title: Sunitinib microspheres based on [PDLLA-PEG-PDLLA]-b-PLLA multi-block copolymers for ocular drug delivery.
abstract: Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that blocks several angiogenesis related pathways. The aim of this study was to develop sunitinib-loaded polymeric microspheres that can be used as intravitreal formulation for the treatment of ocular diseases. A series of novel multi-block copolymers composed of amorphous blocks of poly-(D,L-lactide) (PDLLA) and polyethylene glycol (PEG) and of semi-crystalline poly-(L-lactide) (PLLA) blocks were synthesized. Sunitinib-loaded microspheres were prepared by a single emulsion method using dichloromethane as volatile solvent and DMSO as co-solvent. SEM images showed that the prepared microspheres (∼ 30 μm) were spherical with a non-porous surface. Sunitinib-loaded microspheres were studied for their degradation and in-vitro release behavior. It was found that increasing the percentage of amorphous soft blocks from 10% to 30% accelerated the degradation of the multi-block copolymers. Sunitinib microspheres released their cargo for a period of at least 210 days by a combination of diffusion and polymer erosion. The initial burst (release in 24h) and release rate could be tailored by controlling the PEG-content of the multi-block copolymers. Sunitinib-loaded microspheres suppressed angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These microspheres therefore hold promise for long-term suppression of ocular neovascularization.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands; Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Ramazani
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Hiemstra
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Steendam
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Kazazi-Hyseni
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors.forename: C F
authors.initials: CF
authors.lastname: Van Nostrum
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands; Department of Controlled Drug Delivery, University of Twente, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Storm
authors.affiliation: Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Kiessling
authors.affiliation: Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen, Germany; Department of Controlled Drug Delivery, University of Twente, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Lammers
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors.forename: W E
authors.initials: WE
authors.lastname: Hennink
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands. Electronic address: r.j.kok@uu.nl.
authors.forename: R J
authors.initials: RJ
authors.lastname: Kok
mesh_terms: D060433:Administration, Ophthalmic; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D058449:Intravitreal Injections; D019344:Lactic Acid / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011758:Pyrroles / Q000008:administration & dosage* / Q000494:pharmacology; D012997:Solvents / Q000737:chemistry; D000077210:Sunitinib; D013997:Time Factors
chemical_list: D020533:Angiogenesis Inhibitors; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007211:Indoles; D011091:Polyesters; D011108:Polymers; D011758:Pyrroles; D012997:Solvents; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D000077210:Sunitinib
keywords: Angiogenesis; Microspheres; Multi-block copolymers; Ocular drug delivery; Release and degradation; Single emulsion (O/W); Sunitinib malate; Thermal analysis; [PDLLA-PEG-PDLLA]-b-PLLA