Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model

Tatsuaki Tagami; Amr S Abu Lila; Mariko Matsunaga; Naoto Moriyoshi; Hiroyuki Nakamura; Kazuya Nakamura; Takuya Suzuki; Yusuke Doi; Tatsuhiro Ishida; Hiroshi Kiwada

doi:10.1007/s13346-012-0059-1

Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model

Drug Deliv Transl Res. 2012 Apr;2(2):77-86. doi: 10.1007/s13346-012-0059-1.

Authors

Tatsuaki Tagami¹, Amr S Abu Lila, Mariko Matsunaga, Naoto Moriyoshi, Hiroyuki Nakamura, Kazuya Nakamura, Takuya Suzuki, Yusuke Doi, Tatsuhiro Ishida, Hiroshi Kiwada

Affiliation

¹ Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima, 770-8505, Japan.

PMID: 25786716
DOI: 10.1007/s13346-012-0059-1

Abstract

Efficient systemic siRNA delivery to cells in the target tissue is a current critical challenge in the drug delivery field. Several studies have demonstrated that nanoparticles such as polyethylene glycol (PEG)-coated siRNA-lipoplexes may enhance the systemic delivery of siRNA to tumor. However, the disordered tumor microenvironment still poses a potential impediment with respect to the efficient delivery of PEG-coated siRNA-lipoplexes. Recently, we showed that metronomic S-1 dosing (daily oral administration) enhanced the accumulation of PEG-coated siBcl-2-lipoplex in DLD-1 solid tumor mouse model. In this study, to extend our work, we investigated the effect of metronomic S-1 dosing on the intratumoral accumulation and, thereby, therapeutic efficacy of PEG-coated siAgo2-lipoplex in Lewis lung carcinoma cells (LLCC) solid tumor mouse model. Also, we tried to elucidate the probable mechanism of the enhanced intratumoral accumulation of PEG-coated siRNA-lipoplexes induced by S-1 combination therapy. Results showed that metronomic S-1 dosing improved systemic delivery of intravenously injected PEG-coated siAgo2-lipoplexes into a LLCC solid tumor. In addition, the combined therapy of S-1 and PEG-coated siRNA-lipoplexes resulted in potent tumor growth suppression. These findings offer proof-of-concept for the improved systemic delivery of PEG-coated siRNA-lipoplexes by metronomic S-1 dosing in whatever tumor model used, and this may pose a promising therapeutic strategy to conquer cancer progression.