Microspheres containing insulin-like growth factor I for treatment of chronic neurodegeneration.
The therapeutic potential of peptide growth factors as insulin-like growth factor I (IGF-I) is currently under intense scrutiny in a wide variety of diseases, including neurodegenerative illnesses. A new poly(lactic-co-glycolide)-based microsphere IGF-I controlled release formulation for subcutaneous (SC) delivery has been developed by a triple emulsion method. The resulting microspheres displayed a mean diameter of 1.5microm, with an encapsulation efficiency of 74.3%. The protein retained integrity after the microencapsulation process as evaluated by circular dichroism and SDS-PAGE. The administration of IGF-I in microspheres caused at least a 30-fold increase in IGF-I mean residence time in rats and mice when compared with the conventional SC solution. Therefore, dosing can be changed from the conventional twice a day to once every 2 weeks. Therapeutic efficacy of this new formulation has been studied in mutant mice with inherited Purkinje cell degeneration (PCD). These mice show a chronic limb discoordination that is resolved after continuous systemic delivery of IGF-I. Normal motor coordination was maintained as long as IGF-I microsphere therapy is continued. Moreover, severely affected PCD mice, with marked ataxia, muscle wasting and shortened life-span showed a significant improvement after continuous IGF-I microsphere therapy as determined by enhanced motor coordination, marked weight gain and extended survival. This new formulation can be considered of great therapeutic promise for some chronic brain diseases.
Carrascosa
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C
Department of Pharmaceutical Technology, School of Pharmacy, Complutense University, Cajal Institute, CSIC, Madrid, Spain.
Torres-Aleman
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I
Lopez-Lopez
C
C
Carro
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Espejo
L
L
Torrado
S
S
Torrado
J J
JJ
D000818:Animals; D001259:Ataxia / Q000188:drug therapy*; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage / Q000138:chemical synthesis; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D008422:Materials Testing; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D020099:Coated Materials, Biocompatible; D003692:Delayed-Action Preparations; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007334:Insulin-Like Growth Factor I