1. ¹Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan
2. ²CREST, Japan Science and Technology Agency, Japan
3. ³Tsukuba Research Center for Interdisciplinary Material Science (TIMS), University of Tsukuba, Tsukuba, Ibaraki, Japan
4. ⁴Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama, Japan
5. ⁵Daiichi Pharmaceutical Co., Ltd. Edogawa-ku, Tokyo, Japan

Correspondence: Dr H Harashima, Laboratory for Molecular Design of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Sapporo city, Hokkaido, 060-0812, Japan. E-mail: harasima@pharm.hokudai.ac.jp

Received 20 December 2005; Revised 30 May 2006; Accepted 28 June 2006; Published online 17 August 2006.

Abstract

For successful cancer gene therapy via intravenous (i.v.) administration, it is essential to optimize the stability of carriers in the systemic circulation and the cellular association after the accumulation of the carrier in tumor tissue. However, a dilemma exists regarding the use of poly(ethylene glycol) (PEG), which is useful for conferring stability in the systemic circulation, but is undesirable for the cellular uptake and the following processes. We report the development of a PEG-peptide-lipid ternary conjugate (PEG-Peptide-DOPE conjugate (PPD)). In this strategy, the PEG is removed from the carriers via cleavage by a matrix metalloproteinase (MMP), which is specifically expressed in tumor tissues. An in vitro study revealed that the PPD-modified gene carrier (Multifunctional Envelope-type Nano Device: MEND) exhibited pDNA expression activity that was dependent on the MMP expression level in the host cells. In vivo studies further revealed that the PPD was potent in stabilizing MEND in the systemic circulation and facilitating tumor accumulation. Moreover, the i.v. administration of PPD or PEG/PPD dually-modified MEND resulted in the stimulation of pDNA expression in tumor tissue, as compared with a conventional PEG-modified MEND. Thus, MEND modified with PPD is a promising device, which has the potential to make in vivo cancer gene therapy achievable.