Abstract 5529: The advanced strategy for novel EGCG derivative modified liposome with high targeting ability to tumor
Authors: Sugiyama Ikumi , Kaihatsu Kunihiro , Kato Nobuo , Sadzuka Yasuyuki 
Published: August 2015

Purpose: The aim of this study is increase of antitumor effect and decrease of adverse effect by liposomes which have high affinity with 67 kDa laminin receptor (67LR). It was reported that 67LR is expression specifically on tumor cell membrane. When (-)-epigallocatechin-3-gallate (EGCG) as one of the green tea polyphenol are connected with 67LR, apoptosis is induced on tumor cells. On the other hand, liposome is often used for cancer chemotherapy. Then we have studied about EGCG modified liposome containing antitumor agent as drug delivery system. In this study, important strategies are 3 points. The first point is targets to 67LR on tumor cell by EGCG modification around liposomal membrane. The second point is to induce apoptosis mediated by 67LR. Last point is to increase antitumor effect by antitumor agent loaded into liposome. Based on these strategies, EGCG modified liposome was evaluated in vivo distribution.

Methods: Three derivatives were synthesized for EGCG modification on liposomal membrane. The liposome with each EGCG derivative were prepared and assessed by measuring particle sizes and zeta potentials. EGCG was only modified liposome (EL) and both EGCG and polyethyleneglycol (PEG) were modified liposome (EPL). On P388 leukemia cells, cytotoxicity was evaluated by WST-8 assay and shown IC50. In the distribution study, C57BL/6 mice were injected (i.v.) each liposome, and collected blood and removed organs with definite time after injection.

Results and Discussion: Synthesized EGCG derivatives with di-palmitoyl base were inserted directly into liposomal membrane. Two structures of other derivatives obtained PEG or is able to connect with PEG. In all liposomes, the particle sizes were from 100 to 200 nm and zeta potentials were negative charge. The cytotoxicity of EL was stronger than EGCG unmodified liposome. Moreover, 50% inhibitory concentration of EPL was smaller than EL, namely the cytotoxicity of EPL was strong. It was suggested that this effect was mediated with 67LR needed gallate base in the structure of EGCG because EPL showed strong effect compared with EL. The EGCG derivative in EL had di-palmitoyl base at gallate base, and its bind was not free. In mice experiment, EL rapidly disappeared from the blood circulation after injection. This concentration was one sixteenth of common PEG modified liposome at 15 min after injection. On the other hand, accumulation levels into liver and spleen as reticuloendothelial system (RES) reached high level immediately after injection. This phenomenon indicated that disappearance of EL depends on RES trap. EPL which had EGCG-PEG was significantly improved blood circulating time. In conclusion, it was expected that EGCG-PEG modified liposome (EPL) maintains long circulation time in blood, and increases targeted ability to tumor cells and antitumor activity.

Citation Format: Ikumi Sugiyama, Kunihiro Kaihatsu, Nobuo Kato, Yasuyuki Sadzuka. The advanced strategy for novel EGCG derivative modified liposome with high targeting ability to tumor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5529. doi:10.1158/1538-7445.AM2015-5529