Medical and Health Sciences

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Browsing Medical and Health Sciences by Author "Ansam Sous"

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    SYNTHESIS OF DOXORUBICIN-URSODEOXYCHOLIC ACID CONJUGATES FOR TARGETED LIVER CANCER THERAPY
    (2023-09-05) Ansam Sous
    Abstract Liver cancer is a highly aggressive disease with high mortality rates. Doxorubicin has been utilized to treat hepatocellular carcinoma due to its broad-spectrum anticancer effect. However, due to the potential of cardiotoxicity and the development of multidrug resistance, it is typically dose-limited in therapeutic use, limiting its long-term usefulness. Ursodeoxycholic acid is a hydrophilic bile acid that binds to the bile acid receptors with higher affinity than any other type of bile acids. The primary objective of this project is to develop a UDCA-DOX conjugate and evaluate its targeting capabilities in vitro to specifically deliver DOX to HCC cells. With these objectives, we aim to exploit the affinity of UDCA for HCC cell lines to minimize DOX toxicity on normal cells, while maintaining enough cytotoxicity against liver cancer cells. UDCA-DOX conjugate was synthesized with an acid-labile linkage, then, its characteristics and release profile were studied by the HPLC. After that, the cytotoxicity of this conjugate was investigated by the MTS test in vitro in HepG2 ,Hep3B hepatic cancer cell lines, LX-2 cells the normal hepatic cells, and the none hepatic cells 3T3. The targeted cellular uptake of UDCA specifically by hepatic cancer cells was studied by fluorescence microscopy. UDCA-DOX can spontaneously hydrolyze in acidic media. This conjugate showed significant cytotoxicity in hepatic cancer cell lines (HepG2 and, Hep3B). The successful delivery of DOX into the cancerous cells was confirmed by fluorescence microscopy. However, the cytotoxicity of UDCA-DOX was limited in non-cancerous cell lines (LX-2 and 3T3), suggesting that the delivery of UDCA-DOX into the cells is dependent on specific features in the hepatic cancer cells. Moreover, the observed cytotoxicity of UDCA-DOX was less than that of free DOX, suggesting that the drug reached the cell via a rate-limited process, which endorses the hypothesis that the internalization of UDCA-DOX could be through bile acid receptor-mediated endocytosis. This study demonstrated valuable insights into the potential of UDCA-DOX as a targeted therapeutic strategy for HCC to reduce the adverse effects associated with DOX therapy. Further investigations are required to test the in vivo efficacy and safety of this conjugate. Keywords: Hepatocellular Carcinoma; Ursodeoxycholic acid; Doxorubicin; Cancer targeting; Acid-labile Linkage; Fluorescence.