Bone targeted new zoledronate derivative: design, synthesis, ^99mTc-coupling, in-silico study and preclinical evaluation for promising osteosarcoma therapy

Abstract

Background: Zoledronate suppresses human sarcomas by blocking the formation of geranylgeranyl diphosphate (GGPP) via inhibiting GGPP synthase.

Objectives: Designing of new derivative of dronic acid (1-hydroxy-2-(4-nitro-1H-imidazol-1-yl)ethan-1,1-diyl)bis phosphonic acid), structurally related to zoledronate to be used for osteosarcoma therapy.

Methods: 1-hydroxy-2-(4-nitro-1H-imidazol-1-yl)ethan-1,1-diyl)bis(phosphonic acid) was synthesized in one pot reaction with a yield of 65 ± 4%. The synthesized nitro-zoledronate compound was successfully radiolabeled with ^99mTc with a radiochemical purity of 92.05%. Docking accuracy and scoring reliability for the new nitro-zoledronate with human GGPPS using MOE software has been presented.

Results and Conclusion: The nitro-zoledronate successfully coupled with technetium-99m at high yield to investigate its in-vivo biodistribution which indicated highly selective uptake in the skeletal system and rapid clearance from soft tissues. The in-vitro cytotoxicity of the nitro-zoledronate was evaluated and potently inhibited the osteosarcoma cell line (MG-63) after 72 hours with an IC50 value of 10 μM. To summarize, our data point to a promising candidate to improve osteosarcoma therapy.

Graphical Abstract

Keywords:

• Zoledronate
• 4-nitroimidazole
• osteosarcoma
• technetium-99m
• GGPPS

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Notes on contributors

Hend Fayez

Hend Fayez, PhD, Assistant Professor of Radio-pharmaceutics, Hot Labs center, Egyptian Atomic Energy Authority, Cairo, Egypt. Interested in development of radiopharmaceutical compounds for diagnostic and therapeutic application

Adli Abdallah Selim

Adli A. Selim, PhD, Researcher at the Egyptian Atomic Energy Authority in the area of development of radiolabeled biomolecules and targeted radiopharmaceuticals for theranostics applications. An operator on I-131 production hot cell at Radioisotope Production Facility- Egyptian Research Nuclear Reactor complex, Egyptian Atomic Energy Authority, Cairo, Egypt.