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 polymer's 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 drug's 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.

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 emulsion's formulation parameters. The former's release profile is affected mainly through the emulsion stability and the resulting porous microstructure, whereas the latter's 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).

Drug-eluting medical implants.

Drug-eluting medical implants are actually active implants that induce healing effects, in addition to their regular task of support. This effect is achieved by controlled release of active pharmaceutical ingredients (API) into the surrounding tissue. In this chapter we focus on three types of drug-eluting devices: drug-eluting vascular stents, drug-eluting wound dressings and protein-eluting scaffolds for tissue regeneration, thus describing both internal and external implants. Each of these drug-eluting devices also presents an approach for solving the drug release issue. Most drug-eluting vascular stents are loaded with water-insoluble antiproliferative agents, and their diffusion from the device to the surrounding tissue is relatively slow. In contrast, most drug-eluting wound dressings are loaded with highly water-soluble antibacterial agents and the issue of fast release must therefore be addressed. Growth factor release from scaffolds for tissue regeneration offers a new approach of incorporating high-molecular-weight bioactive agents which are very sensitive to process conditions and preserve their activity during the preparation stage. The drug-eluting medical implants are described here in terms of matrix formats and polymers, incorporated drugs and their release profiles from the implants, and implant functioning. Basic elements, such as new composite core/shell fibers and structured films, can be used to build new antibiotic-eluting devices. As presented in this chapter, the effect of the processing parameters on the microstructure and the resulting drug release profiles, mechanical and physical properties, and other relevant properties, must be elucidated in order to achieve the desired properties. Newly developed implants and novel modifications of previously developed approaches have enhanced the tools available for creating clinically important biomedical applications.

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 emulsion's 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.

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 emulsion's composition (formulation) and process kinetics on the long-term drug release from the fibers, in light of the shell's 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.

Approaches for prevention of restenosis.

Coronary artery disease is characterized by a narrowing (stenosis) of the arteries that supply blood to the tissue of the heart. Continued restriction of blood flow manifests itself as angina and ultimately myocardial infarction (heart attack) for the patient. Heart bypass was once the only treatment for this condition, but over the years percutaneous coronary intervention (PCI) has become an increasingly attractive alternative to medical therapy and surgical revascularization for the treatment of coronary artery disease. A vascular stent is a medical device designed to serve as a temporary or permanent internal scaffold, to maintain or increase the lumen of a blood vessel. Metallic coronary stents were first introduced to prevent arterial dissections and to eliminate vessel recoil and intimal hyperplasia associated with PCI. Further advancement in the treatment of coronary artery disease is the development of drug-eluting stents that dramatically reduce the incidence of in-stent restenosis to less than 5%. Local drug delivery offers the advantages of allowing a relatively high local concentration of drug at the treatment site while minimizing systemic toxic effect. This review describes approaches for prevention of restenosis. It focuses on drugs for prevention of restenosis, bare metal stents, and drug-eluting stents. It also describes recent advances in bioresorbable stents. One of the chapters is dedicated to our novel composite bioresorbable drug-eluting fibers, designed to be used as basic elements in drug-eluting stents.

Paclitaxel-eluting composite fibers: drug release and tensile mechanical properties.

New core/shell fiber structures loaded with paclitaxel were developed and studied. These composite fibers are ideal for forming thin, delicate, biomedically important structures for various applications. Possible applications include fiber-based endovascular stents that mechanically support blood vessels while delivering drugs for preventing restenosis directly to the blood vesel wall, or drug delivery systems for treatment of cancer. The core/shell fiber structures were formed by "coating" dense core fibers with porous paclitaxel-containing poly(DL-lactic-co-glycolic acid) (PDLGA) structures. Shell preparation ("coating") was performed by freeze-drying water in oil emulsions. The present study focused on the effects of the emulsion's formulation (composition) and processing conditions on the paclitaxel release profile and on the fibers' tensile mechanical properties. In general, the porous PDLGA shell released approximately 40% of the paclitaxel, with most of the release occurring during the first 30 days. The main release mechanism during the tested period is diffusion, rather than polymer degradation. The release rate and quantity increased with increased drug content or decreased polymer content, whereas the organic:aqueous phase ratio had practically no effect on the release profile. These new composite fibers are strong and flexible enough to be used as basic elements for stents. We demonstrated that proper selection of processing conditions based on kinetic and thermodynamic considerations can yield polymer/drug systems with the desired drug release behavior and good mechanical properties.

Paclitaxel-loaded composite fibers: microstructure and emulsion stability.

New core/shell fiber structures loaded with paclitaxel were developed and studied. These composite fibers are ideal for forming thin, delicate, biomedically important structures for various applications. Possible applications include fiber-based endovascular stents that mechanically support blood vessels while delivering drugs for preventing restenosis directly to the blood vessel wall, or drug delivery systems for cancer treatment. The core/shell fiber structures were formed by "coating" nylon fibers with porous paclitaxel-containing poly(DL-lactic-co-glycolic acid) structures. Shell preparation ("coating") was performed by freeze-drying water in oil emulsions. The present study focused on the effects of the emulsion's formulation (composition) and processing conditions on the porous shell structure, which actually reflects the emulsion's stability and also the drug release profile from the fibers. In general, extremely porous "shell" structures were obtained with good adhesion to the core fiber. An increase in the emulsion's drug content and copolymer composition demonstrated a significant effect on pore size and distribution, because of enhanced emulsion instability, whereas the homogenization rate and duration had only a slight effect on the pores' microstructure. The thermodynamic parameters in the studied system are thus more important than the kinetic parameters in determining the emulsion's stability and the shell's porous structure.