1. [An antitumor osteotropic agent based on tumor necrosis factor].
- Author
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Lebedev LR, Danilenko ED, Telegina YV, and Zaitsev BN
- Subjects
- Animals, Antineoplastic Agents chemistry, Bone Neoplasms, Cell Line, Cell Survival drug effects, Durapatite chemistry, Fibroblasts cytology, Fibroblasts drug effects, Humans, Mice, Molecular Structure, Molecular Targeted Therapy, Nanoparticles ultrastructure, Particle Size, Tumor Necrosis Factor-alpha chemistry, Alendronate chemistry, Antineoplastic Agents pharmacology, DNA chemistry, Dextrans chemistry, Nanoparticles chemistry, Tumor Necrosis Factor-alpha pharmacology
- Abstract
A novel drug for treatment of bone metastases based on human recombinant tumor necrosis factor (TNF-alpha) has been designed. The drug is a molecular structure containing yeast double-stranded ribonucleic acid (dsRNA) covered by the conjugate of polyanion dextran with TNF-alpha and bisphosphonate, alendronic acid. The structure is characterized by the combination of substances possessing antitumor activity (TNF-alpha, dsRNA) and a vector molecule (bisphosphonate) providing tropism to hydroxyapatite, the main mineral component of the bone tissue matrix. The conjugation conditions were optimized and the conjugates of TNF-alpha and alendronic acid with dextran were synthesized. Molecular structures were obtained by self-assembly, and the resulting complexes were separated by gel filtration on Sepharose CL-6B. The electrophoretic analysis method revealed decreased mobility of dsRNA in the complex with the conjugate as compared to the mobility of the original dsRNA. This confirms formation of the designed structures. Transmission electron microscopy confirmed the presence of particles with sizes of 30-40 nm in the drug. Evaluation by the sorption/desorption method showed a higher affinity of TNF-alpha conjugates to hydroxyapatite as compared to the original TNF-alpha molecules (from 1.0 to 1.8 mol/L vs. 0.3 mol/L of potassium phosphate buffer for desorption, respectively).
- Published
- 2015
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