Preparation And Characterization Of Environmentally Responsive Core Cross-linked Polycarbonate Micelles

It is known to all that cancer has become one of the major threats to human health and the treatment of it has become the focus of research both at home and abroad. There are many drawbacks of the traditional treatment, which greatly limits the application of anti-cancer drugs, so the new therapies have become the focus of attention for all people. In recent years,biodegradable environmental responsive polymer micelles as carriers for controlled drug releaser has become a hot point in biomedical engineering research. It can increase the drug effect time, improve the selectivity of drugs and reduce the toxicity of small molecule drugs.In addition, it can improve the stability by crosslinking. This can prolong the cycle time of polymer micelle in the body and release the loading drug in target pathological tissue at a specific time. All of those enhance the usage efficieney of drugs. Furthermore, the polymer carrier can be out of the body through the normal metabolism and does not accumulate in the body for long time, which greatly reduced the side effects to normal tissues and organs. At present, the most of research is the biodegradable polymer micelles based on polyethylene glycol(PEG) and aliphatic polycarbonate.In this study, two different biodegradable and environment sensitive core cross-linked polycarbonate micelles were prepared. The main contents are as following:(1) First, a novel six-membered cyclic carbonate monomer, acryloyl carbonate(AC), was synthesized from 1, 1, 1-tris(hydroxymethyl)ethane. Second, 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 acryloyl carbonate(AC), using hydrophilic PEG as macroinitiator and DBU as catalyst. Third,cross-linked polymer was synthesized via thiol-acrylate Michael addition reaction between the pendant acrylate groups in the hydrophobic block and the cross-linker 1, 6-hexanedithiol.1H NMR spectroscopy, dynamic light scattering(DLS) and transmission electron microscopy(TEM) and fluorescence spectroscopy were used to study the structures, self-assembly,stability and pH-specific sustained-release properties of the uncross-linked micelles and the cross-linked micelles.(2) Another novel six-membered cyclic carbonate monomer, 2, 2-di(propynyloxy methyl)-trimethylene carbonate(DPTC), was synthesized from pentaerythritol. Then biodegradable amphiphilic block copolymer monomethoxy poly(ethylene glycol)-b-Poly(DPTC)(mPEG-b-poly(DPTC)) with pendant alkynyl groups was synthesized in the same way as the first part. mPEG-b-poly(DPTC) was then used to prepare crosslinking polymer via Cu(I)-catalyzed azide-alkyne cycloaddition(CuAAC) reaction between the pendant alkynylgroups in the hydrophobic block of polycarbonate and the azide groups from4-(4-azidebutyloxy)-4-trifluoromethoxy-azobenzene and bis-(azidoethyl) disulfide. Such cross-linked polymer micelles was designed to possess reduction and light dual-sensitive functionalities positioned repeatedly in the side chain of the hydrophobic block. Finally, we show structures, self-assembly, stability and light-induced rapid burst release and reduction-induced slow sustained release properties of the uncross-linked micelles and the cross-linked micelles.