Novel Multifunctional Inorganic Nanomaterials For Phototherapy Of Deep Tumor

Phototherapy,as an emerging tumor therapy modality,has attracted more and more attentions in recent years.The basic principle of phototherapy is as follows: light with particular wavelength is utilized to irradiate photoabsorbing agent to generate local temperature elevation or reactive oxygen species,leading to apoptosis or death of tumor cells.According to the different responses of photoabsorbing agent upon light irradiation,phototherapy can be branched out into two different categories:photothermal therapy(PTT)and photodynamic therapy(PDT).Benefiting from the merits such as high selectivity,intrinsic safety and non-invasion,phototherapy has been extensively applied in researches of tumor treatment.Unfortunately,the clinical application of phototherapy is largely impeded by comprehensive drawbacks such as low energy conversion efficacy of photoabsorbing agent,insufficient tumor targeting delivery,limited penetration depth of excitation light and hypoxic feature of tumor microenvironment,leading to disappointing performance of tumor therapy,especially with the tumor seated in deep body.Owing to the outstanding physicochemical characteristics,inorganic nanoparticles hold great potential to overcome the limitations mentioned above.On one hand,many inorganic nanoparticles can be directly utilized as efficient photoabsorbing agents to enhance the anti-tumor effects of phototherapy.On the other hand,novel phototherapy strategies capable of deep tumor treatment can be fabricated based on inorganic nanoparticles,which will distinctly expand the scope of phototherapy.Moreover,tumor targeting delivery of inorganic nanomaterials can be achieved using the EPR effects of tumor tissue or other targeting strategies.Herein,albumin-platinum coordination was manipulated to direct the controlled synthesis of multifunctional Pt nanodots(Pt@HSA),which served as novel photothermal agents for multimodal imaging and near infrared(NIR)excited photothermal tumor ablation.Moreover,in order to further expand the scope of phototherapy,Tb3+ doped LaF3 scintillating nanoparticles(ScNPs)and rose bengals(RB)that exhibits perfect spectrum match with Tb3+ were selected as energy transducers and photosensitizer,respectively.ScNPs/RB nanocomposites were constructed and their potential application for X-ray stimulated deep PDT was investigated.The main results are as follows:(1)Pt@HSA were synthesized in a controlled manner and the properties were optimized.Albumin-platinum coordination was utilized to control the synthesis of Pt@HSA in water phase under mild condition.The controlled synthesis of Pt@HSA was conducted based on the study of reaction kinetics and the analysis of reaction mechanism via monitoring reaction progress.The vital role of albumin for controlled synthesis and the growth mechanism of Pt@HSA were investigated in details.NIR absorption and photothermal effects of Pt@HSA were optimized by adjusting various reaction parameters.Characterization results showed that Pt@HSA exhibited spherical morphology with core diameter and hydrodynamic diameter of 6.66±0.92 nm and 58.4 nm,respectively.The Pt@HSA possessed high crystalline with well-defined nanostructure and preferable colloidal stability.Pt@HSA had intense absorption in the whole NIR region and exhibited potent photothermal effects under the irradiation of 785 nm laser with photothermal conversion efficiency of 35.0% and tough photostability.Moreover,Pt@HSA exhibited obvious photoacoustic(PA)and Computed Tomography(CT)signals,indicating the multimodal imaging capability.(2)Multimodal imaging and NIR laser excited PTT were conducted.Pt@HSA were efficiently internalized by 4T1 cells via clathrin-mediated endocytosis and mainly located in the lysosomes.Upon the irradiation of 785 nm laser,Pt@HSA exhibited intense cytotoxicity on 4T1 cells.In mice,Pt@HSA showed long plasma circulation time,distinct tumor accumulation and long-term tumor retention,leading to significant NIR fluorescence imaging,PA imaging and CT imaging for precise tumor location.Upon 785 nm laser irradiation,a single injection of Pt@HSA could completely eradicate the tumor without any regrowth,while inducing ignorable impact to healthy tissues.In addition,Pt@HSA exhibited preferable biosafety in vivo with renal excretion characteristic.(3)ScNPs/RB nanocomposites capable of X-ray stimulated deep PDT were fabricated using various strategies.Mesoporous ScNPs(MScNPs)and amino group functionalized ScNPs(ScNPs-AEP)were synthesized in water phase via hydrothermal procedure and precipitation reaction,respectively.The highly crystalline MScNPs possesses pure hexagonal phase with diameter of 38.9 nm and ScNPs-AEP exhibited spherical morphology with ultrasmall diameter of 2.95 nm.Upon the irradiation of UV light or X-ray,both ScNPs emitted intense green fluorescence which was optimized by adjusting various reaction parameters.Using pore embedding and covalent conjugation strategies,two ScNPs/RB nanocomposites were fabricated,respectively.Both steady-state spectra and fluorescence delay dynamic analysis demonstrated that high FRET efficiency was achieved in these nanocomposites.Moreover,enhanced singlet oxygen generation from ScNPs/RB nanocomposites was detected as compare to RB alone,suggesting great potential of ScNPs/RB nanocomposites for X-ray stimulated deep PDT.In this dissertation,several kinds of multifunctional nanocomposites base on platinum nanodots or ScNPs were constructed and applied to NIR-/X-ray-stimulated phototherapy of tumor,which may provide new insights into phototherapy of deep tumor.