Abstract 1443: Dual effect of novel polyethyleneglycol modified liposome on antitumor activity and liver metastasis
Authors: Sugiyama Ikumi , Sadzuka Yasuyuki 
Published: February 2011

Abstract
[Purpose] We synthesized polyethyleneglycol-lipid with different double arms (DDA-PEG) as the novel modification material on liposomal membrane, and reported that doxorubicin (DOX) contained DDA-PEG modified liposome (DDA-LDOX) had superior properties (cytotoxicity and DOX uptake into tumor cells). On the other hand, it was suggested that fixed aqueous layer thickness (FALT) around the liposomal membrane was concerned with long circulation in blood or antitumor effect. In 100th AACR meeting (2009), we reported the connection with the FALT and the biological factor (amount of DOX uptake / IC50 of cell cytotoxicity) in vitro. In this study, DDA-LDOX had been studied the antitumor activity on primary tumor in vivo. Moreover, another activity of DDA-LDOX was examined against liver metastasis as the risk factor in cancer therapy.
[Methods] Liposome (DSPC/cholesterol/DSPG/PEG/DOX = 100:100:60:15:18 μmol) was prepared according to the method of Bangham. PEG2000 modified liposome and PEG2000/PEG500 modified liposome was expressed as Single-LDOX and Mixed-LDOX, respectively. Zeta potentials of liposomes were measured by the change of NaCl concentration in buffer and FALT was calculated. In the study of antitumor activity to primary tumor, M5076 ovarian sarcoma cells were transplanted into the backs of mice, and each liposomes were injected intravenously at a dose of 2.5 mg/kg on 19th, 22nd and 25th day after tumor inoculation. The mice were sacrificed after 48 hr from last administration, and the tumor was removed and weighed. In the study of anti-metastasis activity, M5076 ovarian sarcoma cells were inoculated in tail vein of mice. These mice were injected various liposomes at a dose of 2.5 mg/kg (i.v.) on 6th, 9th and 12th day after tumor inoculation. After 48 hr from last administration, the liver was removed and weighed, and score of liver metastasis was recorded (0-5 stage, 0: non-metastasis). [Results and discussion] In the result of antitumor activity, the tumor weight after Single-LDOX treatment was reduced to 65.5% of control level (1.13±0.45 g). In contrast, after DDA-LDOX treatment, it was reduced to 36.4% of control level. In anti-metastasis activity, the score of hepatic metastasis was DOX sol &gt; plain-LDOX &gt; Single-LDOX = DDA-LDOX. The inhibitory effect on liver metastasis by Single-LDOX and DDA-LDOX were obviously. The metastasis score correlated with the liver weight, namely, inhibition of metastasis by DDA-LDOX was supported from liver weight. DOX concentration in the liver was plain-LDOX &gt; Single-LDOX = DDA-LDOX &gt; DOX sol. Thus, we speculated that weak effect of plain-LDOX was caused by DOX accumulation into hepatic normal cell. In this study, the character of Single-LDOX was similar to DOXIL®, namely, it was suggested that DDA-LDOX increase the therapeutic efficacy, compared with DOXIL®. In conclusion, we expected that DDA-LDOX had the dual effect on antitumor activity and liver metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1443.