Degradation, intra-articular retention and biocompatibility of monospheres composed of [PDLLA-PEG-PDLLA]-b-PLLA multi-block copolymers.

Autor: Sandker MJ; Department of Orthopaedics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Electronic address: m.sandker@erasmusmc.nl., Duque LF; InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands. Electronic address: luisa.duque@fu-berlin.de., Redout EM; Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80163, 3508 TD Utrecht, The Netherlands. Electronic address: e.redout@uu.nl., Chan A; Percuros B.V., P.O. Box 217, 7500 AE Enschede, The Netherlands. Electronic address: achan@percuros.com., Que I; Department of Radiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: I.que@lumc.nl., Löwik CWGM; Department of Radiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: c.w.g.m.lowik@lumc.nl., Klijnstra EC; InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands. Electronic address: klijnstra@innocorepharma.com., Kops N; Department of Orthopaedics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Electronic address: n.kops@erasmusmc.nl., Steendam R; InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands. Electronic address: r.steendam@innocorepharma.com., van Weeren R; Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80163, 3508 TD Utrecht, The Netherlands. Electronic address: r.vanweeren@uu.nl., Hennink WE; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Postbus 80082, 3508 TB Utrecht, The Netherlands. Electronic address: w.e.hennink@uu.nl., Weinans H; Department of Orthopaedics and Department of Rheumatology, UMC Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands; Department of Biomechanical Engineering TUDelft, Mekelweg 2, 2628 CD Delft, The Netherlands. Electronic address: h.h.weinans@umcutrecht.nl.
Jazyk: angličtina
Zdroj: Acta biomaterialia [Acta Biomater] 2017 Jan 15; Vol. 48, pp. 401-414. Date of Electronic Publication: 2016 Nov 02.
DOI: 10.1016/j.actbio.2016.11.003
Abstrakt: In this study, we investigated the use of microspheres with a narrow particle size distribution ('monospheres') composed of biodegradable poly(DL-lactide)-PEG-poly(DL-lactide)-b-poly(L-lactide) multiblock copolymers that are potentially suitable for local sustained drug release in articular joints. Monospheres with sizes of 5, 15 and 30μm and a narrow particle size distribution were prepared by a micro-sieve membrane emulsification process. During in vitro degradation, less crystallinity, higher swelling and accelerated mass loss during was observed with increasing the PEG content of the polymer. The monospheres were tested in both a small (mice/rat) and large animal model (horse). In vivo imaging after injection with fluorescent dye loaded microspheres in mice knees showed that monospheres of all sizes retained within the joint for at least 90days, while the same dose of free dye redistributed to the whole body within the first day after intra-articular injection. Administration of monospheres in equine carpal joints caused a mild transient inflammatory response without any clinical signs and without degradation of the cartilage, as evidenced by the absence of degradation products of sulfated glycosaminoglycans or collagen type 2 in the synovial fluid. The excellent intra-articular biocompatibility was confirmed in rat knees, where μCT-imaging and histology showed neither changes in cartilage quality nor quantity. Given the good intra-articular retention and the excellent biocompatibility, these novel poly(DL-lactide)-PEG-poly(DL-lactide)-b-poly(L-lactide)-based monospheres can be considered a suitable platform for intra-articular drug delivery.
Statement of Significance: This paper demonstrates the great potential in intra-articular drug delivery of monodisperse biodegradable microspheres which were prepared using a new class of biodegradable multi-block copolymers and a unique membrane emulsification process allowing the preparation of microspheres with a narrow particle size distribution (monospheres) leading to multiple advantages like better injectability, enhanced reproducibility and predictability of the in vivo release kinetics. We report not only on the synthesis and preparation, but also in vitro characterization, followed by in vivo testing of intra-articular biocompatibility of the monospheres in both a small and a large animal model. The favourable intra-articular biocompatibility combined with the prolonged intra-articular retention (>90days) makes these monospheres an interesting drug delivery platform. What should also be highlighted is the use of horses; a very accurate translational model for the human situation, making the results not only relevant for equine healthcare, but also for the development of novel human OA therapies.
(Copyright © 2016. Published by Elsevier Ltd.)
Databáze: MEDLINE
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