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Abstract: In this study, carboxymethyl chitosan was prepared, characterized, and then photo-induced graft copolymerized with poly(ethylene glycol) under a nitrogen atmosphere in aqueous solution using 2,2-dimethoxy-2-phenyl acetophenone (DMPA) as the photo-initiator. The grafting copolymerization process was confirmed and the resulting copolymers were characterized using differential scanning calorimetry (DSC), FTIR spectroscopy, 2D-X ray diffraction, and elemental analysis. The kinetics of the grafting reactions was also studied. Under the applied experimental conditions, the optimum grafting values were obtained at: CMCs=0.2g, PEGA=249mM, DMPA=10.4mM at a 2h reaction time. Some of the resulting copolymers were selected and used in the presence of methylene bisacrylamide (MBA) as a crosslinking agent to develop pH-responsive hydrogel matrices. The swelling characteristics and the in vitro release profiles of 5-fluorouracil (5-FU), as a model drug, from the hydrogels were investigated. The results revealed that the hydrogel matrices developed in this study can be customized to act as good candidates in drug delivery systems. [ABSTRACT FROM AUTHOR]

Abstract: Design of appropriate inhaled carriers with adequate aerodynamic properties, drug release, biodegradation and evasion of macrophage uptake is a major challenge for controlled release pulmonary drug delivery. In this study, PEG graft copolymerized onto N-phthaloyl chitosan (NPHCs) was synthesized then characterized using FTIR, EA, DSC and 2D-XRD. The resulting PEG-g-NPHCs copolymers were self-assembled into drug-loaded nanoparticles and encapsulated in respirable/swellable sodium alginate semi-IPN hydrogel microspheres as novel biodegradable carriers for controlled release pulmonary drug delivery. The developed nano-/microspheres carrier systems were formed via spray drying followed by ionotropic crosslinking in mild aqueous medium. The size of the developed self-assembled nanoparticles and the microspheres was measured using dynamic light scattering and laser diffraction, respectively. Morphology, moisture content, in vitro biodegradation and dynamic swelling studies were also investigated for the developed carriers. A model protein was entrapped and the in vitro release profiles were determined in PBS, pH 7.4 at 37°C. A dry powder aerosolization study was conducted using a Next Generation Impactor (NGI). The developed microspheres had suitable aerodynamic diameters (1.02–2.63μm) and an excellent fine particle fraction, FPF of 31.52%. The microspheres showed also a very fast initial swelling within the first 2min and started to enzymatically degrade within the first 2h. Moreover, the microspheres entrapped up 90% of the model drug and showed promising in vitro sustained release profiles as compared to the control formulation. [Copyright &y& Elsevier]

Abstract: In the present study, carboxymethyl chitosan was prepared and characterized. Photo-induced graft copolymerization of 2-hydroxyethyl methacrylate (HEMA) onto carboxymethyl chitosan (CMCs) was then carried out under nitrogen atmosphere in aqueous solution using 2,2-dimethoxy-2-phenyl acetophenone (PI) as photo-initiator. Grafting process was confirmed and the produced copolymers were characterized with aid of elemental analysis, FTIR, 2D-X ray diffraction, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The effects of HEMA and PI concentrations and the reaction time on the grafting yield were investigated by determining the grafting percentage and grafting efficiency. Under the applied experimental conditions, the optimum grafting conditions were obtained at: CMCs=0.2g, HEMA=0.615mol/L, PI=0.0078mol/L and reaction time=90min. The synthesized copolymers revealed a self-ability to form physically crosslinked hydrogels. The hydrogel nature of the copolymers was investigated by studying the solubility profiles and the cyclic swelling–deswelling behavior of copolymers with different grafting extents. These investigations of the photo-synthesized graft copolymers showed that they can be tailored and exploited as promising carriers for drug delivery purposes. [Copyright &y& Elsevier]

[Display omitted] • New chitosan-hyaluronic acid (CS-HA) core–shell nanoparticles (NPs) were developed. • The CS-HA NPs are the first sequential targeting delivery system of doxorubicin. • Mitotropic triphenylphosphonium-doxorubicin conjugate was synthesized. • The drug conjugate-loaded NPs were tested for sequential targeting of breast cancer. • In-vivo studies confirmed efficiency of CS-HA core–shell NPs for dual-stage delivery. Targeted therapy exploits cancerous niches' properties including acidic extracellular environment, hypoxic tumor core, and over expression of tumor-specific surface antigens. The present study aims to develop and evaluate a sequential targeted core–shell nanoparticulate (NPs) system for treatment of breast cancer. Sequential (double-stage) targeting was achieved at the cellular-level through employing the selective CD44- receptor binding hyaluronic acid (HA), followed by subcellular mitochondrial drug-delivery using the mitotropic triphenylphosphonium-conjugated doxorubicin (DOX-TPP+). NPs were prepared through incorporation of the electrostatic-complexes of DOX.HCl/DOX-TPP+ with tripolyphosphate (STPP-) into chitosan (CS) forming the core that was further coated with HA shell. Physicochemical characterization techniques namely; FTIR, DSC, DLS, morphological evaluation and spectroscopic assessments were implemented. Moreover, the drug entrapment efficiency (EE%), loading capacity (LC%), drug release profile and kinetics were investigated. Lastly, to validate the biological efficiency of the developed NPs, cytotoxic activity was evaluated as well as flow cytometric analyses to assess apoptosis induction and cell-cycle arrest were studied. Results showed that, the obtained core–shell NPs possessed a spherical shape with a mean size of 220–280 nm and attained high EE% and LC%. In-vitro cytotoxicity evaluations demonstrated successful apoptosis induction and cell-cycle abrogation. Moreover, in-vivo studies on Solid Ehrlich carcinoma (SEC)-bearing mice confirmed the efficient anticancer activity of the mitotropic DOX-TPP+-loaded NPs. Conclusively, the developed core–shell NPs proved efficient in sequential targeting of DOX to breast cancer. [ABSTRACT FROM AUTHOR]

In this investigation, novel biodegradable physically crosslinked hydrogel microparticles were developed and evaluated in vitro as potential carriers for sustained pulmonary drug delivery. To facilitate sustained release in the lungs, aerosols must first navigate past efficient aerodynamic filtering to penetrate to the deep lung (requires small particle size) where they must then avoid rapid macrophage clearance (enhanced by large particle size). The strategy suggested in this study to solve this problem is to deliver drug-loaded hydrogel microparticles with aerodynamic characteristics allowing them to be respirable when dry but attain large swollen sizes once deposited on moist lung surfaces to reduce macrophage uptake rates. The microparticles are based on PEG graft copolymerized onto chitosan in combination with Pluronic® F-108 and were prepared via cryomilling. The synthesized polymers used in preparation of the microparticles were characterized using FTIR, EA, 2D-XRD, and differential scanning calorimetry (DSC). The microparticles size, morphology, moisture content, and biodegradation rates were investigated. Swelling studies and in vitro drug release profiles were determined. An aerosolization study was conducted and macrophage uptake rates were evaluated against controls. The microparticles showed a respirable fraction of approximately 15% when prepared as dry powders. Enzymatic degradation of microparticles started within the first hour and about 7–41% weights were remaining after 240 h. Microparticles showed sustained release up to 10 and 20 days in the presence and absence of lysozyme, respectively. Preliminary macrophage interaction studies indicate that the developed hydrogel microparticles significantly delayed phagocytosis and may have the potential for sustained drug delivery to the lung. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2343–2356, 2010 [ABSTRACT FROM AUTHOR]

The RNA interference (RNAi) constitutes a conservative mechanism in eukaryotic cells that induces silencing of target genes. In mammalians, the RNAi is triggered by siRNA (small interfering RNA) molecules. Due to its potential in silencing specific genes, the siRNA has been considered a potential alternative for the treatment of genetic and acquired diseases. However, the siRNA therapy has been limited by its low stability and rapid degradation in presence of nucleases, low cellular uptake, and immune response activation. In order to overcome these drawbacks, we propose the synthesis and characterization of non-viral delivery systems using chitosan derivatives to obtain siRNA complexes (polyplexes). The non-viral delivery systems synthesized included PEG-g-OCs (oligochitosan) and PEG-g-Cs (chitosan medium molecular weight). Both systems allowed the formation of siRNA polyplexes, increased the stability of siRNA in the presence of nucleases, enhanced cellular internalization, and showed low toxicity in the A549 cell line. Finally, the complexes obtained with the PEG-g-OCs system showed silencing activity in a GFP model in the cell line A549 in comparison with naked siRNA. [ABSTRACT FROM AUTHOR]