Synthesis And Application Of Monodisperse Polyethylene Glycols-Based Fluorine-19 Magnetic Resonance Imaging Traceable Drug Carriers

Water-soluble,biocompatible and thermo-responsive polymers are key components for the develop of smart materials for biomedical applications.Polyethylene glycols(PEGs)is one of the few FDA approved polymers that has been proven to be safe for humans.PEGs can improve the pharmacokinetics of drugs and prolong the half-life of drugs and nanoparticles.Therefore,it is one of the most used polymers in medical and biological fields.Its non-toxicity,non-immunogenicity,biocompatibility and solubility in a wide range of solvents offer various possibilities of utilization.PEGs introduced into the polymer backbone significantly changed particles hydrophilicity,surface roughness,surface charge and water content and could provide a steric barrier to reduce particles aggregation.On the basis of our previous research,we developed a series of peptidic monodisperse polyethylene glycol(M-PEG)“combs”with fine-tunable LCST through accurately programming their structures with solid phase peptide synthesis(SPPS),in which M-PEG-containing ω-amino acids and the lysine modified by fluorine atoms are arranged together in a precisely controlled manner.In the M-PEG“combs”,PEG were employed as hydrophilic backbones and biocompatibility enhancer;the fluorine-modified L-lysines were interactively inserted into the M-PEG backbone of the peptidic molecule as 19F magnetic resonance imaging singal groups,and their hydrophobility is used to induce molecular self-assembly.At the same time,for the convenience of purification in peptide synthesis and imaging in downstream applications,fluorescent group was introduced to the N-terminals of the M-PEG“combs”.This kind of M-PEG“combs”with many imaging modalities,which has accurate structure,adjustable LCST and high biocompatibility,can be applied in many fields of biomedicine.During the study of F-PEG-aNS compounds,we found that Comparing to thermosensitive PEG block copolymers with polydisperse components,high molecular weight(usually>10000 Da),and unpredictable LCST,the M-PEG“combs”are featured with accurate and programmable chemical structures,low molecular weights of 3000-6000 Da,sharp and fine-tunable LCSTs,and“hot spot”and“smart”imaging modalities.By comparing the physicochemical properties of the series of F-PEG-aNS compounds,we can obtain prefered LCST and biocompatibility through solid phase peptide synthesis which can accurately manipulate the composition and size of F-PEG-aNS.The PEGs in F-PEG-aNS acts as solubility enhancer,biocompatibility and LCST modulator.It was found that the reversible limpidity-turbidity transition at LCST is a result of thermoresponsive phase transition in the self-assembly of amphiphilic M-PEG“combs”F-PEG-aNS,which is accompanied by thermo-responsive“on”and“off”fluorescent imaging.DOX-loaded P12-12 nanoemulsion can cross HepG2 cell membrane more efficiently than free DOX and releasing DOX in a thermo-responsive manner.The fluorine atoms and naphthyl group in the molecule provide the drug delivery system with 19F MRI and fluorescence imaging traceability.In a proof-of-concept tumor-bearing mouse experiment,P12-12@BODIPY nanoemulsion effectively delivers the loaded drug to the tumor area with fluorescent imaging traceability.Based on the result of F-PEG-aNS study,we designed a new M-PEG“comb”molecule F45-PEG12-TPE,in which the fluorine content was increased and TPE with AIE effect was introduced as a fluorophore.It has the advantages of M-PEG“combs”,such as thermosensitive and good biocompatibility,and the effect of aggregation-induced fluorescence enhancement which can be used for cell imaging.The amphiphilic F45-PEG12-TPE can self-assemble into nanoparticles in water with a particle size of about 10-15 nm.In vitro 19F MRI experiments showed that F45-PEG12-TPE had high 19F MRI sensitivity because of its high fluorine cotent and short 19F MRI data collection time(T1=542 ms,T2=152 ms).In vivo experiments showed that F45-PEG12-TPE had long in vivo half time and accumulated in the tumor site through the EPR effect which would be preferred for long-term 19F MRI monitoring of the tumor.F45-PEG12-TPE would be used for image-guided cancer therapy system due to its good imaging performance and high biocompatibility.Drug-loaded F45-PEG12-TPE liposome LI has thermosensitivity,uniform particle size and good stability,and great potential in the diagnosis and treatment of cancer.