Modulation of protein release from penta-block copolymer microspheres.

Releasing a protein according to a zero-order profile without protein denaturation during the polymeric microparticle degradation process is very challenging. The aim of the current study was to develop protein-loaded microspheres with new PLGA based penta-block copolymers for a linear sustained protein release. Lysozyme was chosen as model protein and 40 µm microspheres were prepared using the solid-in-oil-in-water solvent extraction/evaporation process.

Behavior of poly(d,l-lactic-co-glycolic acid) (PLGA)-based droplets falling into a complex extraction medium simulating the prilling process.

Hypothesis: Prilling process is one of advanced techniques for manufacturing microspheres of controlled and uniform size. In this process, homogenous polymer droplets fall into an extraction medium. The aim of this study was to identify the key parameters influencing the behavior of PLGA polymer-based droplets falling into a complex extraction medium, to select appropriate conditions for prilling.

Penta-block copolymer microspheres: Impact of polymer characteristics and process parameters on protein release.

Here, we aimed to develop protein loaded microspheres (MSs) using penta-block PLGA-based copolymers to obtain sustained and complete protein release. We varied MS morphology and studied the control of protein release. Lysozyme was used as a model protein and MSs were prepared using the solid-in-oil-in-water emulsion solvent extraction method.

Nanoprecipitated catestatin released from pharmacologically active microcarriers (PAMs) exerts pro-survival effects on MSC.

Catestatin (CST), a fragment of Chromogranin-A, exerts angiogenic, arteriogenic, vasculogenic and cardioprotective effects. CST is a very promising agent for revascularization purposes, in "NOOPTION" patients. However, peptides have a very short half-life after administration and must be conveniently protected.

Pharmacologically active microcarriers delivering BDNF within a hydrogel: Novel strategy for human bone marrow-derived stem cells neural/neuronal differentiation guidance and therapeutic secretome enhancement.

Unlabelled: Stem cells combined with biodegradable injectable scaffolds releasing growth factors hold great promises in regenerative medicine, particularly in the treatment of neurological disorders. We here integrated human marrow-isolated adult multilineage-inducible (MIAMI) stem cells and pharmacologically active microcarriers (PAMs) into an injectable non-toxic silanized-hydroxypropyl methylcellulose (Si-HPMC) hydrogel. The goal is to obtain an injectable non-toxic cell and growth factor delivery device.

Scaffolds for Controlled Release of Cartilage Growth Factors.

In recent years, cell-based therapies using adult stem cells have attracted considerable interest in regenerative medicine. A tissue-engineered construct for cartilage repair should provide a support for the cell and allow sustained in situ delivery of bioactive factors capable of inducing cell differentiation into chondrocytes. Pharmacologically active microcarriers (PAMs), made of biodegradable and biocompatible poly (D,L-lactide-co-glycolide acid) (PLGA), are a unique system which combines these properties in an adaptable and simple microdevice.

Pharmacologically active microcarriers associated with thermosensitive hydrogel as a growth factor releasing biomimetic 3D scaffold for cardiac tissue-engineering.

The challenge of tissue engineering of the infarcted heart is how to improve stem cell engraftment, survival, homing, and differentiation for myocardial repair. We here propose to integrate human adipose-derived stem cells (ADSCs) and pharmacologically active microcarriers (PAMs), a three-dimensional (3D) carrier of cells and growth factors, into an injectable hydrogel (HG), to obtain a system that stimulates the survival and/or differentiation of the grafted cells toward a cardiac phenotype. PAMs are biodegradable and non-cytotoxic poly(lactic-co-glycolic acid) (PLGA) microspheres conveying cells on their 3D surface that deliver continuously and in a controlled manner a growth factor (GF) acting on the transported cells and on the microenvironment to improve engraftment.

New PLGA-P188-PLGA matrix enhances TGF-β3 release from pharmacologically active microcarriers and promotes chondrogenesis of mesenchymal stem cells.

The use of injectable scaffolding materials for in vivo tissue regeneration has raised great interest in various clinical applications because it allows cell implantation through minimally invasive surgical procedures. In case of cartilage repair, a tissue engineered construct should provide a support for the cell and allow sustained in situ delivery of bioactive factors capable of inducing cell differentiation into chondrocytes. Pharmacologically active microcarriers (PAMs), made of biodegradable poly(d,l-lactide-co-glycolide acid) (PLGA), are a unique system, which combines these properties in an adaptable and simple microdevice.

Protein-loaded PLGA-PEG-PLGA microspheres: a tool for cell therapy.

A promising strategy to repair injured organs is possible by delivering a growth factor via poly-(d,l lactide-co-glycolide) (PLGA) microspheres; the latter are coated with adhesion molecules that serve as a support for cell delivery. At present, PLGA is not the optimal choice of polymer because of poor or incomplete protein release. The use of a more hydrophilic PLGA-PEG-PLGA (A-B-A) copolymer increases the degree of protein release.

Why and how to prepare biodegradable, monodispersed, polymeric microparticles in the field of pharmacy?

Drug delivery via biodegradable microparticles benefits from both the protection of the encapsulated drug from hazardous conditions and the controlled release of the encapsulated drug, thereby reducing the administration frequency and improving patient compliance. Microsphere-size particle distribution is considered as being an important factor that affects the choice of the administration route and the drug-release rate. Significant research efforts have been directed towards the production of monodispersed "designer" particles.

The potential of combinations of drug-loaded nanoparticle systems and adult stem cells for glioma therapy.

The prognosis of patients with malignant glioma remains extremely poor, despite surgery and improvements in radio- and chemo-therapies. Nanotechnologies hold great promise in glioma therapy as they protect the therapeutic agent and allow its sustained release. However, new paradigms permitting tumor-specific targeting and extensive intratumoral distribution must be developed to efficiently deliver nanoparticles.

Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors.

The prognosis of patients with malignant glioma remains extremely poor, despite surgery and improvements in radio- and chemo-therapies. Nanotechnologies represent great promise in glioma therapy as they protect therapeutic agent and allow its sustained release. However, new paradigms allowing tumor specific targeting and extensive intratumoral distribution must be developed to efficiently deliver nanoparticles (NPs).

The role of pharmacologically active microcarriers releasing TGF-beta3 in cartilage formation in vivo by mesenchymal stem cells.

Cartilage engineering using mesenchymal stem cells (MSC) will require the use of a scaffold which will act as a support for cell adhesion keeping the cells in the cartilage defect. Optimally, a tissue engineered construct should allow sustained delivery of bioactive factors capable of inducing MSC differentiation into chondrocytes and should be easily injected inside the cartilage lesions to avoid surgical operations. We therefore developed pharmacologically active microcarriers (PAM) made of poly-lactic-co-glycolic acid (PLGA) produced using an oil-in-water (o/w) emulsion method.

Effect of various additives and polymers on lysozyme release from PLGA microspheres prepared by an s/o/w emulsion technique.

Incomplete protein release from PLGA-based microspheres due to protein interactions with the polymer is one of the main issues in the development of PLGA protein-loaded microspheres. In this study, a two-dimensional adsorption model was designed to rapidly assess the anti-adsorption effect of formulation components (additives, additives blended with the polymer or modified polymers). Lysozyme was chosen as a model protein because of its strong, non-specific adsorption on the PLGA surface.

Reversible protein precipitation to ensure stability during encapsulation within PLGA microspheres.

Proteins were precipitated to ensure their stability upon subsequent encapsulation within PLGA microspheres. Spherical, nanosized protein particles were formed by the addition of a salt (sodium chloride) and a water-miscible organic solvent (glycofurol) to protein solutions. Various process parameters were modified to optimize the precipitation efficiency of four model proteins: lysozyme, alpha-chymotrypsin, peroxidase and beta-galactosidase.

How to achieve sustained and complete protein release from PLGA-based microparticles?

One of the most challenging tasks in the delivery of therapeutic proteins from PLGA-based microparticles is the sustained and complete release of the protein in its native form. The mechanisms responsible for incomplete protein release from these devices are numerous and complex; the beneficial effect of different formulations has often been evaluated in vitro. Strategies employed for overcoming protein destabilization during the release step are reviewed in this paper.

5-ASA loaded chitosan-Ca-alginate microparticles: Preparation and physicochemical characterization.

The objective of the work was to prepare chitosan-Ca-alginate microparticles that can effectively deliver 5-ASA to the colon after peroral administration. For these requirements, a spray-drying technique was applied to 5-ASA/sodium alginate aqueous solution to obtain spherical particles having a mean diameter less than 10microm. The microparticles formed were cross-linked and coated into solution of CaCl(2) and chitosan to obtain stable microsystem.

Intravitreous injection of PLGA microspheres encapsulating GDNF promotes the survival of photoreceptors in the rd1/rd1 mouse.

Purpose: To evaluate the potential delay of the retinal degeneration in rd1/rd1 mice using recombinant human glial cell line-derived neurotrophic factor (rhGDNF) encapsulated in poly(D,L-lactide-co-glycolide) (PLGA) microspheres.

Methods: rhGDNF-loaded PLGA microspheres were prepared using a water in oil in water (w/o/w) emulsion solvent extraction-evaporation process. In vitro, the rhGDNF release profile was assessed using radiolabeled factor.

Preparation of PLGA microparticles by an emulsion-extraction process using glycofurol as polymer solvent.

Purpose: To develop biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles prepared by an original emulsion-extraction process, with glycofurol, a nontoxic excipient, as polymer solvent.

Methods: The preparation of microparticles consisted in dissolving polymer in glycofurol. This solution was emulsified in a vegetable oil, and then amphiphilic agent was added into the emulsion to extract glycofurol and lead to microparticle formation.

Pharmacologically active microcarriers: a tool for cell therapy.

To overcome certain problems encountered in cell therapy, particularly cell survival, lack of cell differentiation and integration in the host tissue, we developed pharmacologically active microcarriers (PAM). These biodegradable particles made with poly(D,L-lactic-co-glycolic acid) (PLGA) and coated with adhesion molecules may serve as a support for cell culture and may be used as cell carriers presenting a controlled delivery of active protein. They can thus support the survival and differentiation of the transported cells as well as their microenvironment.

In vivo evaluation of pharmacologically active microcarriers releasing nerve growth factor and conveying PC12 cells.

Cell therapy will probably become a major therapeutic strategy in the coming years. Nevertheless, few cells survive transplantation when employed as a treatment for neuronal disorders. To address this problem, we have developed a new tool, the pharmacologically active microcarriers (PAM).

Influence of 5-fluorouracil-loaded microsphere formulation on efficient rat glioma radiosensitization.

Purpose: To determine (i) the efficiency of radiosensitizing 5-FU-loaded microspheres and (ii) the impact of microparticle formulation on response to treatment.

Methods: C6 tumor-bearing rats were stereotactically implanted with microspheres and/or allocated to: control groups (untreated) or treatment (only radiotherapy; fast-release 5-FU microspheres + radiotherapy; slow-release 5-FU microspheres + radiotherapy). The next day, fractionated radiotherapy, limited to the hemibrain, was initiated in all treated animals.

Striatal tyrosine hydroxylase immunoreactive neurons are induced by L-dihydroxyphenylalanine and nerve growth factor treatment in 6-hydroxydopamine lesioned rats.

Only a few studies mention the existence of tyrosine hydroxylase immunoreactive neurons in the striatum. These neurons are known to be increased following lesion of the dopaminergic nigrostriatal pathway. Recently it has been shown that glial cell line-derived neurotrophic factor treatment was able to increase the number of these neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated primate.

New thermoluminescent dosimeters (TLD): optimization and characterization of TLD threads sterilizable by autoclave.

To improve the performance of mono-extruded TLD threads as a dosimetric thermoluminescent tool (French Patent 9903729), a new process was developed by co-extrusion methodology leading to threads of 600 microm diameter with a 50 microm homogeneous polypropylene sheath. In this optimization work, study of parameters such as LiF:Mg,Cu,P powder granulometry, load rate and proportion of components led to an increased sensitivity of around 40%. Moreover, the co-extrusion technique allowed the threads to be sterilized by humid steam (134 degrees C/18 min) without significant variation of the linearity response between 0 and 30 Gy after gamma irradiation (60Co).