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Tantalum-Zirconium Co-Doped Metal-Organic Frameworks Sequentially Sensitize Radio-Radiodynamic-Immunotherapy for Metastatic Osteosarcoma.

ABSTRACT: Due to radiation resistance and the immunosuppressive microenvironment of metastatic osteosarcoma, novel radiosensitizers that can sensitize radiotherapy (RT) and antitumor immunity synchronously urgently needed. Here, the authors developed a nanoscale metal-organic framework (MOF, named TZM) by co-doping high-atomic elements Ta and Zr as metal nodes and porphyrinic molecules (tetrakis(4-carboxyphenyl)porphyrin (TCPP)) as a photosensitizing ligand. Given the 3D arrays of ultra-small heavy metals, porous TZM serves as an efficient attenuator absorbing X-ray energy and sensitizing hydroxyl radical generation for RT. Ta-Zr co-doping narrowed the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gap and exhibited close energy levels between the singlet and triplet photoexcited states, facilitating TZM transfer energy to the photosensitizer TCPP to sensitize singlet oxygen (¹ O₂ ) generation for radiodynamic therapy (RDT). The sensitized RT-RDT effects of TZM elicit a robust antitumor immune response by inducing immunogenic cell death, promoting dendritic cell maturation, and upregulating programmed cell death protein 1 (PD-L1) expression via the cGAS-STING pathway. Furthermore, a combination of TZM, X-ray, and anti-PD-L1 treatments amplify antitumor immunotherapy and efficiently arrest osteosarcoma growth and metastasis. These results indicate that TZM is a promising radiosensitizer for the synergistic RT and immunotherapy of metastatic osteosarcoma.

SUBMITTER: Li T

PROVIDER: S-EPMC10074130 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Tantalum-Zirconium Co-Doped Metal-Organic Frameworks Sequentially Sensitize Radio-Radiodynamic-Immunotherapy for Metastatic Osteosarcoma.

Li Tao T Gao Mingquan M Wu Zifei Z Yang Junjun J Mo Banghui B Yu Songtao S Gong Xiaoyuan X Liu Jing J Wang Weidong W Luo Shenglin S Li Rong R

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230205 10

Due to radiation resistance and the immunosuppressive microenvironment of metastatic osteosarcoma, novel radiosensitizers that can sensitize radiotherapy (RT) and antitumor immunity synchronously urgently needed. Here, the authors developed a nanoscale metal-organic framework (MOF, named TZM) by co-doping high-atomic elements Ta and Zr as metal nodes and porphyrinic molecules (tetrakis(4-carboxyphenyl)porphyrin (TCPP)) as a photosensitizing ligand. Given the 3D arrays of ultra-small heavy metals ...[more]

PMID: 36739599

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Project description:In a reaction of tantalocene trihydride with the low valent aryl tin cation [Ar*Sn(C6H6)][Al(OC{CF3}3)4] (1a) the hydridostannylene complex [Cp2TaH2-Sn(H)Ar*][Al(OC{CF3}3)4] (2) was synthesized. Hydride bridged adducts [Cp2WH2EAr*][Al(OC{CF3}3)4] (E = Sn 3a, Pb 3b) were isolated as products of the reaction between Cp2WH2 and cations [Ar*E(C6H6)][Al(OC{CF3}3)4] (E = Sn 1a, Pb 1b). The tin adduct 3a exhibits a proton migration to give the hydridostannylene complex [Cp2W(H)[double bond, length as m-dash]Sn(H)Ar*][Al(OC{CF3}3)4] 4a. The cationic complex 4a is deprotonated at the tin atom in reaction with base MeNHC at 80 °C to give a hydrido-tungstenostannylene [Cp2W(H)SnAr*] 5a. Reprotonation of metallostannylene 5a with acid [H(Et2O)2][BArF] provides an alternative route to hydridotetrylene coordination. Complex 4a adds hydride to give the dihydrostannyl complex [Cp2W(H)-SnH2Ar*] (7). With styrene 4a shows formation of a hydrostannylation product [Cp2W(H)[double bond, length as m-dash]Sn(CH2CH2Ph)Ar*][Al(OC{CF3}3)4] (8). The lead adduct 3b was deprotonated with MeNHC to give plumbylene 5b [Cp2W(H)PbAr*]. Protonation of 5b with [H(Et2O)2][Al(OC{CF3}3)4] at -40 °C followed by low temperature NMR spectroscopy indicates a hydridoplumbylene intermediate [Cp2W(H)[double bond, length as m-dash]Pb(H)Ar*]+ (4b). Hydrido-tungstenotetrylenes of elements Ge (5c), Sn (5a) and Pb (5b) were also synthesized reacting the salt [Cp2W(H)Li]4 with organotetrylene halides. The metallogermylene [Cp2W(H)GeAr*] (5c) shows an isomerization via 1,2-H-migration to give the hydridogermylene [Cp2W[double bond, length as m-dash]Ge(H)Ar*] (9), which is accelerated by addition of AIBN. 9 is at rt photochemically transferred back to 5c under light of a mercury vapor lamp. Zirconocene dihydride [Cp2ZrH2]2 reacts with tin cation 1a to give the trinuclear hydridostannylene adduct 10 [({Cp2Zr}2{μ-H})(μ-H)2μ-Sn(H)Ar*][Al(OC{CF3}3)4]. Deprotonation of 10 was carried out using benzyl potassium to give neutral [({Cp2Zr}2{μ-H})(μ-H)μ-Sn(H)Ar*] (11). 11 was also obtained from the reaction of low valent tin hydride [Ar*SnH]2 with two equivalents of [Cp2ZrH2]2. The trihydride Ar*SnH3 reacts with half of an equivalent of [Cp2ZrH2]2 under evolution of hydrogen and formation of a dihydrostannyl complex 13 [Cp2Zr(μ-H)SnH2Ar*]2 and with further equivalents of Ar*SnH3 to give bis(hydridostannylene) complex [Cp2Zr{Sn(H)Ar*}2].

Dataset Information

Tantalum-Zirconium Co-Doped Metal-Organic Frameworks Sequentially Sensitize Radio-Radiodynamic-Immunotherapy for Metastatic Osteosarcoma.

Publications

Tantalum-Zirconium Co-Doped Metal-Organic Frameworks Sequentially Sensitize Radio-Radiodynamic-Immunotherapy for Metastatic Osteosarcoma.

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