The antileukemic activity of modified fibrinogen–methotrexate conjugate

• Published in: Biochimica et biophysica acta Vol. 1830; no. 3; pp. 2526 - 2530
• Main Authors: Goszczyński, Tomasz, Nevozhay, Dmitry, Wietrzyk, Joanna, Omar, Mohamed Salah, Boratyński, Janusz
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2013
• Subjects: Animals; Antileukemic activity; Antimetabolites, Antineoplastic - pharmacology; antineoplastic agents; aqueous solutions; bioactive properties; Cattle; Cell Survival - drug effects; drug carriers; Drug Carriers - pharmacology; educational institutions; Fibrinogen; Fibrinogen - analogs & derivatives; Fibrinogen - chemistry; Fibrinogen - pharmacology; hydrolysis; in vivo studies; leukemia; Leukemia P388 - drug therapy; Leukemia P388 - mortality; Leukemia P388 - pathology; Male; Methotrexate; Methotrexate - analogs & derivatives; Methotrexate - pharmacology; Mice; pharmaceutical industry; physicochemical properties; Protein–drug conjugate; Survival Analysis; Tumor Cells, Cultured; Protein–drug conjugate; Antileukemic activity; Methotrexate; Fibrinogen
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.11.005

The search for new, innovative methods to treat all types of diseases, especially cancer-related ones, is a challenge taken by pharmaceutical companies and academic institutions. The use of conjugates containing widely-known and widely-used bioactive substances is one of the ways to solve this problem. Research into drug binding with macromolecular carrier systems has joined the search for new therapeutic strategies. The main goal of this paper is the potential offered by the use of fibrinogen derivatives as an antileukemic drug carrier. Physicochemical properties of the obtained conjugate were analyzed, characterizing alterations in relation to the starting carrier and analyzing biological implications. The intraperitoneally (i.p.) inoculated P388 mouse leukemia model for in vivo studies was used. Conjugates consisting of a fibrinogen derivative with a covalently bound anticancer drug were developed. Carrier preparation and a conjugate synthesis in aqueous solution were formulated, as well as purification of the conjugate was performed. The study showed that the survival of leukemia mice treated with FH–MTX conjugate was indeed significantly longer than survival in both untreated animals (control) and mice treated with unbound MTX. A significant increase in the antileukemic activity of MTX conjugated with hydrolysed fibrinogen was observed as compared with the unconjugated drug. Reported data suggest that hydrolysed fibrinogen can serve as a carrier molecule for the MTX drug with the aim of enhancing its antileukemic activity. Conjugates consisting of a fibrinogen derivative with a covalently bound anticancer drug seem to be a promising anticancer drug. ► Covalent conjugation of methotrexate with fibrinogen was performed. ► Conjugate is more active against leukemia in the in vivo model vs free drug. ► Partial hydrolysis of fibrinogen provides a promising anti-cancer drug carrier.