The Synthesis,characterization Of Polytypic Bismuth Telluride Nanoplates And Their Metabolism,Tumor Radiosensitization Mechanisms In Vivo

Bismuth(⁸³Bi)is the least toxic metal element and is well-tolerated by the human body.High dosages of Bi³⁺-based Helidac are frequently prescribed for patients suffering from various gastrointestinal disorders,indicating its in vivo biosafety.The unique band structure of two-dimensional Bi-based nanomaterials has natural advantages in the generation of non-oxygen dependent free radicals,providing attracted extensive attention and research in photoresponsive tumor therapy.Bismuth telluride（Bi₂Te₃）is an available thermoelectric material with the lowest band gap among binary bismuth chalcogenides,revealing a broad application in photocatalysis.Unfortunately,its size and morphology related to a radio-catalysis property have rarely been explored.The preparation of Bi₂Te₃ with high safety and catalytic activity by a simple strategy is the primary problem to be solved in the biomedical applications.In addition,the in vivo metabolic mechanism of Bi-based nanomaterials is still unclear in biomedicine for nearly ten years,which is impeding clinical application.In this study,an ethylenediaminetetraacetic acid（EDTA）-assisted hydrothermal strategy was introduced to synthesize polytypic Bi₂Te₃ nanoplates（BT NPs）that exhibit crystalline and size-dependent radio-sensitization and metabolism characteristics in vivo.The following specific researches have been carried out:1.By simply varying the molar ratio of EDTA/Bi³⁺,BT NPs with different morphologies,sizes,crystallines and thickness（named polytypic）were obtained.With an increase in the molar ratio of EDTA/Bi³⁺,the surface energy decreased so that the BT NPs grew along the out-of-plane direction,resulting in an increase in thickness.EDTA acting as chelating agent and“capping”agent contributed to the homogeneous growth of BT NPs by eliminating dangling bonds and reducing the surface energy of different facets.The size,morphology,and surface properties of the BT NPs could also be controlled by the hydrothermal temperature,concentrations of the reducing agent,and alkaline environment.We demonstrated that the EDTA-assisted strategy can be successfully used as templates in the synthesis of metal chalcogenides having different morphologies,sizes,and thicknesses.2.The types of ROS generated by polytypic BT NPs under X-ray irradiation are related to their crystalline and size.The effective separation of electron-hole（e^--h⁺）pairs and long diffusion lengths are beneficial for improving the radio-catalytic performance of higher-crystallinity and smaller-sized BT NPs.The Auger annihilation process of photoexcited carriers,were lower in the higher-crystallinity and smaller-sized BT NPs when irradiated with X-rays,demonstrating that BT NPs transfer energy efficiently to adjacent carriers.Unexpectedly,the lower-crystallinity and larger-sized irradiated BT NPs generated holes that preferentially facilitated the conversion of OH^-to·OH.The X-ray preferentially imparts its energy to higher-crystallinity and smaller-sized BT NPs.After this,electrons were excited to a higher energy level and emitted energy as photons,thus accelerating molecular oxygen（³O₂）to ¹O₂conversion.3.Molecular mechanism of polytypic BT NPs and X-ray synergy in killing cancer cells are depend on the types of ROS.Polytypic BT NPs enhances the radiosensitivity of tumor cells to X-rays but not toxic to a variety of tested normal cells,demonstrating the responsiveness to tumor microenvironments.After being endocytosed by tumor cells,BT NPs with lower crystalline and larger size enhanced tumor radiosensitivity by generating O₂^-·and·OH to an arrested cell cycle in the radiosensitive G2/M phase.The caspase-mediated apoptotic pathway was triggered by ¹O₂ generated from the synergistic effects of higher crystallinity and smaller-sized BT NPs combined with X-rays.These events amplified the ROS-mediated apoptosis pathway and eventually led to irreversible DNA damage.4.Crystalline and size-dependent metabolic mechanism and synergistically enhances the radio-sensitization efficacy of the BT NPs in vivo.A metabolomic analysis revealed that lower-crystallinity and larger-sized BT NPs were oxidized into Bi（O_x）in the liver via a citrate cycle pathway,whereas higher-crystallinity and smaller-sized BT NPs accumulated in the kidney and were excreted in urine in the form of Bi²⁺and Te^2-by regulating the metabolism of glutamate.In a cervical cancer model,higher-crystallinity and smaller-sized BT NPs are more promising for photoacoustic（PA）and computed tomography（CT）imaging due to their remarkable enhanced permeability and retention effect（EPR）effect,which is vital for synergistically enhanced radio-therapeutic effects in vivo.Under X-ray irradiation,higher-crystallinity and smaller-sized BT NPs generated a higher yield of ROS,increased cell apoptosis with nuclear pyknosis,reduced tumor angiogenesis.Blood routine,inflammatory factors,hematological and histological examination of major organs in combined therapy mice also exhibited no significant chronic pathological toxicity,which once again confirmed their biosafety.Consequently,this study provides not only a prospect for the development of BT NPs as an efficient radio-sensitizer to address the clinical need for cancer radio-resistant therapy but also a universal strategy to synthesize metal chalcogenides for use as radio-catalysts.