporous inorganic scaffolds loaded with a particular cargo. The caps or "gates" can then be opened and the cargo delivered at will upon the application of a given stimulus. In this Account, we report some of the recent advances we have made in designing such materials for drug delivery and as new chromo-fluorogenic probes. For controlled release applications, we have prepared capped hybrid mesoporous supports capable of being selectively opened by applying certain physical and chemical stimuli. We report examples of gated materials opened by changes in pH (using polyamines as caps), light (employing spiropyran derivatives or gold nanoparticles), and temperature (using selected paraffins). We also report gated materials opened by enzymes that cleave capping molecules based on lactose, hydrolyzed starch, and peptides. The use of enzymes is especially appealing because molecular caps built of enzyme-specific sequences made of peptides or other cleavable molecules could allow on-command delivery of drugs and biomolecules in specialized contexts. In the second part of the manuscript, we revisit the possibility of using hybrid gated nanomaterials as sensory systems. In such systems, when target analytes interact with the cap, their presence triggers the transport of a dye from pores to the solution, resulting in a chromo-fluorogenic signal that allows their detection. Two approaches are possible. In the first one, pores remain open and the dye can diffuse into the solution, until the presence of a target analyte binds to receptors in the caps and closes the gate. In the second approach, the caps are closed and the presence of a target analyte induces pore opening and dye delivery. One of the most interesting properties of these sensory hybrid materials is their inherent amplification features, because few target analyte molecules can modulate the transport of a significant amount of dye molecules within the porous network. We describe such systems for the recognition and sensing of anionic (ATP, long-chain carboxylates, anionic surfactants, borate, and oligonucleotides), cationic (methylmercury), and neutral (nerve agent simulants and sulfathiazole) species.

Design of enzyme-mediated controlled release systems based on silica mesoporous supports capped with ester-glycol groups.

An ethylene glycol-capped hybrid material for the controlled release of molecules in the presence of esterase enzyme has been prepared. The final organic-inorganic hybrid solid S1 was synthesized by a two-step procedure. In the first step, the pores of an inorganic MCM-41 support (in the form of nanoparticles) were loaded with [Ru(bipy)(3)]Cl(2) complex, and then, in the second step, the pore outlets were functionalized with ester glycol moieties that acted as molecular caps. In the absence of an enzyme, release of the complex from aqueous suspensions of S1 at pH 8.0 is inhibited due to the steric hindrance imposed by the bulky ester glycol moieties. Upon addition of esterase enzyme, delivery of the ruthenium complex was observed due to enzymatic hydrolysis of the ester bond in the anchored ester glycol derivative, inducing the release of oligo(ethylene glycol) fragments. Hydrolysis of the ester bond results in size reduction of the appended group, therefore allowing delivery of the entrapped cargo. The S1 nanoparticles were not toxic for cells, as demonstrated by cell viability assays with HeLa and MCF-7 cell lines, and were found to be associated with lysosomes, as shown by confocal microscopy. However, when S1 nanoparticles were filled with the cytotoxic drug camptothecin (S1-CPT), S1-CPT-treated cells undergo cell death as a result of S1-CPT cell internalization and subsequent cellular enzyme-mediated hydrolysis and aperture of the molecular gate that induced the release of the camptothecin cargo. These findings point to a possible therapeutic application of these nanoparticles.