The ever increasing improvements of pharmaceutical formulations have been often obtained by means of the use of hydrogels. In particular, environmentally sensitive hydrogels have been investigated as ...“smart” delivery systems capable to release, at the appropriate time and site of action, entrapped drugs in response to specific physiological triggers. At the same time the progress in the tissue engineering research area was possible because of significant innovations in the field of hydrogels. In recent years multicomponent hydrogels, such as semi-Interpenetrating Polymer Networks (semi-IPNs) and Interpenetrating Polymer Networks (IPNs) have emerged as innovative biomaterials for drug delivery and as scaffolds for tissue engineering. These interpenetrated hydrogel networks, which can be obtained by either chemical or physical crosslinking, in most cases show physico-chemical properties that can remarkably differ from those of the macromolecular constituents. Among the synthetic and natural polymers that have been used for the preparation of semi-IPNs and IPNs, polysaccharides represent a class of macromolecules of particular interest because they are usually abundant, available from renewable sources and have a large variety of composition and properties that may allow appropriately tailored chemical modifications. Sometimes both macromolecular systems are based on polysaccharides but often also synthetic polymers are present together with polysaccharide chains.
The description and discussion of (semi)-IPNs reported here, will allow to acquire a better understanding of the potential and wide range of applications of IPN polysaccharide hydrogels.
A quite large number of polysaccharides have been investigated for the design of (semi)-IPNs for drug delivery and tissue engineering applications. This review article however mainly focuses on two of the most studied polysaccharide-based (semi)-IPNs, namely those obtained using alginate and hyaluronic acid. An overview of the methods of preparation, the properties, the performances as drug delivery systems and as scaffolds for tissue engineering, of (semi)-IPNs obtained using these two polysaccharides and their derivatives, will be given.
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During the last decades, it has become evident that inflammation plays a critical role in tumorigenesis: tumor microenvironment is largely orchestrated by inflammatory cells. In the present work, a ...novel gellan gum nanohydrogel system (NH) able to carry and deliver simultaneously anti-cancer and anti-inflammatory drugs was developed. Prednisolone was chemically linked to the carboxylic groups of gellan gum to serve as a hydrophobic moiety promoting nanohydrogel formation, whereas paclitaxel was then physically entrapped in it. NH improved drug performances, acting as paclitaxel and prednisolone solubility enhancer and favoring the drug uptake in the cells. Moreover, NH allowed an increased cytotoxic effect in vitro on several types of cancer cells due to the synergistic effect of the combination of anti-inflammatory and anti-cancer drugs. Thus, NH can be useful in a combination therapy that attacks both, malignant cells and tumor inflammatory components.
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Water structure and dynamics are investigated by 1H NMR in a polysaccharide interpenetrating polymer network (IPN) based on calcium alginate and methacrylated hyaluronic acid. The ...effects of two solvents, water and a saline NaCl solution, on the transport properties of water and on the polymer structure are analyzed. Anomalous diffusion behavior of water in the different samples is investigated and correlated to the polymer structure. Up to three water fractions are detected in the IPN samples having different hydrogen bond network structure and diffusion properties. This work highlights how the aggregation of hydrophobic domains in amphiphilic hydrogels influences the transport properties of solvent water. In addition, the results emphasize the effect of charged ions, used to improve hydrogel biocompatibility, on the polymer network structure and of polymer interpenetration mechanisms.
The ever‐growing need for new tissue and organ replacement approaches paved the way for tissue engineering. Successful tissue regeneration requires an appropriate scaffold, which allows cell adhesion ...and provides mechanical support during tissue repair. In this light, an interpenetrating polymer network (IPN) system based on biocompatible polysaccharides, dextran (Dex) and gellan (Ge), was designed and proposed as a surface that facilitates cell adhesion in tissue engineering applications. The new matrix was developed in glycerol, an unconventional solvent, before the chemical functionalization of the polymer backbone, which provides the system with enhanced properties, such as increased stiffness and bioadhesiveness. Dex was modified introducing methacrylic groups, which are known to be sensitive to UV light. At the same time, Ge was functionalized with RGD moieties, known as promoters for cell adhesion. The printability of the systems was evaluated by exploiting the ability of glycerol to act as a co‐initiator in the process, speeding up the kinetics of crosslinking. Following semi‐IPNs formation, the solvent was removed by extensive solvent exchange with HEPES and CaCl2, leading to conversion into IPNs due to the ionic gelation of Ge chains. Mechanical properties were investigated and IPNs ability to promote osteoblasts adhesion was evaluated on thin‐layer, 3D‐printed disk films. Our results show a significant increase in adhesion on hydrogels decorated with RGD moieties, where osteoblasts adopted the spindle‐shaped morphology typical of adherent mesenchymal cells. Our findings support the use of RGD‐decorated Ge/Dex IPNs as new matrices able to support and facilitate cell adhesion in the perspective of bone tissue regeneration.
Recently, glycerol has been exploited in a number of industrial applications, thanks to its high availability, its low cost and, overall, its peculiar properties which fit well with the green ...chemistry principles. In this work, the ability of glycerol to solubilize high molecular weight polymers and to allow the formation of glycerol-based semi-interpenetrating polymer networks, called “gly-semi-IPNs”, has been investigated. Compared to water, glycerol deeply affects the structural properties of the biopolymers, especially with reference to their chain flexibility. Among the polysaccharides, dextran methacrylate (DexMA) and gellan gum (Ge) were selected. Glycerol solutions of both polysaccharides and their mixtures, as well as a DexMA network (obtained by cross-linking in glycerol and in the presence of a photoinitiator), were rheologically characterized to assess the role of the solvent on the chain conformation and on the mechanical properties of the networks. Interestingly, glycerol was found to deeply influence the mechanical, morphological and optical properties of the formed hydrogels, as well as to improve the cross-linking kinetic of DexMA. Furthermore, glycerol leads to more homogeneous mixtures of the two polysaccharides than those observed in aqueous buffers. As such, novel gly-semi-IPNs, with enhanced formulation and mechanical properties, were prepared and characterized.
We describe here new nanoparticles based on the bioconjugation of penicillin G to squalene in order to overcome severe intracellular infections by pathogen bacteria whose mechanism of resistance ...arises from the poor intracellular diffusion of several antibiotics. Two different squalene–penicillin G conjugates were synthesized (pH-sensitive and pH-insensitive), and their self-assembly as nanoparticles was investigated through morphology and stability studies. These nanoparticles had a size of 140 ± 10 nm (polydispersity index of 0.1) and a negative charge, and they did not display any supramolecular organization. Furthermore, they were found stable in water and in different culture medium. The cellular uptake and localization of these fluorescently labeled nanoparticles were explored on the macrophage cell line J774 by flow cytometry and confocal microscopy analysis. The squalenoylated nanoparticles were found to be cell internalized through clathrin-dependent and -independent endocytic pathways. Moreover, they induced an improved intracellular antibacterial activity on the facultative intracellular pathogen S. aureus, compared with free penicillin G, despite the absence of co-localization between the bacteria and the nanoparticles in the cells. This study suggests that the bioconjugation of an antibiotic to a squalene template could be a valuable approach for overcoming the antibiotic resistance due to intracellular bacterial infections.
ABSTRACT
Purpose
To synthesize a new polymeric prodrug based on α,β-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)-d,l-aspartamide copolymer bearing amine groups in the side chain (PHEA-EDA), ...covalently linked to the anticancer drug doxorubicin and to test its potential application in anticancer therapy.
Methods
The drug was previously derivatized with a biocompatible and hydrophilic linker, leading to a doxorubicin derivative highly reactive with amino groups of PHEA-EDA. The PHEA-EDA-DOXO prodrug was characterized in terms of chemical stability. The pharmacokinetics, biodistribution and cytotoxicity of the product was investigated
in vitro
and
in vivo
on human breast cancer MCF-7 and T47D cell lines and NOD-SCID mice bearing a MCF-7 human breast carcinoma xenograft. Data collected were compared to those obtained using free doxorubicin.
Results
The final polymeric product is water soluble and easily hydrolysable
in vivo
, due to the presence of ester and amide bonds along the spacer between the drug and the polymeric backbone.
In vitro
tests showed a retarded cytotoxic effect on tumor cells, whereas a significant improvement of the
in vivo
antitumor activity of PHEA-EDA-DOXO and a survival advantage of the treated NOD-SCID mice was evidenced, compared to that of free doxorubicin.
Conclusions
The features of the PHEA-EDA-DOXO provide a potential protection of the drug from the plasmatic enzymatic degradation and clearance, an improvement of the blood pharmacokinetic parameters and a suitable body biodistribution. The data collected support the promising rationale of the proposed macromolecular prodrug PHEA-EDA-DOXO for further potential development and application in the treatment of solid cancer diseases.
PURPOSE. Aim of this research was to prepare and study drug release from a new formulation consisting of non ionic surfactant vesicular structures, niosomes (NSVs), loaded with model molecules ...calcein (CALC), nile red (NR), ibuprofen (IBU) or caffeine (CAFF), and embedded in a hydrogel matrix. METHODS. The system locust bean gum/xanthan (1:1), prepared at 60 °C, was used to entrap the vesicles (Tween 20/cholesterol 1:1), loaded with guest molecules and the release profiles were detected at 32 °C. The hydrogel systems were characterized by means of scanning electron microscopy; niosomes were characterized by means of size and -potential measurements. RESULTS. Size measurements showed that a slight increase in vesicle dimensions occurs after inclusion of CALC or CAFF (hydrophilic molecules) in the vesicular structures. -potential measurements showed that the inclusion of these molecules did not significantly modify the surface charge of empty vesicles. This was probably related to an almost negligible drug adsorption on the vesicle surface. The release from the niosomes-gel systems of two probes (CALC and NR) showed that the diffusion of CALC through the gel was not affected by the niosome entrapment while for NR, the presence of vesicles was crucial. The release profiles from niosomes-gel systems and from the hydrogel alone of model drugs, CAFF and IBU, showed an appreciable difference between the two drugs: the more hydrophilic CAFF was released much faster than IBU. In all release studies turbidity, dimension and -potential analyses indicated that the loaded niosomes were released by the hydrogel matrix without being damaged. CONCLUSIONS. The reported in vitro experiments show the capability of the novel formulation to combine the qualities of both chosen single systems, i.e. the niosomes and the polymeric network. The hydrogel shows a protective effect on vesicle integrity and leads to a slow release of the loaded model molecules from the polysaccharidic system. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Alginate microspheres represent a useful tool for modified drug delivery. Their preparation is quite easy and is usually based on the gelling properties of the polysaccharide in the presence of ...divalent ions; nevertheless, microparticles prepared only with calcium alginate show several problems, mainly related to the mechanical stability and to the release that, in most cases, is too fast. To overcome such inconveniences, polymer-coated alginate microspheres and/or appropriately interpenetrating polymer network (semi-IPNs and IPNs) structures formed with alginate and other macromolecules were developed.
This article reports a synthetic overview on the most recent searches carried out on coated alginate microspheres.
After a section focused on the microsphere preparation, this article is divided into several main topics related to the specific polymer that was used as a coating material to provide a rationale in reporting literature data. In the last section, the advantages and disadvantages of the various approaches are discussed and the authors' opinion on perspectives for further studies and novel applications of coated alginate microspheres are reported.
Ca(2+)-alginate microparticles could experience a new era if scientists will increase their efforts in developing microparticles with smart properties.
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