Construction Of Near-Infrared Light Nanotransducers For Biomedical Applications

As light can be converted into fluorescence/phosphorescence/photoacoustic signals and/or photothermal/photodynamic effects,it provides great potential in the fields of biological imaging,medical diagnosis,phototherapy and theranostics.In comparison with conventional ultraviolet and visible light,near-infrared(NIR)light has lower phototoxicity,lower tissue absorption,less photon scattering,and deeper tissue penetration.Thus,NIR light is highly desired to achieve biological applications.In addition,nanomaterials hold the advantages of simple preparation,easy integration of multiple functions and nano-level effects.Therefore,NIR light nanotransducers that combine NIR light and nanomaterials can remotely monitor and regulate various biological events through NIR light to achieve a variety of biological applications.On the basis of such background,a photothermal nanotransducer is first constructed by using peptide supramolecular assemblies as templates to biomineralize Cu_2-xS nanoparticles(x=1-2)for the treatment of metastatic melanoma in this thesis.Furthermore,in order to achieve specific drug delivery and controlled release of drug,we combine photothermal materials with thermosensitive materials to construct light-driven drug release nanoparticles for the degradation of?-amyloid.Due to the many merits of fluorescence in the second near-infrared window(NIR-?,1000-1700nm)such as improved sensitivity,spatial and temporal resolutions of imaging and tissue penetration depth,we develop a methylglyoxal-activated NIR-?emissive fluorescent probe,which further are employed to construct an activated light-driven thermosensitive theranostic nanoprobe for specific NIR-?fluorescence imaging of breast-cancer tumor and combined photothermal and photodynamic therapy.To break through the limitation of blood-brain barrier,we integrate this NIR-?fluorescent probe with magnetic nanoparticles for detection of methylglyoxal in the brain of Alzheimer's disease(AD).This paper mainly includes the following six parts:Chapter 1.OverviewThis chapter first briefly discusses the photophysical process of light and the research significance of NIR light,and then summarizes recent advances of NIR light fluorescent probes,NIR photothermal conversion materials and NIR photosensitive materials.Then the biological applications of NIR light nanotransducers are introduced,mainly including nano-drug delivery systems triggered by NIR light,NIR light-mediated therapy,and NIR light-assisted imaging technology.Finally,the research significance,research content and innovation points of this thesis are presented.Chapter 2.Peptide nanotube-templated biomineralization of Cu_2-xS nanoparticles for combination treatment of metastatic tumorCu_2-xS nanoparticles(Cu_2-xS NPs,x=1-2)have been considered as very promising photothermal materials.However,traditional synthesis methods have drawbacks such as harsh reaction conditions,difficulty in controlled spatial arrangement of nanoparticles and low bioavailability.Therefore,the work in this chapter adopts a gentle method of biomineralization and chooses one-dimensional peptide nanotubes(1D PNTs)as templates to synthesize Cu_2-xS NPs.Due to the specific high affinity of Cu ions to imidazole groups on the surface of peptide nanotubes(PNTs),monodisperse Cu_2-xS NPs spatially distributed along the surfaces of PNTs.1D PNTs exhibit properties such as high biocompatibility,increased cellular uptake,and elongated blood circulation.The Cu_2-xS nanoparticle-integrated PNTs are further grafted with tetravalent oxaliplatin prodrugs for metastatic melanoma tumor.Upon an808 nm laser,Cu_2-xS NPs showed a combined photothermal and photodynamic phototherapy effect.Meanwhile,the oxaliplatin prodrug was reduced to toxic divalent oxaliplatin by the over-expressed glutathione in cancer cells for chemotherapy efficacy.In the B16-F10 melanoma tumor-bearing mouse model,the bifunctional PNTs significantly inhibit the growth and metastasis of melanoma through combined phototherapy and chemotherapy.This study demonstrates that one-dimensional peptide nanomaterials can be widely used in the fields of nanomedicine and biomineralization.Chapter 3.A?-targeting nanoparticles for light-tunable drug release and photothermal degradation of A?Since the deposition or misfolding of?-amyloid(A?)is an important pathological feature of AD,the clearance of A?aggregates may be an effective therapeutic strategy.The work in this chapter prepares versatile nanoparticles(PDLC NPs)based on thermal-responsive polymer for imaging-guided combined chemo-photothermal degradation of A?.The nanoparticle consists of four parts:a conjugated polymer(PDPP3T-O14)as a photothermal core,loaded curcumin as an inhibitor of A?aggregation,and a thermal-sensitive polymer with a characteristic phase transition temperature of 41?(1,2-dipalmitoyl-sn-glycero-3-phosphocholine,DPPC)at the outer layer as the NIR-stimuli gatekeeper,and the surface-modified peptide(LPFFD)as an A?-targeting peptide.The nanoparticles exhibit high A?affinity,and upon an808 nm laser,the PDPP3T-O14 core generates local hyperthermia,which induces the gel-liquid phase transition of DPPC and triggers the release of curcumin.Therefore,the nanoparticles effectively degrade amyloid aggregates by combination chemo-photothermal treatment.In addition,the nanoparticles can also provide A?aggregation-dependent fluorescence detection through the polarity-dependent fluorescence of curcumin.This study provides a novel NIR-stimulus drug release system,which possesses high specificity and biocompatibility,can avoid off-target toxicity of drugs,and can be applied for chemo-photothermal treatment for A?aggregation,thus showing great potential for the application in AD treatment.Chapter 4.MGO metabolism activatable"dual lock-and-key"nanoprobe for tumor NIR-?fluorescence imaging and highly specific therapyAerobic glycolysis is one of tumor metabolism's important pathway.Methylglyoxal(MGO)is a metabolic product of glycolysis with high reactivity,and can post-translationally modify proteins,DNA,phospholipids,etc.,and is closely related to the tumorigenesis and tumor progression.However,the emission wavelengths of the existing fluorescent probes for MGO detection are mostly in the visible light region,which hinders the application of in vivo detection.The work in this chapter first synthesizes an MGO-responsive NIR-?fluorescent molecule(MEM).The molecular probe utilizes o-phenylenediamine coupled with benzothiadiazole as the specific recognition unit and fluorescence emission skeleton of MGO.After reacting with MGO,the structure of methylquinoxaline is generated,and the maximum fluorescence emission is about 1048 nm.Subsequently,we prepared MGO activatable theranostic nanoprobes(GNPs@MEM/HAL).The nanoprobe co-encapsulates MEM and the endogenous photodynamic drug hexyl 5-aminolevulinate hydrochloride(HAL),and employs organic phase change material(PCM)with a low melting point(39?)as a thermo-responsive gatekeeper.Meanwhile,glucose modification is used for enhanced tumor targeting.When the nanoprobe is specifically internalized into tumor cells through a glucose transporter-mediated pathway and reacts with MGO(the first"key"),the probe emits NIR-?fluorescence and acquires the ability of photothermal conversion.Subsequently,upon an 808 nm laser(the second"key"),the local temperature rises to promote the release of HAL.The nanoprobe can sensitively respond to MGO with a detection limit of 41 n M,and can achieve tumor NIR-?fluorescence imaging with high sensitivity and high resolution in vivo,and meanwhile eliminate tumors with combined photothermal and photodynamic therapy under the guidance of NIR-?fluorescence imaging.This study synthesizes an MGO-responsive NIR-?fluorescent probe for the first time,and provides a new feasible strategy for the use of photothermal nanotransducers based on tumor metabolism for tumor treatment.Chapter 5.MGO-responsive magnetic nanoprobe for MGO NIR-?fluorescence imaging and MRI imagingDiagnosis and treatment of brain diseases still have great challenges due to the existence of the blood-brain barrier(BBB).MGO plays a key role in the etiopathogenesis of AD.Therefore,it is of great significance to design a probe for detecting the abnormal level of MGO in the AD brain.In this chapter,we modified MGO-responsive NIR-?fluorescent molecules(MEM)on the surface of water-soluble ultra-small Fe₃O₄ nanoparticles to prepare MGO-responsive magnetic nanoprobes.The nanoprobe exhibits a highly selective and sensitive NIR-?fluorescence response to MGO with a detection limit of 72 n M,which can precisely detect the level of endogenous MGO in nerve cells(SH-SY5Y).In addition,the probe has high longitudinal relaxivity(r₁=4.40 m M s^-1)and transversal relaxivity(r₂=34.42m M s^-1),and can be used as efficient T₁-and T₂-contrast agents.Preliminary in vivo experiments show that the probe can cross the BBB to some extent,and further coupling with the exogenous brain targeting peptide T7(HAIYPRH)is expected to promote BBB traversal and provide high spatiotemporal resolution and signal-to-noise ratio for precise brain diagnostics of MGO.Chapter 6.Summary and outlookThis chapter summarizes the research significance and main content of this thesis as well as the innovation,and then discusses the existing challenges in the relevant directions of this thesis,and provides future perspectives on the clinical application of NIR light nanotransducers.