Abstract 1961: Evaluated mechanism of dual targeting using liposomal doxorubicin-modified novel PEG by imaging analysis

Abstract

Abstract [Purpose] Liposome is one of the useful drug carriers and it may be applying to a lot of diseases from now on. One of the most reasons which liposomes were using as medicine was improvement of circulation time in bloodstream by modifying polyethyleneglycol (PEG)-lipid. We synthesized novel PEG-lipid with two different PEG lengths of 2000 and 500 (different double arms-PEG; DDA-PEG) for developing more superior passive targeting liposome. In our previous study, doxorubicin (DOX) containing liposome which was modified DDA-PEG (DDA-PEG modified liposomal DOX; DDA-LDOX) had dual effect for primary and hepatic metastasis cancer. In this study, we observed tissue distribution at primary tumor using the near infrared fluorescence and analyzed hepatic metastasis by histological observation for explain this dual effect. Moreover, this effect for pulmonary metastasis was also evaluated. [Methods] Liposome (DSPC/cholesterol/DSPG-Na/DDA-PEG = 100:100:60:7.5 μmol) was prepared according to the method of Bangham. For observing tissue distribution of liposome at primary tumor model, liposome was contained indocyanine green (ICG) as fluorescence probe. This liposome was injected in tail vein and sequentially observed using fluorescent imaging device (Clairvivo OPT, SHIMADZU). In histological observation at hepatic metastasis murine model, M5076 ovarian sarcoma cells were inoculated in tail vein of mice. These mice were injected liposome at a dose of 2.5 mg/kg (i.v.) as DOX on 6, 9 and 12 d after tumor inoculation. At 14 d, this liver was removed and examined by microscope after HE stain. At assessment of pulmonary metastasis, B16F10 melanoma cells were implanted in tail vein and treated similarly to liver metastasis.[Results and discussion] In fluorescent imaging of primary tumor, DDA-PEG modified liposome assembled into tumor at 48 h after injection. This analysis supported our previous finding that DDA-LDOX significantly decreased tumor size. Furthermore, it was proved that DDA-PEG modified liposome or encapsulated drug remained in tumor site for a long time. In histological examination for hepatic metastasis, the tumor area in the liver was 5% by DDA-LDOX injection (normal group: 90%). More lymphocytes around tumor thrombus were positive for CD45. It was suggested that macrophage or lymphocytes, especially T cell, were concerned in this therapy. Pulmonary metastasis was depressed by DDA-LDOX compared with control or DOX containing PEG unmodified liposome group. In DDA-LDOX group, DOX concentration in lung was 2.6 times higher than that in PEG unmodified liposome group. It is known that metastasis is the most severe factor in cancer chemotherapy. Antitumor agent containing DDA-PEG modified liposome may have not only superior effect for primary tumor but also hepatic or pulmonary metastasis. Hence, it was suggested that DDA-PEG modified liposome was useful drug carrier for passive targeting. 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 1961. doi:1538-7445.AM2012-1961