Constructions And Applications Of Zn₂Ga_2.98Ge_0.75O₈:Cr³⁺_0.02Based Composite Nanosystems For Precision Photothermal Therapy

Recently,organic and inorganic nanomaterials have attracted more attention in biomedical filed.For example,inorganic photothermal materials,such as gold nanorods(GNRs)and Bi2S3 have shown potential applications in the diagnosis and therapy of cancer due to their strong light absorption ability in the NIR-I biological window.The researchers have successfully achieved in vivo photothermal therapy(PTT),integrated photothermal drug transport,collaborative photodynamic therapy based on integrated photothermal energy transfer,and integrated photothermal fluorescence temperature monitoring of shallow tissues using upconverted luminescence nanoparticles.Thus,it is essential to construct NIR-light-excited composite nanoplatforms with simultaneously realizing subcutaneous bioimaging,deep-tissue temperature sensing and PTT.However,the existence of autofluorescence effect under external light excitation can lead to poor bioimaging and low-resolution temperature sensing for PTT based on photothermal agents.In particular,to positioning and kill tumor cells located in deeper tissue region(i.e.below 10 mm of the surface of local tissues),it is still a challenge for constructing biocompatible composite integrated nanoplatforms with three functions:autofluorescence-free bioimaging,temperature sensing and PTT.To solve the above problems,Zn₂Ga_2.98Ge_0.75O₈:Cr³⁺_0.02(ZGGO:Cr³⁺)persistent luminescent nanoparticles(PLNPs)with NIR emissions(?700 nm)upon X-ray,UV or NIR light excitation were selected as optical probes.Through dispersing inorganic photothermal agents into these PLNPs,trifunctionl composite nanoplatforms for autofluorescence-free bioimaging,temperature sensing and PTT of local tissue can be constructed.In addition,to realize deep-tissue integrated PTT,a 635 nm laser,which wavelength located in the NIR-I window,was selected as an excitation source.In this case,the nanosized photothermal agents and PLNPs can be simultaneously excited to achieve diagnostic and therapeutic efficacies.Our main research results are as follows:Firstly,we prepared uniformly dispersed and nearly spherical ZGGO:Cr³⁺@CTAB persistent luminescent nanoparticles by a CTAB-assisted synthetic method.It can be believed that,during the crystal growth process,the existence of CTAB acted as cationic surfactant can lead to uniform size distribution of nanoparticles due to the oriented transport of growth units,such as Zn(OH)4^2-or Ga(OH)6^3-to crystal nucleus surface.In particular,it is found that,C19H42N⁺groups are adsorbed on the surfaces of nanoparticles and an orderly hydrophobic layer related to CTAB is formed,thus the growth rate of nanoparticles is suppressed.On the other hand,because the long tail group of CTAB constituted by a hydrophobic carbon-chain is unstable in water used as hydrothermal solvent,another layer of CTAB molecules is formed with hydrophilic head groups pointing outside through electrostatic interaction.Therefore,CTAB bilayer is formed on the surfaces of nanoparticles and it leads to the positively charged surface of nanoparticle.Meanwhile the CTAB-assisted self-assembly process generated more anti-site defects in the crystal.When the amount of CTAB reaches the first and second micelle concentration critical point,the morphology,dispersion and afterglow intensity of these nanoparticles can be improved.At the same time,the presence of CTAB bimolecular layer on the surfaces of nanoparticles can effectively passivate their surface defects and make their surface modification and biological applications easier.Secondly,CTAB capped GNRs with averaged size of?50 nm and NIR strong plasma absorption around 635 nm were prepared by a seed-mediated method.To combine GNRs with PTT performance and PLNPs with autofluorescence-free imaging and temperature sensing,non-toxic small molecules(PW12)were introduced to construct integrated PLNP-GNR composite nanosystem through electrostatic adsorption.It can be found that PLNP-GNR composite nanosystem have a good biocompatible and can be further applied in the diagnosis and therapy of cancer.Meanwhile,afterglow nanothermometer based on ZGGO:Cr³⁺@CTAB nanoparticles was also established.Thus,PLNP-GNR composite nanosystem under NIR single wavelength excitation can simultaneously realize deep-tissue(10 nm)afterglow imaging,real-time temperature sensing and PTT.In addition,it can effectively reduce the light damage to normal tissues around cancer cells and achieve accurate localization of tumor cells as well as photothermal ablation in vivo.Finally,ultra-small spherical Bi2S3 nanoparticles were successfully synthesized by one-step aqueous phase method due to their extinction coefficient at 635 nm being larger than that of GNRs.Biocompatible PLNP-Bi2S3 composite nanosystem were constructed through electrostatic adsorption of Bi2S3 nanoparticles on the surface of PLNPs and following encapsulation with biocompatible polystyrene sodium sulfonate(PSS).Compared with PLNP-GNR composite nanosystem(37%),PLNP-Bi2S3composite nanosystem exhibit higher photothermal conversion efficiency(44%)and can successfully realize precision afterglow imaging,real-time temperature monitoring and PTT of deep-tissue under the condition of meeting the maximum permissible laser irradiation(MPE)of 635 nm.More importantly,PLNP-Bi2S3 composite nanosystem can maintain good stability and dispersion in the long blood circulation process.When the composite nanosystem reach the tumor sites,it can be rapidly aggregation in the tumor sites through acid-induced deposition and the improved precise targeted diagnostic and therapeutic efficiencies of cancer can be acquired.