Physicochemical properties and cellular responses of strontium-doped gypsum biomaterials.

This paper describes some physical, structural, and biological properties of gypsum bioceramics doped with various amounts of strontium ions (0.19-2.23 wt%) and compares these properties with those of a pure gypsum as control. Strontium-doped gypsum (gypsum:Sr) was obtained by mixing calcium sulfate hemihydrate powder and solutions of strontium nitrate followed by washing the specimens with distilled water to remove residual salts. Gypsum was the only phase found in the composition of both pure and gypsum:Sr, meanwhile a shift into lower diffraction angles was observed in the X-ray diffraction patterns of doped specimens. Microstructure of all gypsum specimens consisted of many rod-like small crystals entangled to each other with more elongation and higher thickness in the case of gypsum:Sr. The Sr-doped sample exhibited higher compressive strength and lower solubility than pure gypsum. A continuous release of strontium ions was observed from the gypsum:Sr during soaking it in simulated body fluid for 14 days. Compared to pure gypsum, the osteoblasts cultured on strontium-doped samples showed better proliferation rate and higher alkaline phosphatase activity, depending on Sr concentration. These observations can predict better in vivo behavior of strontium-doped gypsum compared to pure one.

Nanocarriers and nonviral methods for delivering antiangiogenic factors for glioblastoma therapy: the story so far.

Angiogenesis, the formation of new blood vessels, is an essential component of glioblastoma (GB) progression. The development of angiogenesis inhibitor therapy, including treatments targeting vascular endothelial growth factor (VEGF) in particular, raised new hopes for the treatment of GB, but no Phase III clinical trial to date has reported survival benefits relative to standard treatment. There are several possible reasons for this limited efficacy, including VEGF-independent angiogenesis, induction of tumor invasion, and inefficient antiangiogenic factor delivery to the tumor. Efforts have been made to overcome these limitations by identifying new angiogenesis inhibitors that target angiogenesis through different mechanisms of action without inducing tumor invasion, and through the development of viral and nonviral delivery methods to improve antiangiogenic activity. Herein, we describe the nonviral methods, including convection-enhanced delivery devices, implantable polymer devices, nanocarriers, and cellular vehicles, to deliver antiangiogenic factors. We focus on those evaluated in intracranial (orthotopic) animal models of GB, the most relevant models of this disease, as they reproduce the clinical scenario of tumor progression and therapy response encountered in GB patients.

Development and characterization of sorafenib-loaded lipid nanocapsules for the treatment of glioblastoma.

Anticancer agents that target both tumor cells and angiogenesis are of potential interest for glioblastoma (GB) therapy. One such agent is sorafenib (SFN), a tyrosine kinase inhibitor. However, poor aqueous solubility and undesirable side effects limit its clinical application, including local treatment. We encapsulated SFN in lipid nanocapsules (LNCs) to overcome these drawbacks. LNCs are nanocarriers formulated according to a solvent-free process, using only components that have received regulatory approval. SFN-LNCs had a diameter of 54 ± 1 nm, high encapsulation efficiency (>90%), and a drug payload of 2.11 ± 0.03 mg/g of LNC dispersion. They inhibited in vitro angiogenesis and decreased human U87MG GB cell viability similarly to free SFN. In vivo studies showed that the intratumoral administration of SFN-LNCs or free SFN in nude mice bearing an orthotopic U87MG human GB xenograft decreased the proportion of proliferating cells in the tumor relative to control groups. SFN-LNCs were more effective than free SFN for inducing early tumor vascular normalization, characterized by increases in tumor blood flow and decreases in tumor vessel area. These results highlight the potential of LNCs as delivery systems for SFN. The vascular normalization induced by SFN-LNCs could be used to improve the efficacy of chemotherapy or radiotherapy for treating GB.

Human mesenchymal stromal cells as cellular drug-delivery vectors for glioblastoma therapy: a good deal?

BACKGROUND: Glioblastoma (GB) is the most malignant brain tumor in adults. It is characterized by angiogenesis and a high proliferative and invasive capacity. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) is of limited efficacy. Innovative anticancer drugs targeting both tumor cells and angiogenesis are urgently required, together with effective systems for their delivery to the brain. We assessed the ability of human mesenchymal stromal cells (MSCs) to uptake the multikinase inhibitor, sorafenib (SFN), and to carry this drug to a brain tumor following intranasal administration. METHOD: MSCs were primed with SFN and drug content and release were quantified by analytical chemistry techniques. The ability of SFN-primed MSCs to inhibit the survival of the human U87MG GB cell line and endothelial cells was assessed in in vitro assays. These cells were then administered intranasally to nude mice bearing intracerebral U87MG xenografts. Their effect on tumor growth and angiogenesis was evaluated by magnetic resonance imaging and immunofluorescence analyses, and was compared with the intranasal administration of unprimed MSCs or SFN alone. RESULTS: MSCs took up about 9 pg SFN per cell, with no effect on viability, and were able to release 60% of the primed drug. The cytostatic activity of the released SFN was entirely conserved, resulting in a significant inhibition of U87MG and endothelial cell survival in vitro. Two intranasal administrations of SFN-primed MSCs in U87MG-bearing mice resulted in lower levels of tumor angiogenesis than the injection of unprimed MSCs or SFN alone, but had no effect on tumor volume. We also observed an increase in the proportion of small intratumoral vessels in animals treated with unprimed MSCs; this effect being abolished if the MSCs were primed with SFN. CONCLUSION: We show the potential of MSCs to carry SFN to brain tumors following an intranasal administration. However, the therapeutic effect is modest probably due to the pro-tumorigenic properties of MSCs, which may limit the action of the released SFN. This calls into question the suitability of MSCs for use in GB therapy and renders it necessary to find methods guaranteeing the safety of this cellular vector after drug delivery.

Comparative study of mesenchymal stem cells osteogenic differentiation on low-temperature biomineralized nanocrystalline carbonated hydroxyapatite and sintered hydroxyapatite.

Hydroxyapatite with different characteristics in terms of morphology and chemistry were prepared via conventional sintering and low temperature biomimetic mineralization methods. The biomineralization route introduced nanocrystalline carbonate-substituted hydroxyapatite (n-CHA) with needle-like crystals ranging 20-30 nm whereas sintered HA (S-HA) comprised of polygonal grains ranging 2-5 µm. The response of fibroblastic cells was investigated using the extract of the samples whereas Wistar rat-derived mesenchymal stem cells (MSCs) were evaluated on top of each sample while maintaining in an osteogenic-free medium. The proliferation, activity, and morphology of adherent MSCs were determined at different culturing periods. The osteogenic differentiation of MSCs was also assayed by determining expression of runx2, osteonectin, osteopontin, and osteocalcin genes using real time-PCR analysis. The fibroblastic cells exhibited better proliferation rate at the presence of n-CHA compared to S-HA. Furthermore, the MSCs attached and spread well on both n-CHA and S-HA with better proliferation rate and alkaline phosphatase activity on n-CHA. Interestingly, the osteogenic differentiation of MSCs on n-CHA was confirmed by the expression of bone specific proteins whereas poor expression of these proteins was detected for the cells on S-HA. The results showed that the role of morphology, crystallinity, and chemistry of hydroxyapatite is crucial for osteogenesis differentiation of MSCs. The results predict osteoinductivity of n-CHA, because MSCs differentiation occurred at the absence of osteogenic medium. However, in vivo data are also required to support this suggestion.

Amorphous calcium phosphate nanoparticles could function as a novel cancer therapeutic agent by employing a suitable targeted drug delivery platform.

Employment of nanovehicular system for delivering apoptogenic agent to cancer cells for inducing apoptosis has widely been investigated. Loading efficacy and controlled release of the agents are of the inseparable obstacles that hamper the efforts in reaching an efficacious targeted cancer therapy method. When the carrier itself is apoptogenic, then there is no need to load the carrier with apoptogenic agent and just delivering of the particle to the specific location matters. Hence, we hypothesize that amorphous calcium phosphate nanoparticle (ACPN) is a potent candidate for apoptosis induction, although encapsulation in liposome shell, and surface decoration with targeting ligand (TL), and cell-penetrating peptide (CPP) plays a pivotal role in the employment of this agent. It is well understood that elevation in cytosolic Ca2+ ([Ca2+]c) would result in the induction of apoptosis. ACPN has the potential to cause imbalance in this medium by elevating [Ca2+]c. Owning to the fact that the nanoparticles should be delivered into cytosol, it is necessary to trap them in a liposomal shell for evading endocytosis. It was demonstrated that employment of the trans-activator of transcription (TAT) as CPP eminently enhances the efficacy of endosomal escape; therefore, the platform is designed in a way that TAT is positioned on the surface of the liposome. Due to the fact that the apoptosis should be induced in sole cancer cells, Folate as TL is also attached on the surface of the liposome. This hypothesis heralds the new generation of chemotherapeutic agents and platforms which could have less side effect than the most common ones, in addition to other advantages they have.

Polymerizable nanoparticulate silica-reinforced calcium phosphate bone cement.

Bone cements based on calcium phosphate powder and different concentrations of colloidal silica suspensions were developed. Setting time and washout behavior of the cements were recorded and compared with those of a control group prepared by the same powder phase and distilled water as liquid. The phase composition, compressive strength, and morphology of the cements were determined after incubation and soaking in simulated body fluid. Proliferation of osteoblasts seeded on samples was also determined as a function of time. The results showed that the long setting time, poor compressive strength, and undesirable washout behavior of the cement made with distilled water were considerably improved by adding colloidal silica in a dose-dependent manner. On the basis of XRD and SEM results, both control group and nanosilica-added cements composed of nanosized apatite flakes after 7 days soaking, in addition to tetracalcium phosphate residual for the latter. It was found that the rate of hydraulic reactions that are responsible for conversion of the cement reactants to nanostructured apatite was increased by the presence of colloidal silica. Furthermore, the osteoblasts exhibited better proliferation on nanosilica added cements compared to control one. This study suggests better applied properties for nanosilica-added calcium phosphate cement compared to traditional cements.

Scope of nanotechnology-based radiation therapy and thermotherapy methods in cancer treatment.

The main aim of nanomedicine is to revolutionize the health care system and find effective approaches to fighting fatal diseases. Therapeutic beams, which are employed in radiation therapy, do not discriminate between normal and cancerous cells and must rely on targeting the radiation beams to specific cells. Interestingly, the application of nanoscale particles in radiation therapy has aimed to improve outcomes in radiation therapy by increasing toxicity in tumors and reducing it in normal tissues. This review focuses on approaches to nanotechnology-based cancer radiation therapy methods such as radionuclide therapy, photodynamic therapy, and neutron capture therapy. Moreover, we have investigated nanotechnology-based thermotherapy methods, including hyperthermia and thermoablation, as non-ionizing modalities of treatment using thermal radiation. The results strongly demonstrate that nanotechnology-based cancer radiation therapy and thermotherapy methods hold substantial potential to improve the efficacy of anticancer radiation and thermotherapy modalities.