The Development Of A Novel Drug On The Basis Of Conjugates Of Cytokines With Bisphosphonates For The Treatment Of Bone Metastases | 58936
Journal of Biotechnology & Biomaterials
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The interest to tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) as drug agents for the treatment of bone
metastases is explained by antitumor properties of these proteins as well as by their ability to regulate the remodeling
processes in bone tissue. Bisphosphonates characterized by the ability to accumulate in bone tissue and to regulate the activity
of osteoclasts/osteoblasts can be used as vector molecules for the targeted delivery of cytokines into the bone. The purpose of
this study was to develop the method for synthesizing the conjugates of TNFα and IFNγ with bisphosphonate alendronic acid
(ALN) and to explore their antitumor activity. The conjugates of TNFα or IFNγ with ALN were obtained by the synthesis on
a solid media using 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride. The method involving the fixation of
active components on a solid phase yielded conjugates of high degree homogeneity (up to 95.7%) and a stoichiometry close to
1:1. The output of conjugates in the synthesis reaction was 90±3%. In an experimental model of bone metastases of melanoma
B16-F10, induced in C57Bl/6 mice by intracardiac administration was showed that the conjugates of TNFα-ALN and IFNγ-
ALN had the ability to trigger necrotic changes in the tumor tissue, covering 40-90% and 30-100% of the metastasis area,
respectively. The administration of TNFα-ALN conjugates reduced melanoma lesions of epiphyseal and diaphyseal bone tissue
of the femur. These findings confirm the prospects of further development of a novel drug based on the conjugates of cytokines
for the treatment of bone metastases.
Elena Dmitriyevna Danilenko was graduated from Novosibirsk State University and defended her dissertation for PhD in 2006. She is currently the Director of the Institute of Medical Biotechnology, the branch of the State Research Center of Virology and Biotechnology "Vector". She is the author of more than 50 articles in refereed journals and 4 patents.