Preparation Of Core-crosslinked Poly(Carbonate)s Micelles

Polymeric micelles from amphiphilic block copolymer have shown excellent application potential in drug controlled release due to their easy synthesis and adjustable structure and properties.Polymeric micelles have been extensively used for drug delivery because they offer several advantages,such as significantly enhancing drug water solubility,prolonging circulation time,targeting tumor tissues via the enhanced permeation and retention(EPR)effect,decreasing side effects,and improving drug bioavailability.During the past two decades,there have been numerous reports on stimuli-sensitive block copolymer(BCP)micellar systems developed for controlled drug delivery.Changes in the physico-chemical properties of BCP micelles can be triggered by diverse stimuli such as ultrasound,magnetic field,electrical field,enzymes,temperature,pH and light.However,the polymeric micelle is a dynamic equilibrium and thermodynamic unstable system with a tendency to dissociate at low concentrations,especially upon intravenous administration.The instability may lead to poor drug capacity,premature drug release and low selective absorption by pathological tissues for drug loaded micellar carriers.Therefore,stabilization of polymeric micelles becomes a critical strategy to promote their performance as drug carriers.Nowadays,crosslinking of the cores or shells of polymeric micelles has emerged as a viable strategy for improving micellar stability by providing covalent linkages between polymer chains.This strategy has been employed to prepare core-crosslinked micelles,shell crosslinked micelles,and also other nano-objects such as nanocages and nanoporous films.Compared with noncrosslinked precursors,these crosslinked nano-objects can maintain a stable structure under severe environments.In this thesis,a novel six-membered cyclic carbonate monomer,acryloyl carbonate(AC),was synthesized using 1,1,1-tris(hydroxymethyl)ethane,benzaldehyde,acryloyl chloride and ethyl chloroformate as raw materials in four steps.Biodegradable amphiphilic block copolymer monomethoxy poly(ethylene glycol)-b-poly(AC)(mPEG-b-poly(AC))with pendant acrylate groups was synthesized by means of ring opening polymerization of AC in dichloromethane at room temperature,using hydrophilic monomethoxy poly(ethylene glycol)as macroinitiator and DBU as catalyst.Self-assembly behavior of the obtained amphiphilic mPEG-b-poly(AC)in aqueous solution were investigated via fluorescence spectrophotometer using Nile Red(NR)as a fluorescence probe.Results showed that the critical micelle concentration for mPEG-b-poly(AC)was about 0.02 mg/mL.Size distribution and morphology of the micelles were measured by DLS and TEM.DLS results showed that the diameters of the uncrosslinked micelles prepared from mPEG-b-poly(AC)25 in water were found to be about 50 nm.Spherical morphology was observed with an average size of 30 nm for the uncrosslinked micelles.Cross-linked polymeric micelles was synthesized via thiol-acrylate Michael addition reaction between the pendant acrylate groups in the poly(carbonate)s hydrophobic block and the cross-linker 1,6-hexanedithiol.The stability of the crosslinked micelles upon dilution was further investigated.DLS results showed that the obtained cross-linked polymeric micelles remained its structure upon dilution of 10-fold DMF.Moreover,drug release of the Nile Red and DOX from uncrosslinked micelles and core-crosslinked under different pH PBS buffer were determined.The results revealed a significantly faster release of NR and DOX from core-crosslinked micelles pH 5.0 compared to pH 7.4,which was attributed to introduction of the pH-responsive ?-thiopropionate linkage derived from the thiol-acrylate Michael addition reaction during the core-crosslinking process.But the uncrosslinked polymeric micelles showed none pH-responsiveness.The obtained biodegradable amphiphilic block copolymer mPEG-b-poly(AC)s showed pH-responsiveness and good biocompatibility All the results demonstrated that the cross-linked micelles have potential as efficient intracellular smart drug delivery platforms used in biomedical field.