Design,fabrication And Mechanisms Of Near-infrared Long-lasting Afterglow Nanoprobes For Precision Medicine

Recently,near-infrared?NIR?long-lasting afterglow nanoprobes have received intense attention because of their great application prospect in the fields of precise medical diagnosis and therapy guided by autofluorescence-free afterglow imaging.In particular,some breakthroughs,such as in vivo bioimaging,local tissue temperature sensing and photodynamic therapy induced by afterglow emissions,have been made based on Cr³⁺-doped zinc gallogermanate long-lasting afterglow nanoprobes with NIR-I emissions at ⁷00 nm.However,there still remain several unsolved issues on accurate diagnosis and therapy of tumors based on ZGGO:Cr afterglow nanoprobes.For example,how to construct and prepare high-quality NIR afterglow nanoprobes for simultaneously realizing autofluorescence-free temperature sensing and afterglow imaging,how to design and prepare autofluorescence-free NIR-II/III long-lasting afterglow nanoprobes for tumors in deep tissue,how to develop multifunctional integrated NIR afterglow nanoplatforms for autofluorescence-free bioimaging and photothermal therapy of tumors,etc.In this dissertation,to overcome the aforementioned proplems,spinel-phased Zn₂Ga_3.98-4x/3Ge_xO₄:Cr_0.02?ZGGO:Cr?and Zn₂Ga_2.98-xGe_0.75O₈:Cr_0.02,R_x(ZGGO:Cr,R;R = Nd³⁺,Er³⁺)nanoprobes were prepared by a hydrothermal method combined with a subsequent heattreatment in vacuum.For the obtained nanoprobes,the effects of doping concentration on the microstructure,particle size distribution,NIR luminescence and afterglow properties,persistent energy transfer,afterglow bioimaging,temperature sensing and photothermal conversion performance were studied systematically and their afterglow mechanisms were discussed.The main results of our study are summarized as follows:Based on the nonequivalent substitution of Ga³⁺by Ge⁴⁺,ZGGO:Cr nanoparticles with different Ge⁴⁺doping concentrations were prepared by a hydrothermal method combined with a subsequent heattreatment in vacuum.It is found that near-spherical nanoparticles with spinel phase can be acquired in a wide range of Ge⁴⁺doping concentration?0.45-0.90?,suggesting the current synthesis routes of zinc gallogermanate nanomaterials are further expanded.The average particle size decreases with increasing Ge⁴⁺doping concentration and reaches to be ⁴6 nm when 0.60 ? x ? 0.90.With increasing Ge⁴⁺doping concentration from 0.45 to 0.90,the decreased lattice constants and shortened Zn-O,Ga-O,Cr-O bond lengths of the ZGGO host,the increased crystal field strength around luminescent centers and the significantly enhanced NIR-I emissions of ZGGO:Cr were found.Furthermore,the non-equivalent substitution of Ga³⁺by Ge⁴⁺leads to the generation of anti-site Zn?_Ga-Ga°_Zn,and defects,the decreased trap depth and narrowed bandgap of the host,thereby enhancing NIR-I afterglow intensity by one order of magnitude and making the afterglow time of ZGGO:Cr nanoparticles longer than 15 h.On the other hand,a modified ratiometric afterglow nanothermometer was constructed based on the temperature-dependent afterglow intensity ratios of ⁴T₂ ? ⁴A₂to ²E ? ⁴A₂ emissions of interior Cr³⁺doped in ZGGO:Cr nanoparticles and bifunctional afterglow nanoprobes for autofluorescence-free bioimaging and temperature sensing were acquired.Our results suggest that Ge⁴⁺doping strategy can improve the relative thermal sensitivity of the afterglow nanothermometer.When x = 0.90,the maximum relative sensitivity in the physiological temperature window?295-328 K?reaches 1.0% K^-1.ZGGO:Cr_x,Nd_y afterglow nanoprobes with different Nd³⁺concentrations were prepared by a hydrothermal method combined with a subsequent heattreatment in vacuum.On one hand,for a series of samples with low Nd³⁺doping concentrations?0 ? y ? 0.04?,the average particle size increases from 45.4 to 86.2 nm with a rise of Nd³⁺concentration.After stopping 635 nm excitation,the afterglow emissions in the NIR-I and NIR-II regions,which are ascribed to the ²E,⁴T₂?⁴A₂transitions of Cr³⁺?696 nm?and the ⁴F_3/2?⁴I_11/2transition of Nd³⁺?1067 nm?,respectively,were simultaneously acquired based on the persistent energy transfer process from Cr³⁺to Nd³⁺.For ZGGO:Cr_0.02,Nd_0.02nanoparticles,the afterglow time related to Cr³⁺and Nd³⁺dopants exceeds 800 min and 10 min,respectively.Thus,the operating wavelength of ZGGO nanoprobes for afterglow bioimaging can be extended from NIR-I to NIR-II window via Nd³⁺/Cr³⁺co-doping strategy.Furthermore,ZGGO:Cr_0.02,Nd_0.02nanoparticles exhibit better dispersibility in?H₂O and human serum albumin?HSA?solution than in simulated lysosomal environment?SLS?due to the time-dependent dissolution of the metal-containing nanoparticles in a acid medium.Meanwhile,the repeatable afterglow imaging based on ZGGO:Cr_0.02,Nd_0.02nanoparticles dispersed in SLS solution was realized through an X-ray reexcitation strategy.In particular,both the X-ray excitation strategy accompanied with NIR-I afterglow emission and the red light?635 nm?excitation strategy accompanied with NIR-II afterglow emission can realize deep tissue bioimaging at the pork thickness ranging from 0-2.5 cm.Our results show that ZGGO:Cr,Nd nanoprobe is suitable for deep tissue NIR-I/II afterglow imaging.On the other hand,for a series of samples with high Nd³⁺doping concentration?y = 0.2,0.4?,little variation in the particle size?⁸1 nm?was observed.Notably,the NIR-I emission and afterglow intensities decrease dramatically with increasing Nd³⁺doping concentration.Meanwhile,the photothermal conversion effect of ZGGO:Cr,Nd?y = 0.2,0.4?nanoparticles upon 808 nm irradiation is more pronounced compared to that of the nanoparticles with low Nd³⁺doping concentrations?y ? 0.04?.It was found that the temperature increment of ZGGO:Cr_0.02,Nd_0.2nanoparticles dispersed in water?20 mg/mL?was proportional to the incident power of 808 nm laser.In addition,the photothermal conversion efficiency of the aforementioned aqueous dispersion upon 808 nm irradiation(1W cm^-2)was figured out to be 42.7%.Our results suggest that ZGGO:Cr_0.02,Nd_y nanoparticles?y = 0.2,0.4?are promising candidates as the multifunctional nanoprobes for simultaneous bioimaging and photothermal therapy without autofluorescence background.ZGGO:Cr_0.02,Er_y?0 ? y ? 0.04?nanoparticles with different Er³⁺doping concentrations were prepared by a hydrothermal method combined with a subsequent heattreatment in vacuum.It is found that the average size decreases with increasing Er³⁺concentration owing to the increased nucleation rate after Er³⁺doping.Meanwhile,the incorporation of Er³⁺ions leads to the decrease in the NIR-I emission and afterglow intensities of ZGGO:Cr,Er nanoparticles.In addition,the increased trap depth in ZGGO host was found to be responsible for the weakened NIR-I afterglow intensity.After stopping NIR-I light?651 nm?irradiation,the NIR-I?696 nm?and NIR-III?1540 nm?afterglow emissions deriving from the ²E,⁴T₂?⁴A₂transitions of Cr³⁺and the ⁴I_13/2?⁴I_15/2transition of Er³⁺,respectively,were simultaneously acquired based on the persistent energy transfer from Cr³⁺to Er³⁺.The afterglow emissions monitored at 696 nm and 1540 nm last more than 850 min and 5 min,respectively.Thus,based on Cr³⁺and Er³⁺co-doped ZGGO nanoparticles,the operating wavelength involved in afterglow bioimaging was further expanded,which is helpful for the realization of deep tissue bioimaging without autofluorescence background.