Abstract 3907: Enhanced chemotherapeutic effect with matrix metalloproteinase sensitive liposomes

Abstract

Abstract Introduction: Drug bioavailability following intra-tumoral accumulation is a major challenge in existing drug delivery systems. A site-specific trigger for obtaining drug release specifically in tumor tissue would overcome this problem and enhance the antitumor effect of the carried drug. Our aim was to develop a new drug delivery platform based on liposomes that are sensitive to matrix metalloproteinases (MMPs). Methods: In the present work, we have designed a matrix metalloproteinase (MMP)-sensitive liposomal drug delivery system encapsulating oxaliplatin, which by tumor-specific enzymatic dePEGylation allows for controlling the precision of drug release. The dePEGylation is provided by a cholesterol-anchored PEGylated lipopeptide containing a short peptide sequence cleavable by MMP-2 and MMP-9. These MMP-sensitive liposomes are designed to make a charge-reversal transformation upon encountering MMPs in the tumor environment. The surface charge of the liposome turns from slightly negative to positive, resulting in cationic liposomes. In vitro cellular uptake of the liposomes was assessed using flow cytometry and ICP-MS, and further confirmed by confocal microscopy in CT26 and HT1080 cell lines. In vivo studies was evaluated in a syngeneic murine model of MMP-positive CT26 colon cancer. Results: We successfully formulated MMP-sensitive, oxaliplatin encapsulated liposomes and characterized their zeta potential, size, stability and encapsulation efficiency. The results showed uniformly dispersed particles, and the charge-reversal properties were confirmed as the surface charge changed from slightly negative to distinct positive upon enzymatic cleavage generating cationic liposomes. These MMP-sensitive liposomes were evaluated in vitro and in vivo with a high correlation. In vivo studies showed a prolonged circulation profile with minimal leakage, and similar accumulation in tumors as conventional Stealth liposomes. Efficacy experiment in the same model demonstrated significantly improved antitumor activity relative to free oxaliplatin, and with a superior effect compared to the conventional Stealth liposomes. Conclusion: With this study, we establish a promising liposomal drug delivery platform for the carriage and release of numerous anticancer drugs into the microenvironment of an MMP-positive tumor. Citation Format: Rikke Y. Brogaard, Rasmus Eliasen, Fredrik Melander, Anders E. Hansen, Andreas Kjær, Thomas Lars Andresen. Enhanced chemotherapeutic effect with matrix metalloproteinase sensitive liposomes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3907.