Design,Synthesis And Application Of Several Nanodrug Carriers With Tumor Microenvironment Sensitivity

Malignant tumor is abnormal growth of tissue caused by uncontrolled cell proliferation.Compared with normal cells,malignant tumor usually shows abnormal mitosis,necrosis,structure and development of cells.Although some drugs have been proved for tumor therapy in clinic,they usually cause serious side effects because of the poor tumor-targeting effects and the increased drug resistance of tumor cells.In the past few years,researchers have achieved tumor-targeting therapy through linking of specific tumor targeted molecules on traditional drugs.In addition,the rational selection of trigger mechanism for drug release will also benefit tumor therapy.Normally,there are two main mechanisms for drug release.The first one is external stimuli,such as light,heat,X-ray,magnetic field and ultrasound.Another way is to stimulate drug release through tumor internal factors.The solid tumors usually have unique growth patterns,which could result in significant changes of tumor microenvironment(TME).TME usually has low pH value,high reduction potential,serious hypoxia and over-expressed enzymes.Therefore,considering the specific TME,exploring novel nanodrugs is of great significance to improve the drug efficacy,reduce side effects and alleviate the suffering of patients.In view of the above problems,the contents of this paper can be summarized as follows:(1)An intelligent nanoplatform,DOX-UCNPs@PAA-b-PEG-RGD,was fabricated for upconversion imaging(UCL)of tumor cells and targeted tumor therapy.The multi-shell structured upconversion nanoparticles,NaYF4:Yb/Tm@NaYbF4:Gd@NaNdF4:Yb@NaYF4,were presented.The shell coating strategy could adjust the excitation light from 980nm to 808nm for achieving high penetration depth while maintain low thermal effect.In addition,the luminescent intensity of this core-shell structured nanoparticle is enhanced obviously compared with NaYF4:Yb/Tm.The increased luminescence will facilitate UCL of tumor cells.Since the luminescent intensity in the ultraviolet region increased by 44 times after shell coating,the material can be further used to initiate RAFT polymerization.Acrylic monomer(AA)and oligomer polyvinyl glycol monomers(PEGMA and DEGMA)were grown onto the surface of nanoparticles through surface RAFT polymerization under 808 nm laser irradiation successively.The Fourier transform infrared(FT-IR)spectra,thermogravimetric analysis(TGA)and X-ray photoelectron spectra(XPS)directly prove the successful fabrication of surface polymer brushes.Anti-cancer drug DOX was electrostatic adsorbed on nanoparticles.In neutral condition,DOX is tied to nanoparticles.However in acidic TME,DOX could be quickly released.The protein adsorption experiments prove that after PEGylation this nanodrug could resist the adsorption of various proteins which have different surface charges.Finally,the trithiocarbonate residues in the outermost layer of polymer brushes was aminolysised for further function of targeting molecules RGD.This well-designed drug delivery system with multi-layered structure demonstrates drug release behavior that is extremely sensitive to the unique acidic TME.Finally,this system realizes efficient diagnosis and treatment of cancer cells.(2)A multifunctional nanodrug system,UC@mSiO2-RB@ZIF-O2-DOX/PEGFA,was designed to overcome the hypoxic TME for enhanced photodynamic therapy(PDT)and chemotherapy.NaYF4:Yb/Er@NaYbF4:Nd@NaGdF4 upconversion nanoparticles were synthesized by one-step hot injection method.This core-shell structure not only enables the material to be used for upconversion and magnetic resonance bioimaging,but also ensures that the material can generate intense green light after being stimulated by 808nm laser.The green light could excite photosensitizer RB to generate 1O2 and realize oxygen-enhanced PDT.The ZIF-90 shell act as the carrier of oxygen,DOX and PEG-FA.Considering that ZIF-90 could degradable in weak acidic environment,this system could on-demand release oxygen and DOX in TME(pH-6.5),which will directly overcome hypoxia and enhance the therapeutic efficacy of PDT and DOX.Transmission electron microscopy(TEM),powder X-ray diffraction(PXRD),FT-IR and UV-Vis absorption spectra prove that UC@mSiO2-RB@ZIF-O2-DOX/PEGFA was successfully synthesized.Magnetic resonance imaging and UCL imaging showed that the synthesized nanoparticles had good imaging ability both in vitro and in vivo.The dissolved oxygen experiment proves that the material can release oxygen rapidly in weak acidic environment.DPBF absorption spectra and in vitro ROS measurements show that oxygen-loaded nanoparticles could generate abundant ROS after irradiation of 808nm laser.MTT and in vivo experiments demonstrated the biological safety of this system for normal cells.At the same time,these methods also prove that the oxygen-loaded synergetic therapeutic system is more effective in the treatment of solid tumors than the oxygen-free system,single drug-loaded system or small molecule drugs.(3)Considering the low pH value,high GSH content and hypoxia in TME,a novel biodegradable nanotherapeutic system,O2-Cu/ZIF-8@Ce6/ZIF-8@F127(OCZCF),was synthesized.Firstly,copper-doped ZIF-8(Cu/ZIF-8)crystal was prepared by ion doping strategy.Then a layer of ZIF-8 containing photosensitizer Ce6 was coated on Cu/ZIF-8 for PDT.The amphiphilic polymer F127 was coated on the surface of nanoparticles to enhance the biocompatibility.XRD,FT-IR and UV-Vis absorption spectra proved the successful synthesis of the nanocomposite.After tail vein injection,OCZCF can accumulate at the tumor site through the enhanced permeability and retention(EPR)effect.The use of ZIF-8,a biodegradable substrate,could enhance the biosafety of nanoparticles.In addition,OCZCF disintegrates completely in the weak acidic TME,resulting in the on-demand release of oxygen,Ce6 and Cu2+.Under 650nm laser irradiation,a large amount of oxygen can alleviate the hypoxic TME and enhance the PDT effect induced by Ce6.The released Cu2+will consume GSH and improve the efficiency of ROS.Furthermore,the generated Cu+could catalyze excessive H2O2 in tumors and produce OH and oxygen through Fenton-like reaction,achieving chemodynamic therapy and alleviation of tumor hypoxia.In vitro and in vivo experiments show that this biodegradable nanocomposite has high anti-tumor effects and is of great significance for further clinical application.