Highly Efficient Preparation And Application Of Functionalized PEG And Responsive Functional Systems

Poly(ethylene glycol)(PEG)has been widely used in the fields of pharmaceutics,biomaterials,cosmetics,and analytical science.Due to its biologically inertness and biocompatible nature,PEG has been covalently conjugated with proteins,peptides,oligonucleotides,drugs,and lipids to extend their vivo circulation lifetime and stability,optimize pharmacokinetics,and reduce systemic toxicity.Up to date,over 10 PEGylated proteins and peptides have approved by FDA.In addition,amphiphilic block copolymers(BCPs)synthesized using PEGbased initiators have been increasingly utilized to self-assemble into drug delivery nanocarriers,exhibiting extended blood circulation lifetime and reduced uptake by the reticuloendothelial system(RES).All the above applications are closely relevant to end-group functionalized of PEG.On the other hand,fluorometry offers distinct advantages in terms of sensitivity,selectivity,fast response,and enhanced spatial and temporal resolution.In recent years,various kinds of fluorescent probes and fluorescence analysis methods have been explored for high efficient and sensitive detection of physical signals,chemical analytes,bioactive molecules,as well as the corresponding processes.In the first part of this dissertation,the functionalization of PEG based on stable carbamate linkage was performed and further used to synthesize BCPs for the construction of nanoassemblies.In the second part,polymer gels with aggregation-induced emission(AIE)property and dual acid-and redox-reponsiveness was prepared.In the last chapter,based on 3-hydroxyflavone moieties protected by tert-butyl trimethyl silicon groups,a polymer fluorescent probe was designed to detect fluorine ions in aqueous solution.The dissertation mainly includes the following three parts:1.It is an open "secret" that commercial PEG with amine end group(PEG-NH2)is of unreliable quality,which should be ascribe to both flawed manufacturing protocols and storage stability issues.In addition,conventional functionalization of PEG relies on esterification and etherification strategies,suffering from incomplete conversion,harsh reaction condition,and incompatibility between functional groups.To solve these practical challenges,we propose an efficient strategy for PEG functionalization based on carbamate linkages.By finely tuning the structure and basicity of the terminal amine group,stable and high-fidelity PEG-NH2 with carbamate linkage was successfully obtained,as evidenced from the MALDI-TOF MS pattern.The "carbamate" strategy was further applied to the synthesis of high-fidelity multi-functionalized PEG with varying reactive groups.2.Amphiphilic diblock copolymers bearing 3-hydroxyflavone(3-HF)moieties in the side chains of hydrophobic poly(methyl methacrylate)(PMMA)blocks were synthesized via reversible addition-fragmentation chain transfer(RAFT)polymerization followed by click chemistry.Then the 3-HF moieties were caged through reaction with excessive tert-butyldimethylsilyl chloride(TBSC1)to give amphiphlic PEG-b-P(MMA-co-3-HF-TBS),which can can self-assemble into micelles in aqueous solution exhibiting blue emission because of the blocked excited state intramolecular proton transfer(ESIPT).However in the presence of F-ions,the specific F-induced desilylation reaction led to the deprotection of the 3-HF moieties and the formation of intramolecular hydrogen bond interaction.Thus the ESIPT process was activated and caused blue-to-green transition of the fluorescence emission of the micellar solution with a detection limit down to～3.8μM.As a result,the amphiphilic diblock copolymer micelles can serve as a highly efficient and sensitive ratiometric probe for F-ions in aqueous media.In addition,when dissolved in acetone in unimer state,the similar fluorescence emission change also can be observed upon addition of F-ions,and the corresponding detection limit was～0.2 μM.However higher concentration of F-ions will partially quench the fluorescence emission of 3-HF moieties due to the destruction of the intramolecular hydrogen bond interaction caused by the competition of F-ions,which again blocked the ESIPT process.Compared to that with ester linkage,amphiphilic PEG-PS block copolymers bearing carbamate junction linkage exhibits preferential tendency to self-assembe into vesicles.Moreover,the obtained nanoparticles demonstrate higher drug loading efficiency,enhanced encapsulation stability against enzymatic hydrolysis,and improved in vivo retention at the tumor region.3.Stimuli-responsive polymer gels have recently attracted great attention due to their heat/solvent resistance,dimensional stability,and unique sensitivity to external stimuli.In this work,we synthesized thiol-functionalized TPE and constructed polymer gels through thiol-ene click reaction with disulfide bond-containing bisacrylate or bisacrylamide derivatives.Based on the AIE property of TPE moieties,the preparation process of the polymer gels could be monitored by fluorescence light-up.In addition,due to the presence of redox-reponsive disulfide bond and the acid-sensitive β-thiopropionate linkers in the network,the polymer gels can be disintegrated upon addition of DTT and TFA,resulting in fluorescence quenching of TPE moieties.This stimuli-responsive characteristics endows the polymer gels with potential applications in fluorescent sensing and imaging,cancer diagnosis and self-healing materials.