Design,Synthesis And In Vitro Antitumor Properties Of Cyclic Topology-based Tumor Microenvironment-responsive Polymeric Drug Delivery Systems

In recent years,polymeric nanodrug carriers with advanced topological have become a hot research in cancer treatment.Traditional linear polymer self-assembled drug loaded micelles will be greatly diluted by body fluids and blood after intravenous injection,resulting in destabilization of the polymer carrier and premature release of the loaded drugs.On the one hand,it causes great toxicity to normal tissues and organs.it will also significantly reduce the effective drug concentration accumulated in the lesion and the therapeutic effect.Therefore,enhancing the stability of the drug delivery system during the long cycle has become a key scientific problem that needs to be solved urgently.At present,there are mainly two methods to enhance the stability of drug delivery system reported in literature:（1）constructing polymer with advanced topological structure,such as cyclic,brush and dendritic;（2）crosslinking the carrier.The advanced topology enables the polymeric carrier to exist as a stable monomolecular micelle even when highly diluted by blood.Among many reported polymers with advanced topological structures,cyclic polymers have unique physical and chemical properties due to the lack of the end of the polymer chain.However,the current preparation methods for cyclic polymers are still very limited,and the synthesis and purification process is complex.Therefore,it is very necessary to develop simple and efficient new strategy for the preparation of cyclic polymers.At the same time,polymeric carriers that are responsive to the tumor microenvironment can achieve high-efficiency release of drugs in tumor cells and achieve the purpose of enhancing the therapeutic effect.By organically combining the cyclic topological structure with the tumor microenvironment-responsive polymer,novel drug carrier materials with their respective advantages can be obtained.For this purpose,in this dissertation,starting from the synthesis-structure-performance of cyclic polymers.In the second chapter,a simple and effective strategy was developed to prepare p H-sensitive cyclic copolymers with both extracellular stability and efficient intracellular destabilization;In chapter three,a novel method for further synthesis of crosslinked micelles and ring-like colloids via multivalent templates based on cyclic polymers was developed,and the morphology,stability and in vitro antitumor performance of the obtained polymer as a drug carrier were studied.The specific research contents of this dissertation are as follows:1.In the second chapter of the dissertation,A stable,p H-sensitive cyclic statistical copolymer（c-P（OEGMA-st-DMAEMA））and its linear analogs were prepared by direct random copolymerization of the hydrophilic monomer oligo（ethyleneglycol）monomethyl ether methacrylate（OEGMA）with N,N-dimethylaminoethyl methacrylate（DMAEMA）by a one-pot ATRP method.Compared with linear copolymers of the same molecular weight,the self-assembled micelles of cyclic statistical copolymers have lower CMC value,smaller particle size,higher drug loading,higher cell uptake efficiency and lower cytotoxicity in vitro.It has good colloidal stability under salt and serum conditions,and under intracellular acidic conditions,PDMAEMA nuclear protonization causes the destabilization of drug-loaded micelles and accelerates the release of intracellular drugs,showing excellent antitumor effects.Therefore,this study not only developed a facile approach to improve the colloidal stability of a cyclic polycation,but also presented a p H-sensitive cyclic copolymer-based nanoplatform with great potential for anticancer drug delivery.2.In chapter three,we controllable synthesis of crosslinked micelles and ring-like colloids by using a well-prepared and characterized cyclic polymer,cyclic poly（2-hydroxyethyl methacrylate）₅₀(c-P（HEMA）₅₀)as multivalent template.The advantage of a cyclic polymer over a three-arm star-shaped polymer as a template lies likely in the multivalent structure with greater stability and steric hindrance,which results in a significantly increased preparation concentration of 1.0 mg/m L.Specifically,the pendant hydroxyl groups of c-P（HEMA）₅₀were decorated with ferrocene（Fc）by click coupling to afford the multivalent cyclic polymer template c-P（HEMA-Fc）₅₀,which could be used as a core template to direct the supramolecular complexation with both hydrophilic poly oligo（ethylene glycol）monomethyl ether methacrylate P（OEGMA）and poly（ethylene glycol）（PEG）and lipoic acid（LA）-functionalizedβ-cyclodextrin（β-CD）（β-CD-POEGMA/PEG-LA）viaβ-CD/Fc host-guest inclusion complexation.The resulting supramolecular micelle based on c-P（HEMA-Fc）₅₀/β-CD-POEGMA/PEG-LA could be next crosslinked to serve as a sacrificing precursor of the cyclic structure via dithiothreitol（DTT）-catalyzed intramolecular self-crosslinking of the decorated LA units.Further comparison of the crosslinked micelles with two different hydrophilic moieties,i.e.,（m PEG350）and P（OEGMA300）revealed a smaller dimension of the latter formulation for in vitro anticancer drug delivery.Therefore this study not only reported the use of a cyclic polymer as a novel template for the production of ring-like colloids at a relatively high concentration,but also presented a useful comparison study between two different hydrophilic segments-functionalized micelle formulations for controlled release applications.