RESUMO
Local drug delivery has become indispensable in biomedical engineering with stents being ideal carrier platforms. While local drug release is superior to systemic administration in many fields, the incorporation of drugs into polymers may influence the physico-chemical properties of said matrix. This is of particular relevance as minimally invasive implantation is frequently accompanied by mechanical stresses on the implant and coating. Thus, drug incorporation into polymers may result in a susceptibility to potentially life-threatening implant failure. We investigated spray-coated poly-l-lactide (PLLA)/drug blends using thermal measurements (DSC) and tensile tests to determine the influence of selected drugs, namely sirolimus, paclitaxel, dexamethasone, and cyclosporine A, on the physico-chemical properties of the polymer. For all drugs and PLLA/drug ratios, an increase in tensile strength was observed. As for sirolimus and dexamethasone, PLLA/drug mixed phase systems were identified by shifted drug melting peaks at 200 °C and 240 °C, respectively, whereas paclitaxel and dexamethasone led to cold crystallization. Cyclosporine A did not affect matrix thermal properties. Altogether, our data provide a contribution towards an understanding of the complex interaction between PLLA and different drugs. Our results hold implications regarding the necessity of target-oriented thermal treatment to ensure the shelf life and performance of stent coatings.
RESUMO
The successive incorporation of several drugs into the polymeric bulk of implants mostly results in loss of considerable quantity of one drug, and/or the loss in quality of the coating and also in changes of drug release time points. A dual drug delivery system (DDDS) based on poly-L-lactide (PLLA) copolymers combining the effective inhibition of smooth muscle cell proliferation while simultaneously promoting re-endothelialization was successfully developed. To overcome possible antagonistic drug interactions and the limitation of the polymeric bulk material as release system for dual drugs, a novel concept which combines the bulk and surface drug immobilization for a DDDS was investigated. The advantage of this DDDS is that the bulk incorporation of fluorescein diacetate (FDAc) (model drug for paclitaxel (PTX)) via spray coating enhanced the subsequent cleavable surface coupling of vascular endothelial growth factor (VEGF) via the crosslinker bissulfosuccinimidyl suberate (BS3). In the presence of the embedded FDAc, the VEGF loading and release are about twice times higher than in absence. Furthermore, the DDDS combines the diffusion drug delivery (FDAc or PTX) and the chemical controlled drug release, VEGF via hydrolysable ester bonds, without loss in quantity and quality of the drug release curves. Additionally, the performed in vitro biocompatibility study showed the bimodal influences of PTX and VEGF on human endothelial EA.hy926 cells. In conclusion, it was possible to show the feasibility to develop a novel DDDS which has a high potential for the medical application due to the possible easy and short modification of a polymer-based PTX delivery system.