Dextran-polycaprolactone Micellar Alzheimer's Disease Inflammation Multi-drug Combined Treatment System

Alzheimer's disease(AD)is a progressive neurodegenerative disease,genomics studies suggest that inflammatory is involved in the pathogenesis of AD.Although monotargeted anti-inflammatory drug show weak anti-inflammatory effect in moderate AD patient,yet most anti-inflammatory drug has failed to reverse the progression of advanced AD.Meanwhile,long-term use of these drugs may have serious toxic side effects,and thus pathological microenvironment responsive drug delivery biomedicine have important significance in reducing such toxic side effects.Small molecule initiator 2-(benzylsulfanylthiocarbonylsulfanyl)ethanol(BSTSE)and monomer 3-acrylamidophenyl boronic acid(PBA)were first synthesized.Poly(?-caprolactone)-block-poly(3-acrylamidophenylboronicacid)-Dex(PCL-b-PPBA-Dex)of inflammatory microenvironment responsive polymer was prepared by ring opening reaction,reversible addition-fragmentation chain transfer polymerization and esterification reaction.~1H NMR spectra and FT-IR spectra verified that the polymer PCL-b-PPBA-Dex was successfully synthesized.The non-steroidal anti-inflammatory drugs(NSAIDs)ibuprofen,celecoxib,and the clinical hypertension drug telmisartan were encapsulated by nanoparticles respectively.The drug loading of the drug-loaded nanoparticles was measured by a UV-vis spectrophotometer.The encapsulation efficiency of ibuprofen drug-loaded micelles(IBU),celecoxib drug-loaded micelles(CEL)and telmisartan drug-loaded micelles(TEL)was 22.6±1.1%,16.2±1.5%,15.5±2.3%as calculated respectively.CEL/IBU and CEL/TEL could effectively diminish the inflammatory response in the lipopolysaccharide-stimulated microglial cell(BV2)inflammation model and play a neuroprotective role in the co-culture system of neuroblastoma cells(SH-SY5Y)and BV2.Animal experimental data indicated that CEL/IBU and CEL/TEL could effectively suppress neuroinflammation through combined of eliminating COX-2 signal and activating PPAR?pathway,thereby reducing neuronal loss and improving the spatial memory ability of mice.The combination of angiotonin receptor blockers(ARBs)and NSAIDs provided a new treatment strategy for the neuroinflammation treatment of AD.