Enhanced Cytotoxicity of Monoclonal Anticancer Antibody 2C5-Modified Doxorubicin-Loaded PEGylated Liposomes against Various Tumor Cell Lines

摘要

Doxorubicin-loaded long-circulating liposomes (Doxil^™, ALZA Corp.) were additionally modified with the nucleosome-specific monoclonal antibody 2C5 (mAb 2C5) recognizing a broad variety of tumor cells via the tumor cell surface-bound nucleosomes. These mAb 2C5-modified PEGylated liposomes demonstrated 3-to-8-fold increase in the in vitro binding and internalization by multiple cancer cell lines of diverse origins (murine LLC, 4T1, C26 & human BT-20, MCF-7 and PC3), as shown by flow cytometry and epi and confocal microscopy. As a result, mAb 2C5-modified Doxil^™ demonstrated significantly higher cytotoxicity towards various cancer cells, including those resistant to doxorubicin, than all control preparations. The specific internalization of the mAb 2C5-Doxil^™ into cytosol, along with the nuclear localization of their drug load, inside the target cancer cells were mainly responsible the superior anticancer activity. The IC50 values of mAb 2C5-Doxil^™ with various murine and human cancer cells were 5-to-8-fold lower than those of control doxorubicin-loaded liposomes, Doxil^™ or Doxil^™ modified with a non-specific IgG.