W.M. Stevels

Formulation and lyoprotection of poly(lactic acid-co-ethylene oxide) nanoparticles : Influence on physical stability and in vitro cell uptake

AbstractPurpose. To investigate the feasibility of producing freeze-dried poly-(ethylene oxide) (PEO)-surface modified nanoparticles and to study their ability to avoid the mononuclear phagocytic system (MPS), as a function of the PEO chain length and surface density. Methods. The nanoparticles were produced by the salting-out method using blends of poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acid-co-ethylene oxide) (PLA-PEO) copolymers. The nanoparticles were purified by cross-flow filtration and freeze-dried as such or with variable amounts of trehalose as a lyoprotectant. The redispersibility of the particles was determined immediately after freeze-drying and after 12 months of storage at −25° C. The uptake of the nanoparticles by human monocytes was studied in vitro by flow cytometry. Results. PLA-PEO nanoparticles could be produced from all the polymeric blends used. Particle aggregation after freeze-drying was shown to be directly related to the presence of PEO. Whereas this problem could be circumvented by use of trehalose, subsequent aggregation was shown to occur during storage. These phenomena were possibly related to the specific thermal behaviours of PEO and trehalose. In cell studies, a clear relationship between the PEO content and the decrease of uptake was demonstrated. Conclusions. The rational design of freeze-dried PEO-surface modified nanoparticles with potential MPS avoidance ability is feasible by using the polymer blends approach combined with appropriate lyoprotection and optimal storage conditions.

Block copolymers of poly(l-lactide) and poly(e-caprolactone) or poly(ethylene glycol) prepared by reactive extrusion

Blends of poly(L-lactide) (PLLA) and poly(-caprolactone) (PCL) were prepared in a co-rotating twin screw miniextruder (40 rpm, 200°). It was attempted to prepare multiblock copolymers by allowing a controlled number of transesterification reactions. Various cat-alysts (n-Bu3SnOMe, Sn(Oct)2, Ti(OBu)4, Y(Oct)3, para-toluene sulphonic acid) were introduced to promote these transesterification reactions. However, PLLA degradation by ring-closing depolymerization was the dominant reaction in every case. Alternatively, after showing that L-lactide can be conveniently polymerized in the extruder, L-lactide and hy-droxyl functionalized prepolymers of PCL or poly(ethylene glycol) (PEG) were fed to the extruder in the presence of stannous octoate. Monomer conversions of over 90% and effective transformation of all hydroxyl end groups present were generally reached. Di-and triblock copolymers could be prepared in this way with characteristics very similar to polymers prepared in a batch-type process, but with considerably reduced reaction times in a fashion, which is, in principle, scaleable to a continuous process for the production of such block copolymers.

Controlled Synthesis of Biodegradable Polyesters

The application of new initiators for the ring-opening polymerization of cyclic esters has markedly improved the macromolecular engineering of biodegradable polyesters. A wide variety of complex macromolecular architectures can nowadays be prepared using these initiators. Decisive factors in achieving this are the range of monomers that can be polymerized, and the favourable rates of polymerization obtained for these monomers. The number of papers dealing with the exciting synthetic aspects of these initiators is rapidly increasing. A historic overview of the developments in this area is presented in this paper.