Plasma protein adsorption on biodegradable microspheres consisting of poly(d,l-lactide-co-glycolide), poly(l-lactide) or ABA triblock copolymers containing poly(oxyethylene): Influence of production method and polymer composition
Introduction
Biodegradable polymers have been used in parenteral drug delivery systems for the past two decades [1]. These polymers do not require removal of the spent device due to their biodegradation to water-soluble monomeric or oligomeric breakdown products [2]. Polyesters of lactic and/or glycolic acid are attractive biomaterials due to their well known safety and tissue compatibility [3]. For the prolonged delivery of peptides and proteins the need for faster degrading systems still, however, exists. In these systems the release profile is significantly affected by the degradation rate. Additionally, the interaction of hydrophilic protein drugs with relatively hydrophobic polyesters can lead to pharmacologically inactive protein aggregates [4]. Therefore, new biodegradable materials with faster degradation rates, improved compatibility with proteins (less aggregates) are desirable. ABA triblock copolymers consisting of hydrophilic poly(oxyethylene) (PEO) B-blocks attached to hydrophobic polyester A-blocks, such as l-(+)-lactic-co-glycolic acid (l-PLGA) have shown interesting release and swelling properties under in vitro conditions [5]. The higher rate of water uptake seems to prevent protein aggregation and influences both the release and the degradation behavior of the carrier. Increased release rate and good encapsulation efficiencies were demonstrated in previous studies 6, 7. An improved compatibility between proteins and ABA was achieved for erythropoietic microspheres [8].
The biocompatibility and tissue reaction of ABA microspheres after intramuscular injection in rats demonstrated that these devices were well tolerated 9, 10. The compatibility and biodistribution of ABA or polyester nanospheres will be influenced by preferentially adsorbed plasma proteins 11, 12, 13, 14, 15. The pattern of adsorbed proteins strongly depends on the surface properties of the carriers and may decisively influence the in vivo distribution after i.v. administration 12, 16, 17, 18. Therefore, the analysis of plasma protein adsorption on biodegradable microspheres used as parenteral drug delivery system is of great interest with regard to their in vivo performance. Recently, two-dimensional electrophoresis (2-DE) was established for a detailed determination of adsorbed proteins on particulate surfaces 18, 19.
The present study addresses the effect of polymer composition and production method on the adsorption of plasma proteins on biodegradable microspheres under in vitro conditions. Different polyesters (poly(l-lactide) (l-PLA), poly(d,l-lactide-co-glycolide) (PLGA)), and ABA triblock copolymers, as well as two different microencapsulation techniques, namely the w/o/w double emulsion evaporation method and the spray-drying technique, were investigated with respect to their influence on the in vitro plasma protein adsorption.
Section snippets
Materials
Two different ABA triblock copolymers were synthesized as described previously [5]with a monomer ratio of lactic acid–glycolic acid–poly(oxyethylene) 56:14:30 and an average molecular mass (MW) of 15 kDa (ABA I) and 41:9:50, MW 15 kDa (ABA II), respectively. Poly(d,l-lactide-co-glycolide) (PLGA), with a monomer ratio of 50:50 (Resomer® RG 503, MW 33.1 kDa), was purchased from Boehringer Ingelheim (Germany). Poly(l-lactide) (l-PLA, MW 40 kDa) was a gift of Novartis Pharma LTD (Switzerland).
Characterization of microparticles and polymers
Fig. 1 shows the scanning electron micrographs of the microspheres prepared from various polymers and by different preparation methods. The particles exhibited acceptable sphericity and size homogenicity in all cases. The spray-drying method produced microparticles with a smooth and poreless surface. Scanning electron micrographs of the microparticles prepared by the double emulsion method revealed that the polymer had a considerable effect on the surface structure. PLGA produced microparticles
Conclusion
Using 2-DE, a detailed analysis of protein adsorption on biodegradable microspheres of varying composition and preparation was possible. It could be demonstrated that the polymer composition and, especially, the method of production of PLGA- and l-PLA-particles had a strong influence on the interactions with plasma proteins. Some adsorbed proteins were found to be characteristic or even specific for particles produced either by the same method or consisting of identical polymers. Thermal
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