A microparticle/hydrogel combination drug-delivery system for sustained release of retinoids.
OBJECTIVE
To design and develop a drug-delivery system containing a combination of poly(D,L-lactide-co-glycolide) (PLGA) microparticles and alginate hydrogel for sustained release of retinoids to treat retinal blinding diseases that result from an inadequate supply of retinol and generation of 11-cis-retinal.


METHODS
To study drug release in vivo, either the drug-loaded microparticle-hydrogel combination was injected subcutaneously or drug-loaded microparticles were injected intravitreally into Lrat(-/-) mice. Orally administered 9-cis-retinoids were used for comparison and drug concentrations in plasma were determined by HPLC. Electroretinography (ERG) and both chemical and histologic analyses were used to evaluate drug effects on visual function and morphology.


RESULTS
Lrat(-/-) mice demonstrated sustained drug release from the microparticle/hydrogel combination that lasted 4 weeks after subcutaneous injection. Drug concentrations in plasma of the control group treated with the same oral dose rose to higher levels for 6-7 hours but then dropped markedly by 24 hours. Significantly increased ERG responses and a markedly improved retinal pigmented epithelium (RPE)-rod outer segment (ROS) interface were observed after subcutaneous injection of the drug-loaded delivery combination. Intravitreal injection of just 2% of the systemic dose of drug-loaded microparticles provided comparable therapeutic efficacy.


CONCLUSIONS
Sustained release of therapeutic levels of 9-cis-retinoids was achieved in Lrat(-/-) mice by subcutaneous injection in a microparticle/hydrogel drug-delivery system. Both subcutaneous and intravitreal injections of drug-loaded microparticles into Lrat(-/-) mice improved visual function and retinal structure.
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Song-Qi
SQ
Gao
Tadao
T
Maeda
Kiichiro
K
Okano
Krzysztof
K
Palczewski
D000217:Acyltransferases / Q000235:genetics; D000284:Administration, Oral; D000464:Alginates / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001766:Blindness / Q000188:drug therapy* / Q000235:genetics; D003692:Delayed-Action Preparations / Q000494:pharmacology; D004195:Disease Models, Animal; D004224:Diterpenes; D016503:Drug Delivery Systems / Q000379:methods*; D004359:Drug Therapy, Combination; D004596:Electroretinography / Q000187:drug effects; D005260:Female; D020723:Glucuronic Acid / Q000737:chemistry / Q000494:pharmacology; D006603:Hexuronic Acids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D058449:Intravitreal Injections; D019344:Lactic Acid / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008863:Microspheres; D011100:Polyglycolic Acid / Q000737:chemistry / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012172:Retinaldehyde / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*
D000464:Alginates; D003692:Delayed-Action Preparations; D004224:Diterpenes; D006603:Hexuronic Acids; D012176:Retinoids; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011100:Polyglycolic Acid; D019344:Lactic Acid; C031390:9-cis-retinal; D020723:Glucuronic Acid; D000217:Acyltransferases; C056942:lecithin-retinol acyltransferase; D012172:Retinaldehyde