Development and evaluation of polymer nanoparticles for oral delivery of estradiol to rat brain in a model of Alzheimer's pathology.
The purpose of this study was to develop tween 80 (T-80) coated polylactide-co-glycolide (PLGA) nanoparticles that can deliver estradiol to the brain upon oral administration. Estradiol containing nanoparticles were made by a single emulsion technique and T-80 coating was achieved by incubating the re-constituted nanoparticles at different concentrations of T-80. The process of T-80 coating on the nanoparticles was optimized and the pharmacokinetics of estradiol nanoparticles was studied as a function of T-80 coating. The nanoparticles were then evaluated in an ovariectomized (OVX) rat model of Alzheimer's disease (AD) that mimics the postmenopausal conditions. The nanoparticles bound T-80 were found to proportionally increase from 9.72 ± 1.07 mg to 63.84 ± 3.59 mg with an increase in the initial concentration T-80 from 1% to 5% and were stable in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Orally administered T-80 coated nanoparticles resulted in significantly higher brain estradiol levels after 24h (1.969 ± 0.197 ng/g tissue) as compared to uncoated ones (1.105 ± 0.136 ng/g tissue) at a dose of 0.2mg/rat, suggesting a significant role of surface coating. Moreover, these brain estradiol levels were almost similar to those obtained after administration of the same dose of drug suspension via 100% bioavailable intramuscular route (2.123 ± 0.370 ng/g tissue), indicating the increased fraction of bioavailable drug reaching the brain when administered orally. Also, the nanoparticle treated group was successful in preventing the expression of amyloid beta-42 (Aβ42) immunoreactivity in the hippocampus region of brain. Together, the results indicate the potential of nanoparticles for oral delivery of estradiol to brain.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
G
G
Mittal
H
H
Carswell
R
R
Brett
S
S
Currie
M N V Ravi
MN
Kumar
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000517:prevention & control; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D004958:Estradiol / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D005260:Female; D005690:Galactose / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D010316:Particle Size; D010446:Peptide Fragments / Q000378:metabolism; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011136:Polysorbates / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D055672:Static Electricity; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; D011136:Polysorbates; D000644:Quaternary Ammonium Compounds; C075222:amyloid beta-protein (1-42); C046112:didodecyldimethylammonium; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004958:Estradiol; D005690:Galactose