Polymeric Hydrogels as Technology Platform for Drug Delivery Applications

Hydrogels have become key players in the field of drug delivery owing to their great versatility in terms of composition and adjustability to various administration routes, from parenteral (e.g., intravenous) to non-parenteral (e.g., oral, topical) ones. In addition, based on the envisioned application, the design of bioadhesive or mucoadhesive hydrogels with prolonged residence time in the administration site may be beneficial. For example, hydrogels are used as wound dressings and patches for local and systemic therapy. In a similar way, they can be applied in the vaginal tract for local treatment or in the nasal cavity for a similar goal or, conversely, to target the central nervous system by the nose-to-brain pathway. Overall, hydrogels have demonstrated outstanding capabilities to ensure patient compliance, while achieving long-term therapeutic effects. The present work overviews the most relevant and recent applications of hydrogels in drug delivery with special emphasis on mucosal routes.Fil: Sosnik, Alejandro Dario. Technion - Israel Institute of Technology; IsraelFil: Seremeta, Katia Pamela. Universidad Nacional del Chaco Austral. Departamento de Ciencias Básicas y Aplicadas. Laboratorio de Ingeniería de las Reacciones Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentin

Chitosan-g-oligo(epsilon-caprolactone) polymeric micelles: microwave-assisted synthesis and physicochemical and cytocompatibility characterization

With the aim to produce mucoadhesive polymeric micelles for drug administration by mucosal routes, chitosan-g-oligo(epsilon-caprolactone) copolymers were synthesized by the microwave-assisted ring-opening polymerization of epsilon-caprolactone using chitosan as the macroinitiator and methanesulfonic acid as the solvent, catalyst and protecting group of the amine moieties. The reaction was conducted under very mild conditions and was completed within 10 min with a monomer conversion above 90%. The grafting of oligo(epsilon-caprolactone) blocks to the free hydroxyl groups of chitosan was confirmed by ATR/FT-IR, 1H- and 13C-NMR, WAXD and thermal analysis (TGA/DSC). The molecular weight of the synthetic hybrid copolymers was determined by GPC and MALDI-ToF mass spectrometry. Polymeric micelles obtained by the solvent diffusion/evaporation method showed a spherical shape (TEM and AFM) with sizes between 111 and 154 nm and highly positive zeta potential (>+50 mV) (DLS). In addition, they displayed good cell compatibility in the human lung adenocarcinoma epithelial line, A549, and were readily up-taken by the cervical cancer cell line, HeLa. Results from the encapsulation of the antituberculosis drug, rifampicin, showed that the micelles had better performance than other nanocarriers previously investigated (e.g., cyclodextrins). Moreover, the micelles conserved the mucoadhesiveness displayed by pristine chitosan and are expected to transiently open tight cell junctions and lead to more prolonged residence times in mucosal tissues and greater drug bioavailability.Fil: Glisoni, Romina Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Nanobiotecnología. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Nanobiotecnología; ArgentinaFil: Quintana Lazópulos, Silvina Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Molina, María. Freie Universität Berlin; AlemaniaFil: Calderon, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Freie Universität Berlin; AlemaniaFil: Moglioni, Albertina Gladys. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Sosnik, Alejandro Dario. Technion - Israel Institute of Technology; Israel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Analysis of CAPZA3 localization reveals temporally discrete events during the acrosome reaction

In mammals, the starting point of development is the fusion between sperm and egg. It is well established that sperm fuse with the egg through the equatorial/post-acrosomal region. Apart from this observation and the requirement of two proteins (CD9 in the egg and IZUMO1 in the sperm) very little is known about this fundamental process. Actin polymerization correlates with sperm capacitation in different mammalian species and it has been proposed that F-actin breakdown is needed during the acrosome reaction. Recently, we have presented evidence that actin polymerization inhibitors block the movement of IZUMO1 that accompany the acrosome reaction. These results suggest that actin dynamics play a role in the observed changes in IZUMO1 localization. This finding is significant because IZUMO1 localization in acrosome-intact sperm is not compatible with the known location of the initiation of the fusion between the sperm and the egg. To further understand the actin-mediated changes in protein localization during the acrosome reaction, the distribution of the sperm- specific plus-end actin capping protein CAPZA3 was analyzed. Like IZUMO1, CAPZA3 shows a dynamic pattern of localization; however, these movements follow a different temporal pattern than the changes observed with IZUMO1. In addition, the actin polymerization inhibitor latrunculin A was unable to alter CAPZA3 movement.Fil: Sosnik, Julian. University Of Massachussets; Estados UnidosFil: Buffone, Mariano Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Visconti, Pablo E.. University Of Massachussets; Estados Unido

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Design of Injectable Biomaterials for Biomedical and Pharmaceutical Applications: The Past, Present and Future of in situ generated implants

El implante de materiales biomédicos macroscópicos sólidos requiere de procedimientos quirúrgicos convencionales, comúnmente asociados con un extenso daño tisular. Con el objetivo de superar estas limitaciones, se han diseñado matrices capaces de ser insertadas a través de metodologías mínimamente invasivas (inyección). De acuerdo a las propiedades estructurales del implante luego de la inyección, los mismos pueden clasifi carse en 2 categorías: (1) implantes carentes de integridad estructural o no continuos y (2) materiales que forman un implante estructuralmente íntegro o continuo. La primera estrategia se basa en la inyección de micro o nanopartículas suspendidas en un vehículo biocompatible. Debido a que no poseen propiedades mecánicas, estos implantes pueden migrar del sitio de inserción. Para sobreponerse a esta desventaja, se han diseñado sistemas que combinan: (1) baja viscosidad y alta fl uidez al momento de la inyección con (2) un aumento pronunciado en las propiedades mecánicas a posteriori, que resultará en la formación de un implante sólido y con límites bien defi nidos. El presente trabajo introduce de manera concisa y detallada las distintas estrategias desarrolladas durante los últimos 20 años para el diseño de este tipo de implantes, así como también las perspectivas futuras en el área.The implantation of solid macroscopic biomedical materials requires conventional surgical procedures, which are commonly associated with extensive tissue damage. In an attempt to overcome these limitations, matrices that may be inserted through minimally invasive methodologies (injection) have been designed. Implants, after injection, may be classifi ed, in accordance with their structural properties, into two categories: (1) implant materials that have no structural or continuous integrity or (2) those that are structurally continuous or integral. The employment of the fi rst method is based on the injection of micro or nano particles, suspended in a biocompatible vehicle. However, the fact that these implants do not possess mechanical properties means that they may migrate from the site in which they have been inserted. In an attempt to overcome this drawback, system combining: (1) low viscosity and high fl uidity on injection with (2) a subsequently pronounced increase in mechanical properties, leading to the formation of a solid implant with well defi ned limits. The present work provides a concise and detailed introduction to the different strategies that have been developed in the design of this type of implants over the past 20 years, as well as an assessment of the future perspectives within this sphere

Cryoprotection–lyophilization and physical stabilization of rifampicin-loaded flower-like polymeric micelles

Rifampicin-loaded poly(ε-caprolactone)-b-poly(ethylene glycol)-poly(ε-caprolactone) flower-like polymeric micelles display low aqueous physical stability over time and undergo substantial secondary aggregation. To improve their physical stability, the lyoprotection- lyophilization process was thoroughly characterized. The preliminary cryoprotectant performance of mono- and disaccharides (e.g. maltose, glucose), hydroxypropyl-β-cyclodextrin (HPβCD) and poly(ethylene glycol) (PEG) of different molecular weights was assessed in freeze-thawing assays at -20°C, -80°C and -196°C. The size and size distribution of the micelles at the different stages were measured by dynamic light scattering (DLS). A cryoprotectant factor (fc) was determined by taking the ratio between the size immediately after the addition of the cryoprotectant and the size after the preliminary freeze-thawing assay. The benefit of a synergistic cryoprotection by means of saccharide/ PEG mixtures was also assessed. Glucose (1 : 20), maltose (1 : 20), HPβCD (1 : 5) and glucose or maltose mixtures with PEG3350 (1 : 20) (copolymer:cryoprotectant weight ratio) were the most effective systems to protect 1 per cent micellar systems. Conversely, only HPβCD (1 : 5) cryoprotected more concentrated drug-loaded micelles (4% and 6%). Then, those micelle/ cryoprotectant systems that displayed fc values smaller than 2 were freeze-dried. The morphology of freeze-dried powders was characterized by scanning electron microscopy and atomic force microscopy and the residual water content analysed by the Karl Fisher method. The HPβCD-added lyophilisates were brittle porous cakes (residual water was between 0.8% and 3%), easily redispersable in water to form transparent systems with a minimal increase in the micellar size, as determined by DLS.Fil: Moretton, Marcela Analía. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chiappetta, Diego Andrés. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sosnik, Alejandro Dario. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

High-grade extracellular vesicles preparation by combined size-exclusion and affinity chromatography

Extracellular vesicles (EVs) have recently gained growing interest for their diagnostic and therapeutic potential. Despite this, few protocols have been reported for the isolation of EVs with preserved biological function. Most EV purification methods include a precipitation step that results in aggregation of vesicles and most available techniques do not efficiently separate the various types of EVs such as exosomes and ectosomes, which are involved in distinct biological processes. For this reason, we developed a new two-step fast performance liquid chromatography (FPLC) protocol for purification of large numbers of EVs. The method comprises size exclusion chromatography followed by immobilized metal affinity chromatography, which is enabled by expression of poly-histidine tagged folate receptor α in the parental cells. Characterisation and comparison of the EVs obtained by this method to EVs purified by differential centrifugation, currently the most common method to isolate EVs, demonstrated higher purity and more selective enrichment of exosomes in EV preparations using our FPLC method, as assessed by comparison of marker proteins and density distribution. Our studies reveal new possibilities for the isolation of defined subpopulations of EVs with preserved biological function that can easily be upscaled for production of larger amounts of EVs