Galactosylated Reduction And PH Dual-Responsive Triblock Terpolymer Gal-PEEP-a-PCL-ss-PDMAEMA: A Multifunctional Carrier For Targeted And Simultaneous Delivery Of Doxorubicin And DNA

The targeted and polymeric nanoparticles are a new kind of drug delivery system,which can reduce drug side effects, improve the bioavailability of drugs at the extreme.They can undergo physical or chemical change from the molecule-level interactionbetween polymer molecular chains or polymer molecular chains with solvent after beingexposed to external signals, so as to control the drug release. Their biological propertieswere evaluated. The main contents of this dissertation are listed as follows:Part1. Synthesis of a pH and reduction dual responsive polymeric nanoparticlesGal-PEEP-a-PCL-ss-PDMAEMA for targeted drug and gene delivery.Firstly, the bifunctional initiator2-hydroxyethyl-2’-(bromoisobutyryl) bromidedisulfide (HO-ss-Br) was used to initiate the ring opening polymerization of ε-CL usingSn(Oct)2as catalyst to prepare the a homopolymer with hydroxyl group and bromo groupin each chain end of PCL (HO-PCL-ss-Br). Cl-a-PCL-ss-Br was then synthesized throughthe reaction between HO-PCL-ss-Br and2-chloroethyl vinyl ether (CEVE). The diblockN3-a-PCL-ss-PDMAEMA was obtained by the ATRP of DMAEMA using Cl-a-PCL-ss-Bras the macroinitiator and CuBr/bpy as the catalyst system, which was further reacted withNaN3.Subsequently, Polyphosphoester was prepared by ring-opening polymerization (ROP)of2-ethoxy-2-oxo-1,3,2-Dioxaphospholane (EOP) using propiolic alcohol as an initiatorand Sn(Oct)2as a catalyst. Finally, the targeted reduction and pH dual-responsive tiblockterpolymer Gal-PEEP-a-PCL-ss-PDMAEMA was obtained by the “Click” reactionbetween propargyl-PEEP and N3-a-PCL-ss-PDMAEMA using CuBr/bpy as the catalystsystem，which was then modified of the D-(+)-galactosamine at the end of the PEEP. Part2. Characterization of Gal-PEEP-a-PCL-ss-PDMAEMA and in vitro BiomedicalProperties1H NMR,13C NMR, FT-IR and gel permeation chromatography (GPC) measurementswere respectively used to confirm their chemical structures, molecular weights andmolecular weight distributions. The self-assembly behaviors were investigated viafluorescence probe technology, TEM and dynamic laser scatter (DLS). The results showedthat The triblock terpolymers were able to self-assemble into micellar nanoparticles in theaqueous solution, and the mean diameter was less than200nm. The micelles could bedestroyed and release the DOX and DNA at the condition of pH5.0and GSH. In vitrocytotoxicity by MTT assay revealed that the triblock terpolymers displayed lowercytotoxicity and possessed favorable biocompatibility. The results of agarose gelelectrophoresis, in vitro drug release, endocytosis and in vitro transfection measuremenindicated that such cationic nanoparticles can be used to encapsulate DOX and condenseDNA. These micelles of Gal-PEEP-a-PCL-ss-PDMAEMA/DOX/DNA complexes couldbe internalized into both HeLa cells and HepG2cells. The Gal-containing micelles couldfacilitate the cellular uptake and transfaction process by a manner of galactose receptormediated endocytosis.