Abstract 5700: Preparation and evaluation of glycosylated paclitaxel loaded in tastuzumab-immunoliposome

Targeted drug delivery is considered to enhance the therapeutic effects of anti-cancer agents because high amount could be administered with least side effects. However, water-insoluble hydrophobic chemical compounds such as paclitaxel are not suitable for efficient drug delivery. We conferred water-solubility of paclitaxel by coupling glucose at 7-OH to produce 7-alpha-glucosyloxyacetylpaclitaxel (7-GLG-PT). Although the 7-GLG-PT showed lower cytotoxicity than paclitaxel, encapsulation of 7-GLG-PT into liposomes was more efficient than that of paclitaxel. In our experiment, paclitaxel encapsulated liposomes was not detectable. Trastuzumab was then conjugated on the surface of 7-GLG-PT liposomes to prepare immunoliposome (GLG-PT-IL). The GLG-PT-IL exhibited cytotoxicity on SK-BR-3 cells overexpressing HER2. The IC50 values of paclitaxel, 7-GLG-PT, 7-GLG-PT liposome and GLG-PT-IL were 6, 126, 130 and 94 nM, respectively. From this evaluation, the concentration of each formula to suppress the cell growth completely was estimated around 30 to 300 nM. At these concentrations, the time required for each formula to suppress the growth at the half maximal level was evaluated. GLG-PT-IL showed the shortest time of 5 hours, which was one third of the others when compared with paclitaxel, 7-GLG-PT and 7-GLG-PT liposome. The specific targeting potential of the immunoliposome on SK-BR-3 cells was assessed. The accumulation on the cell surface was competitively inhibited by the excess amount of free tastuzumab. The endocytosis of the immunoliposomes was simultaneously confirmed by time-lapse imaging. Thus GLG-PT-IL has been successfully demonstrated to target the HER2-overexpressing cancer cells specifically suppressing their growth. Trastumab itself is considered to induce the antibody dependent cellular cytotoxicity, so that the endocytosis of HER2 may not be always necessary. However, HER2-mediated endocytosis was induced by the immunoliposomes while single trastuzumab did not show the endocytosis in SK-BR-3 cells. In this context together with the results demonstrated in this study, the 7-GLG-PT immunoliposome should be a promising candidate of highly efficient drug delivery system of cancer treatment targeting HER2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5700.