title: Sustained-release hydrogels of topotecan for retinoblastoma.
abstract: Treatment of retinoblastoma, the most common primary ocular malignancy in children, has greatly improved over the last decade. Still, new devices for chemotherapy are needed to achieve better tumor control. The aim of this project was to develop an ocular drug delivery system for topotecan (TPT) loaded in biocompatible hydrogels of poly(ε-caprolactone)-poly(ethyleneglycol)-poly(ε-caprolactone) block copolymers (PCL-PEG-PCL) for sustained TPT release in the vitreous humor. Hydrogels were prepared from TPT and synthesized PCL-PEG-PCL copolymers. Rheological properties and in vitro and in vivo TPT release were studied. Hydrogel cytotoxicity was evaluated in retinoblastoma cells as a surrogate for efficacy and TPT vitreous pharmacokinetics and systemic as well as ocular toxicity were evaluated in rabbits. The pseudoplastic behavior of the hydrogels makes them suitable for intraocular administration. In vitro release profiles showed a sustained release of TPT from PCL-PEG-PCL up to 7days and drug loading did not affect the release pattern. Blank hydrogels did not affect retinoblastoma cell viability but 0.4% (w/w) TPT-loaded hydrogel was highly cytotoxic for at least 7days. After intravitreal injection, TPT vitreous concentrations were sustained above the pharmacologically active concentration. One month after injection, animals with blank or TPT-loaded hydrogels showed no systemic toxicity or retinal impairment on fundus examination, electroretinographic, and histopathological assessments. These novel TPT-hydrogels can deliver sustained concentrations of active drug into the vitreous with excellent biocompatibility in vivo and pronounced cytotoxic activity in retinoblastoma cells and may become an additional strategy for intraocular retinoblastoma treatment.
authors.affiliation: Clinical Pharmacokinetics Unit, Hospital de Pediatría JP Garrahan, Argentina; National Council of Scientific and Technical Research, CONICET, Argentina.
authors.forename: Paula
authors.initials: P
authors.lastname: Taich
authors.affiliation: National Council of Scientific and Technical Research, CONICET, Argentina; Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
authors.forename: Marcela A
authors.initials: MA
authors.lastname: Moretton
authors.affiliation: Pharmacology Laboratory, CIVETAN-CONICET, Faculty of Veterinary Science, National University of the Center of Buenos Aires, Argentina.
authors.forename: María Jose
authors.initials: MJ
authors.lastname: Del Sole
authors.affiliation: Clinical Pharmacokinetics Unit, Hospital de Pediatría JP Garrahan, Argentina; National Council of Scientific and Technical Research, CONICET, Argentina.
authors.forename: Ursula
authors.initials: U
authors.lastname: Winter
authors.affiliation: National Council of Scientific and Technical Research, CONICET, Argentina; Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Bernabeu
authors.affiliation: Argentinean Foundation of Ophthalmology Jorge Malbrán, Buenos Aires, Argentina.
authors.forename: Juan O
authors.initials: JO
authors.lastname: Croxatto
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
authors.forename: Javier
authors.initials: J
authors.lastname: Oppezzo
authors.affiliation: Animal Facility Laboratory, Hospital de Pediatria J.P. Garrahan, Argentina.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Williams
authors.affiliation: National Council of Scientific and Technical Research, CONICET, Argentina.
authors.forename: Guillermo L
authors.initials: GL
authors.lastname: Chantada
authors.affiliation: National Council of Scientific and Technical Research, CONICET, Argentina; Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Chiappetta
authors.affiliation: Clinical Pharmacokinetics Unit, Hospital de Pediatría JP Garrahan, Argentina; National Council of Scientific and Technical Research, CONICET, Argentina. Electronic address: paulas@conicet.gov.ar.
authors.forename: Paula
authors.initials: P
authors.lastname: Schaiquevich
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011817:Rabbits; D012160:Retina / Q000378:metabolism; D012175:Retinoblastoma / Q000188:drug therapy; D019772:Topotecan / Q000008:administration & dosage* / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D011091:Polyesters; C515340:poly(epsilon-caprolactone)-b-poly(ethyleneglycol)-b-poly(epsilon-caprolactone); C016240:polycaprolactone; D011092:Polyethylene Glycols; D019772:Topotecan
keywords: Cytotoxicity; Hydrogels; Rabbits; Retinoblastoma; Topotecan