Synthesis and Tumor Theranostic of All-in-one Photothermal Nanoagents

Author:Yu Nuo

Supervisor:chen zhi gang


Degree Year:2019





Near-infrared(NIR)light with the wavelength of 650-1350 nm exhibits stronger penetration capacity than visible light regarding absorption and scattering of biological tissues.Therefore,various kinds of NIR-responsive nanomaterials have been developed for bioimaging and disease treatments.Among them,NIR laser-induced photothermal therapy,using NIR absorbents to rapidly convert laser energy into high temperature to thermally ablate cancer cells,attracts much attention due to minimally invasive ability and high therapeutic efficiency.Based on photothermal nanoagents,the researchers have added more functions such as the tumor targeting,multi-modal imaging ability and combined therapy,which further optimized the treatment conditions and enhanced the therapeutic effect.However,to achieve multi-functionality,the structure of photothermal agents must become more and more complicated,leading to complex synthesis process and a very low yield.If the nanoparticle is single-component and has both imaging and multiple therapeutic approaches,it can be considered as a novel all-in-one nanoagent.Based on this idea,this thesis prepared all-in-one photothermal nanomaterials for tumor theranostic.The specific contents are as follows:(1)Dynamically tuning photothermal performances of TiO2 nanocrystals through Nb doping for tumor theranosticConventional wide-bandgap inorganic semiconductors can absorb ultraviolet and part of visible light but have no photoabsorption band in near-infrared(NIR)region,resulting in their inability to be the photothermal agents.Taking the wide-bandgap TiO2 as an example,this paper reports the synthesis of Nb doped TiO2 nanocrystals through thermal decomposition method,achieving the tuning from UV-responsive TiO2 nanocrystals to blue TiO2 nanocrystals with newly appeared NIR absorption band.The substitution of a Ti4+ion site by a Nb5+ion can generate a free electron,and an effective substitution of a large amount of Nb5+ions will inject a number of free electrons into the crystal lattice,thus producing the NIR band through the significant local surface plasmon resonance effect.Under the irradiation of 1064 nm laser,Nb-doped TiO2 nanocrystals can convert the laser energy to heat,and higher Nb doping content can lead to higher NIR-induced temperature elevation,highlighting that the photothermal performances of TiO2 nanocrystals can be dynamically modulated by adjusting Nb doping levels.After the surface-modification with PEGylated phospholipid,the resulting nanocrystals demonstrate high photothermal conversion efficiency of 40.6%and excellent cytocompatibility.When nanocrystals are injected into a tumor,the tumor can be detected by photoacoustic imaging,and the tumor cells are thermally ablated with1064 nm laser.Therefore,these Nb-doped TiO2 nanocrystals can be used as efficient and heavy-metal-free nanoagents for tumor theranostic in the second biological window.(2)Modulating the photothermal performances of SnO2 through Sb doping for tumor theranosticThe ideal semiconductor photothermal nanoagents should be single-component with imaging and photothermal conversion performance,while such nanomaterials are relatively rare at present.To explore the potential of semiconductors,this chapter uses SnO2 as a model to prepare SnO2nanocrystals with different Sb doping concentrations,realizing the modulation from UV-responsive SnO2 to blue SnO2 nanocrystals imaging ability and photothermal effect.When the doping concentration increased from 0 to 0.2/1.0,the obtained nanocrystals exhibit gradually decreased size and crystallinity,and show the enhanced photothermal effect under 1064 nm laser irradiation.After surface modification,the optimized Sb0.2-SnO2 nanocrystals have good laser stability,48.3%of high photothermal conversion efficiency and low cytotoxicity.When Sb0.2-SnO2 is injected into a tumor,it can be served as CT and photoacoustic imaging contrast agent and induce high temperature for tumor ablation with 1064 nm laser.Therefore,these nanocrystals can be used as an efficient photothermal agent in the second bio-transparent window for tumor theranostic.(3)Te nanoneedles with anticancer and photothermal effects for tumor imaging and chemo-photothermal therapyThe combination of chemotherapy and photothermal(chemo-photothermal)therapy can treat tumors with high efficiency,which usually requires the very nanocomposites that contain anticancer drugs,photothermal nanoagent and nanocapsule,sufferring from complex fabrication procedures and unsatisfactory drug-loading efficiency.Te nanomaterials have great potential to be served as chemo-photothermal agents,this chapter reports the synthesis of blue Te nanoneedles through a facile one-pot reduction route for the first time.The conventional blue Te nanostructures exhibit strong NIR absorbance but have ultralong length,while purple Te nanostructures with small size show extremely low NIR intensity,they cannot achieve simultaneously both the suitable size and high NIR absorption.The obtained blue Te nanoneedles have strong NIR absorbance while maintaining the shortened length(<500 nm)for the first time.Compared to purple Te nanorods,blue Te nanoneedles exhibit higher photothermal conversion efficiency and have laser-enhanced antioxidative activity towards scavenge of free radicals.These blue nanoneedles exhibit higher cytotoxicity of cancer cells than normal cells,demonstrating anticancer activity induced by mitochondrial dysfunction.Furthermore,when blue Te nanoneedles are injected in tumors of mice,tumors can be detected by thermal and photoacoustic imaging,and satisfactory therapeutic effect is achieved through the synergistic chemo-photothermal in contrast to the limited therapeutic effect of Te alone treatment.Therrefore,these blue Te nanoneedles can be used as novel nanoagents for chemo-photothermal therapy of tumors.(4)Thiol-stabilized Bi nanoparticles as sable and all-in-one nanoagents for tumor imaging and thermo-radiotherapyRadiation therapy is one of the main means for treating tumors in deep tissues by using X-ray,while challenges remain considering the hypoxia-associated radio-resistance that limit its efficacy.Interestingly,mild hyperthermia has been proved to be able to improve the oxygen level through increasing the blood flow in the tumor,thus emerging the marriage of photothermal and radiation therapy,also known as thermos-radiotherapy.In this chapter,we report the synthesis of stable Bi nanoparticles capped with thiol ligands(Bi-SR)for thermoradiotherapy.Bi element possesses ultrahigh X-ray attenuation coefficient and Bi-based semiconductors and composites have been well prepared while the development of metallic Bi nanocrystals is rather hindered due to easy-oxidation and unsatisfactory near-infrared photoabsorption.After surface-modified with PEGylated phospholipids,the obtained Bi-SR-PEG has strong NIR absorbance and high photothermal conversion efficiency.Importantly,thiol ligands on the surface of Bi-SR-PEG can significantly prevent the metal Bi core from oxidation because of the strong chemisorption energy between sulfur and metal,thus matianing the high stability and long-term near-infrared photoabsorption.Given the low toxicity,good blood compatibility and high X-ray attenuation coefficient,Bi-SR-PEG can passively acuminate in the tumor area through intravenous injection,endowing them with the simultaneous tumor CT imaging and thermoradiotherapy.Therefore,the satisfying therapeutic effect of tumors can be achieved,undoubtedly verifying that Bi-SR-PEG can be used as a stable and all-in-one type theranostic nanoagent.