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In view of inevitable recurrences despite resection, glioblastoma (GB) is still an unmet clinical need. Dealing with the stromal-cell derived factor 1-alpha (SDF-1α)/CXCR4 axis as a hallmark of infiltrative GB tumors and with the resection cavity situation, the present study described the effects and relevance of a new engineered micro-nanostructured SF-HA-Hep aerogel sponges, made of silk fibroin (SF), hyaluronic acid (HA) and heparin (Hep) and loaded with SDF-1α, to interfere with the GB ecosystem and residual GB cells, attracting and confining them in a controlled area before elimination. 70 µm-pore sponges were designed as an implantable scaffold to trap GB cells. They presented shape memory and fit brain cavities. Histological results after implantation in brain immunocompetent Fischer rats revealed that SF-HA-Hep sponges are well tolerated for more than 3 months while moderately and reversibly colonized by immuno-inflammatory cells. The use of human U87MG GB cells overexpressing the CXCR4 receptor (U87MG-CXCR4+) and responding to SDF-1α allowed demonstrating directional GB cell attraction and colonization of the device in vitro and in vivo in orthotopic resection cavities in Nude rats. Not modifying global survival, aerogel sponge implantation strongly shaped U87MG-CXCR4+ tumors in cavities in contrast to random infiltrative growth in controls. Overall, those results support the interest of SF-HA-Hep sponges as modifiers of the GB ecosystem dynamics acting as "cell meeting rooms" and biocompatible niches whose properties deserve to be considered toward the development of new clinical procedures. Brain tumor glioblastoma (GB) is one of the worst unmet clinical needs. To prevent the relapse in the resection cavity situation, new implantable biopolymer aerogel sponges loaded with a chemoattractant molecule were designed and preclinically tested as a prototype targeting the interaction between the initial tumor location and its attraction by the peritumoral environment. While not modifying global survival, biocompatible SDF1-loaded hyaluronic acid and silk fibroin sponges induce directional GB cell attraction and colonization in vitro and in rats in vivo. Interestingly, they strongly shaped GB tumors in contrast to random infiltrative growth in controls. These results provide original findings on application of exogenous engineered niches that shape tumors and serve as cell meeting rooms for further clinical developments. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: This paper compares six phospholipidic monolayers at the water/chloroform interface by performing dilational rheological measurements with a drop tensiometer apparatus. The chosen lipids differ both in their headgroup structure and fatty acyl chain saturation or symmetry. The study concentrated on monolayers formed with DPPC, DPPE, DOPC, DOPE, POPC and POPE. Using a generalized Maxwell rheological model, transposed at the interface, the intimate intermolecular interactions between amphiphilic molecules are studied on and off the monolayer plane. The equilibrium and nonequilibrium phenomena are analyzed and, respectively, correlated with monolayer cohesion and with monolayer/sub-surface interactions. The purpose of this work is to gain further insights into the influences (as slight as they are) of the weak changes in phospholipid structure and on the behavior of the monolayers. The results, widely described, provide further details on nuances existing between very similar molecules, and likewise, on the synergies created between the different effects. [Copyright &y& Elsevier]

[Display omitted] • Design and synthesis of novel versatile HNMed/siRNA complexes for locoregional therapy of glioblastoma. • HNMed/siRNA complexes showed high siRNA binding and protection against nucleases at N/P ratio of 10. • HNMed/siRNA complexes showed high cell uptake and gene silencing ability in an in vitro GB cell model. • DOTAP HNMed/siRNA complexes showed greater gene silencing ability over DC-Chol ones in vitro. • DOTAP-containing complexes showed higher cytocompatibility over DC-Chol ones in vitro on NIH3T3 cells. Small interfering RNA (siRNA) holds great potential to treat many difficult-to-treat diseases, but its delivery remains the central challenge. This study aimed at investigating the suitability of polymer-lipid hybrid nanomedicines (HNMeds) as novel siRNA delivery platforms for locoregional therapy of glioblastoma. Two HNMed formulations were developed from poly(lactic-co-glycolic acid) polymer and a cationic lipid: 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol). After characterization of the HNMeds, a model siRNA was complexed onto their surface to form HNMed/siRNA complexes. The physicochemical properties and siRNA binding ability of complexes were assessed over a range of nitrogen-to-phosphate (N/P) ratios to optimize the formulations. At the optimal N/P ratio of 10, complexes effectively bound siRNA and improved its protection from enzymatic degradation. Using the NIH3T3 mouse fibroblast cell line, DOTAP-based HNMeds were shown to possess higher cytocompatibility in vitro over the DC-Chol-based ones. As proof-of-concept, uptake and bioefficacy of formulations were also assessed in vitro on U87MG human glioblastoma cell line expressing luciferase gene. Complexes were able to deliver anti-luciferase siRNA and induce a remarkable suppression of gene expression. Noteworthy, the effect of DOTAP-based formulation was not only about three-times higher than DC-Chol-based one, but also comparable to lipofectamine model transfection reagent. These findings set the basis to exploit this nanosystem for silencing relevant GB-related genes in further in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

Calcium carbonate particles are promising candidates as proteins carriers for their controlled delivery in the body. The present paper aims at investigating the protein encapsulation by in situ precipitation of calcium carbonate particles prepared by a process based on supercritical CO 2 and using a new type of degradable well-defined double hydrophilic block copolymers composed of poly(ethylene oxide) and polyphosphoester blocks acting as templating agent for the calcium carbonate. For this study, lysozyme was chosen as a model for therapeutic protein for its availability and ease of detection. It was found that by this green process, loading into the CaCO 3 microparticles with a diameter about 2 μm can be obtained as determined by scanning electron microscopy. A protein loading up to 6.5% active lysozyme was measured by a specific bioassay ( Micrococcus lysodeikticus ). By encapsulating fluorescent-labelled lysozyme (lysozyme-FITC), the confocal microscopy images confirmed its encapsulation and suggested a core–shell distribution of lysozyme into CaCO 3 , leading to a release profile reaching a steady state at 59% of release after 90 min. [ABSTRACT FROM AUTHOR]

The aim of this work was to encapsulate transforming growth factor β1 (TGF-β1) into PLGA microparticles for regenerative medicine applications. TGF-β1 was firstly precipitated to ensure its stability during subsequent encapsulation within microparticles. A novel emulsification/extraction process in CO 2 medium under mild conditions of pressure and temperature was used to encapsulate the protein. Interestingly, non-volatile injectable solvents, isosorbide dimethyl ether (DMI) and glycofurol (GF), were employed to precipitate the protein and to dissolve the polymer. Good encapsulation efficiency was obtained with preserved bioactivity of the protein. The microparticles were characterized in terms of size and zeta potential. In addition, the morphology and surface properties were determined using scanning electron microscopy (SEM) and atomic force microscopy (AFM) respectively. In vitro release study of the protein from microparticles was presented to assess the capacity of these systems to control the protein release. Moreover, cytotoxicity study was performed and showed an excellent cytocompatibility of the obtained microparticles. Thus, we described an effective and original process for TGF-β1 encapsulation into PLGA microparticles. The obtained polymeric carriers could be used in many biomedical applications and were more specifically developed for cartilage regeneration. [ABSTRACT FROM AUTHOR]

Abstract: The development of simple and efficient drug delivery systems for the sustained release of peptides/proteins and low molecular weight hydrophilic molecules is an ongoing challenge. The purpose of this work was to prepare and characterize novel biodegradable in situ-forming implants obtained via the self-assembly of l-alanine derivatives in pharmaceutical oils. Six different amphiphilic organogelators based on l-alanine were synthesized. These derivatives could successfully gel various vegetable and synthetic oils approved for parenteral administration. Gelation was thermoreversible, and phase transition temperatures depended on gelator structure, concentration and solvent. Hydrogen bonds and van der Waals interactions were shown to be the main forces implicated in network formation. Selected formulations were then injected subcutaneously in rats for preliminary assessment of biocompatibility. Histopathological analysis of the surrounding tissues revealed mild, chronic inflammation and an overall good biocompatibility profile of the implants over the 8wk evaluation period. This study demonstrates that in situ-forming organogels represent a potentially promising platform for sustained drug delivery. [Copyright &y& Elsevier]

[Display omitted] • Novel chitosan nanofibrous scaffold containing PLGA nanoparticles. • Electrospun nanofibers with SDF-1α-loaded nanoparticles for sustained release. • High cytocompatibility in vitro and in vivo and slow degradation profile. • Mat structure with good cell attachment of glioblastoma cells. • Bioimplant Intended as a sink for the trapping of CXCR4-expressing tumor cells. Chemokines such as stromal cell-derived factor-1α (SDF-1α) regulate the migration of cancer cells that can spread from their primary tumor site by migrating up an SDF-1α concentration gradient, facilitating their local invasion and metastasis. Therefore, the implantation of SDF-1α-releasing scaffolds can be a useful strategy to trap cancer cells expressing the CXCR4 receptor. In this work, SDF-1α was encapsulated into poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles and subsequently electrospun with chitosan to produce nanofibrous scaffolds of average fiber diameter of 261 ± 45 nm, intended for trapping glioblastoma (GBM) cells. The encapsulated SDF-1α maintained its biological activity after the electrospinning process as assessed by its capacity to induce the migration of cancer cells. The scaffolds could also provide sustained release of SDF-1α for at least 5 weeks. Using NIH3T3 mouse fibroblasts, human Thp-1 macrophages, and rat primary astrocytes we showed that the scaffolds possessed high cytocompatibility in vitro. Furthermore, a 7-day follow-up of Fischer rats bearing implanted scaffolds demonstrated the absence of adverse effects in vivo. In addition, the nanofibrous structure of the scaffolds provided excellent anchoring sites to support the adhesion of human GBM cells by extension of their pseudopodia. The scaffolds also demonstrated slow degradation kinetics, which may be useful in maximizing the time window for trapping GBM cells. As surgical resection does not permit a complete removal of GBM tumors, our results support the future implantation of these scaffolds into the walls of the resection cavity to evaluate their capacity to attract and trap the residual GBM cells in the brain. [ABSTRACT FROM AUTHOR]

• Silk fibroin (SF) and hyaluronic acid (HA) miscibility determines aerogel structure. • Biodegradable SF-HA-heparin sponges have Young's modulus close to that of brain. • SF-HA sponges showed adequate porosity and pore size to be colonized by cells. • SF increases stiffness, while heparin strongly retains SDF-1α into the sponges. • Loading time and heparin ratio regulate heparinase-dependent SDF-1α release profile. This work aims to design biocompatible aerogel sponges that can host and control the release of stromal cell-derived factor-1α (SDF-1α or CXCL12), a key protein for applications ranging from regenerative medicine to cancer therapy (notably for neural tissues). Miscibility of silk fibroin (SF) and hyaluronic acid (HA) was investigated by means of fluorescence and scanning electron microscopy to identify processing conditions. Series of freeze-dried sponges were prepared by associating and cross-linking within the same 3D structure, HA, SF, poly- l -lysine (PLL) and heparin (hep). Aerogel sponges presented high swelling degree and porosity (∼90 %), adequate mean pore diameter (ca. 60 μm) and connectivity for welcoming cells, and a soft texture close to that of the brain (6–13 kPa Young's Modulus). Addition of SF yielded sponges with slower biodegradation. SF-HA and SF-HA-hep sponges retained 75 % and 93 % of the SDF-1α respectively after 7 days and were found to be cytocompatible in vitro. [ABSTRACT FROM AUTHOR]