Low Valence Bismuth-Base Nanoprobes For Near-Infrared Light-Mediated Diagnosis And Treatment Of Tumor

The morbidity and mortality of cancer are continuously increasing.It has become the leading killer threatening human life and health.Although conventional methods such as surgical resection,chemical drug treatment and radiation therapy have specific therapeutic effects,they have corresponding side effects to patients.Phototherapy,as a new type treatment method,mainly depends on the photothermal effect(photothermal therapy,PTT)or photodynamic effect(photodynamic therapy,PDT)produced by the combination of photoactive materials and near-infrared light to kill tumor cells,which has the advantages of minimal invasiveness,low toxicity,precise controllability,evident efficacy and so on.PTT or PDT also has inevitable disadvantages in the application process.The heat shock effect generated during PTT will reduce the therapeutic effect,while the therapeutic effect of PDT changes from strong to weak with the depletion of the oxygen around the tumor tissues.The combination of PTT and PDT not only solves their respective problems,but also possesses a significant synergistic therapeutic effect.The common medical imaging technology and phototherapy are combined to achieve the cancer“theranostics",ensuring the accurate monitoring of the phototherapy.At present,the construction of“theranostics" probes mostly relies on the multi-component complex system,which has many drawbacks such as complicated preparation process,easy collapse of structure,heavy degradation burden,and mutual interaction among components.Based on the aforementioned analysis,three low valence bismuth-based nanoprobes were fabricated for multifunctional“theranostics" nanoplatforms with both tumor medical imaging and phototherapy performance.To solve the problem that traditional single probe is difficult to balance treatment and imaging,bismuth(Bi)nanocrystals of a single component with both PTT and photoacoustic(PA)/CT imaging performances are successfully fabricated by a solvothermal method.The morphology and optical properties of Bi nanocrystals are investigated in details with various parameters,including the solvent volume ratio,reaction time,and reaction temperature.The 1,2-dilauroyl-sn-glycero-3-phosphocho-line(DLPC)molecules are employed to modify on the surface of Bi nanocrystals through hydrophobic interaction.As a result,the Bi@DLPC nanospheres with excellent biocompatibility and cell uptake capacity are successfully prepared.The Bi@DLPC nanospheres have excellent near-infrared optical absorption,and photothermal conversion performance with the photothermal conversion efficiency(?)of?35%.Besides,the Bi@DLPC can not only achieve PA and CT dual-mode imaging,but also effectively inhibit the growth of subcutaneous tumors in mice by combining with 880 nm near-infrared(NIR-880 nm)laser irradiation for 10 min at a power density of 1 W/cm2.The relative volume of subcutaneous tumors in mice is?0.09±0.08 on the 14th day(tumor growth inhibition is?91%).In addition,the possible mechanism of PTT is proposed at the cellular level.To conquer the problems of poor efficacy of single mode in phototherapy and insufficient understanding of solid tumor ablation mechanism,an oxygen-deficient bismuth ferrite(abbreviated as BFO)nanotheranostic agents with both photothermal and photodynamic performances are successfully prepared via a hydrothermal method,and the ablation mechanism of solid tumors in vivo is deeply explored.The effects of the Bi/Fe feed molar ratio and pH on the purity and optical properties of the BFO nanotheranostic agents are investigated in details.The BFO nanotheranostic agents have outstanding near-infrared optical absorption,photothermal conversion performance(?=?51.4%),and photodynamic performance.The BFO can not only realize PA imaging in vivo and in vitro,but also achieve more ideal phototherapy effects than single therapeutic mode in the treatment of cancer cells and subcutaneous tumors of mice upon NIR-880 nm laser irradiation.The relative volume of subcutaneous tumors in mice is?0.08±0.11 on the 14th day(tumor growth inhibition is?92%).In addition,the ablation mechanism of solid tumors in vivo is demonstrated through ultrasound imaging technology and histopathological analysis.To overcome the problem that the subcutaneous tumor models cannot mimic the clinical characteristics of real human tumors,the orthotopic tumor model is successfully constructed by rabbit that can maximally replicate the clinical characteristics of human tumors.The novel oxygen-deficient BiPO4-x nanorods have been synthesized by H2 reduction method,realizing the efficient ablation of the orthotopic tumor in rabbit.The effects of the reduction temperature and reduction time on the morphology and optical properties of the BiPO4-x nanorods are systematically evaluated.To improve the biocompatibility of the BiPO4-x nanorods,their surfaces are modified with polyethylene glycol thiol(mPEG-SH)(named PEG-BiPO4-x).The PEG-BiPO4-x nanotheranostic agents have ideal near-infrared optical absorption,which can not only convert near-infrared light into thermal energy to realize the photothermal effect(?=?44.1%),but also utilize in situ generated reactive oxygen species(ROS)to achieve the photodynamic effect.The enhanced mechanism of optical absorption of the oxygen-deficient BiPO4-x nanorods is theoretically simulated by density functional theory,and the results show that the abundant middle band transitions in the presence of oxygen defects are the primary reason of the BiPO4-x optical absorption enhancement.In addition,the combination of the PEG-BiPO4-x and NIR-880 nm laser can significantly inhibit the growth of subcutaneous tumors in mice and orthotopic tumors in rabbits.The relative tumor volumes of mice and rabbits are?0.02±0.05 and 0 on the 14th day(tumor growth inhibition is up to?98%and?100%),respectively.Combined with PA imaging,the PEG-BiPO4-x can realize the accurate diagnosis and treatment of tumors.