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Anticancer activity of the conjugates:  modified fibrinogen – methotrexate.

Tomasz M. Goszczyński 1Dmitry Nevozhay 2Joanna Wietrzyk 1Janusz Boratyński 1,3

1. Polish Academy of Sciences, Institute of Immunology and Experimental Therapy (IITD), Rudolfa Weigla 12, Wrocław 53-114, Poland
2. The University of Texas M D Anderson Cancer Center, Holcombe Boulevard 1515, Houston, TX 77030, United States
3. Jan Dlugosz Academy, Al. Armii Krajowej 13/15, Częstochowa 42-201, Poland


The majority of currently used anticancer drugs belong to the low molecular weight compounds. These medications demonstrate a range of disadvantages, such as fast metabolism and excretion from an organism, as well as adverse biodistribution and a low selectivity of therapeutic use. Solving these problems involves the binding process of drugs with macromolecular carriers. Such structures were designed with the aim to enhance delivery and to improve the selectivity and pharmacological properties of both conventional  and innovative drugs.

In our laboratory antifoliates conjugated with carriers such as dextrans, albumin, fibrinogen and glycated proteins, were examined. Particularly promising investigations pertained  the use of fibrinogen as a  carrier of methotrexate (MTX). Many  prerequisites such as accumulation in tumors  determined  this type of protein to be selected. Fibrinogen-MTX conjugates were characterized by considerably higher anticancer efficacy in comparison to free drug. One of the proposed mechanisms regarding this phenomenon assumes retention of fibrinogen/fibrin and its conjugates in peritoneum of animals with ascites tumors. It also shows a gradual enzymatic  degradation connected to the drug release.  

In this paper we show examination of anticancer properties of the MTX-fibrinogen subjected to limited hydrolysis conjugates in vivo and previously described generation of these conjugates with native fibrinogen. Leukemia mouse model P388  was used in this study, the cancer cells were engrafed intraperitoneally.  High anticancer efficacy of the examined conjugate was observed by prolonging  mice lifespan  at 145% in comparison to lifespan of the control  mice. Accordingly free methotrexate prolonged the lifespan of mice at 36% in comparison to the control mice.  Toxicity  in the dosage pattern of the preparation used was not observed. Data described above emerges a therapeutic potential in drug binding with macromolecular carriers, as well as the potential use of the derived fibrinogen in this system.

This project was supported by National Science Centre, Poland (N N302 098434)


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Related papers

Presentation: Poster at VIII Multidyscyplinarna Konferencja Nauki o Leku, by Tomasz M. Goszczyński
See On-line Journal of VIII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2012-03-15 13:49
Revised:   2012-03-16 07:49