Amir Kraitzer

Long-term in vitro study of paclitaxel-eluting bioresorbable core/shell fiber structures

Paclitaxel-eluting bioresorbable core/shell fiber structures for stent applications and local cancer treatment were developed and studied. These structures were composed of a polyglyconate core and a porous PDLGA shell loaded with the anti-proliferative agent paclitaxel, prepared using freeze drying of inverted emulsions. The investigation of these new composite fibers focused on the effects of the emulsions composition (formulation) and process kinetics on the long-term drug release from the fibers, in light of the shells morphology and degradation profile. Paclitaxel release from the porous shell was relatively slow due to its extremely hydrophobic nature. It exhibited three phases of release, which corresponded to the degradation profile of the host PDLGA. We found that the effect of the emulsion formulation on the release profile is more significant than the effect of the process kinetics. The copolymer composition had the most dominant effect on the drug release profile from the composite fibers. The polymer content also affected the release profile, whereas the drug content and the organic:aqueous phase ratio resulted in minor effects. Emulsions with a less hydrophobic nature are favorable for effective controlled release of the hydrophobic paclitaxel from the porous shell.

Highly porous drug-eluting structures: From wound dressings to stents and scaffolds for tissue regeneration

For many biomedical applications, there is need for porous implant materials. The current article focuses on a method for preparation of drug-eluting porous structures for various biomedical applications, based on freeze drying of inverted emulsions. This fabrication process enables the incorporation of any drug, to obtain an “active implant” that releases drugs to the surrounding tissue in a controlled desired manner. Examples for porous implants based on this technique are antibiotic-eluting mesh/matrix structures used for wound healing applications, antiproliferative drug-eluting composite fibers for stent applications and local cancer treatment, and protein-eluting films for tissue regeneration applications. In the current review we focus on these systems. We show that the release profiles of both types of drugs, water-soluble and water-insoluble, are affected by the emulsions formulation parameters. The formers release profile is affected mainly through the emulsion stability and the resulting porous microstructure, whereas the latters release mechanism occurs via water uptake and degradation of the host polymer. Hence, appropriate selection of the formulation parameters enables to obtain desired controllable release profile of any bioactive agent, water-soluble or water-insoluble, and also fit its physical properties to the „application.

Composite Fiber Structures with Antiproliferative Agents Exhibit Advantageous Drug Delivery and Cell Growth Inhibition In Vitro

Composite core/shell fiber structures loaded with the antiproliferative drugs paclitaxel or farnesylthiosalicylate (FTS) were developed and studied. The latter is a specific nontoxic Ras inhibitor with a mild hydrophobic nature, which can also be used for local cancer treatment and stent applications. The fibers were composed of a dense polyglyconate core and a porous drug-loaded poly(D,L-lactic-glycolic acid) shell, prepared using freeze drying of inverted emulsions. Our study focused on the release profile of the antiproliferative drugs from the fibers, the shell morphology and its degradation and erosion. The postfabrication antiproliferative effect of the drugs was tested in a cell culture. The process parameters were found to affect the drug-release profile via two routes: (1) direct, through water uptake and swelling of the structure leading to FTS release, or through degradation of the host polymer leading to paclitaxel release at a later stage; (2) indirect effect of the microstructure on the release profile. The fabrication process did not reduce the pharmacological activity of either paclitaxel or FTS. FTS-eluting composite fibers proved to effectively induce growth inhibition or cell death by a gradient effect and dose-dependent manner. The combined effect of the targeted mechanism of FTS as a Ras inhibitor together with the localized and controlled release characteristics of the fiber is an advantageous antiproliferative quality. It is therefore suggested that our drug-eluting fibers may be used in biomedical applications that require short release (restenosis) or prolonged release (cancer therapy).

Novel farnesylthiosalicylate (FTS)-eluting composite structures.

Farnesylthiosalicylate (FTS) is a new specific nontoxic drug with a mild hydrophobic nature, which acts as a Ras antagonist and can therefore be used for stent applications as well as for local cancer treatment. FTS-loaded bioresorbable core/shell fiber structures were developed and studied in order to investigate the FTS release mechanism. These structures were composed of a polyglyconate core and a porous poly(d,l-lactic-glycolic acid) shell loaded with FTS, prepared using freeze drying of inverted emulsions. The effects of the emulsions composition (formulation) and process kinetics on the FTS release from the coatings were studied with reference to the shell morphology and degradation profile. The FTS release profiles exhibited a burst effect accompanied by a release rate which decreased with time and lasted for 15-40 days. The process was found to affect the drug release profile via two routes: (1) Direct, through water uptake and swelling of the structure, leading to a FTS burst release. Degradation of the host polymer affects the FTS release rate at a later stage. (2) Indirect effect of the microstructure on the release profile, which occurs via an emulsion stability mechanism. The copolymer composition is the most important parameter affecting the release behavior in our system. Other parameters, including polymer content, O:A phase ratio and homogenization rate exhibited only minor effects on the FTS release profile. The controlled release of the new drug FTS is reported here for the first time.

Mechanisms of antiproliferative drug release from bioresorbable porous structures

Restenosis (renarrowing of the blood vessel wall) and cancer are two different pathologies that have drawn extensive research attention over the years. Antiproliferative drugs such as paclitaxel inhibit cell proliferation and are therefore effective in the treatment of cancer as well as neointimal hyperplasia, which is known to be the main cause of restenosis. Antiproliferative drugs are highly hydrophobic and their release from porous biodegradable structures is therefore advantageous. The release profiles of four antiproliferative drugs from highly porous polymeric structures were studied in this study in light of the physical properties of both the host polymers and the drug molecules, and a qualitative model was developed. The chemical structure of the polymer chain directly affects the drug release profile through water uptake in the early stages or degradation and erosion in later stages. It also affects the release profile indirectly, through the polymers 3D porous structure. However, this effect is minor. The drug volume and molecular area dominantly affect its diffusion rate from the 3D porous structure and the drugs solubility parameter compared with that of the host polymer has some effect on the drug release profile. This model can also be used to describe release mechanisms of other hydrophobic drugs from porous structures.