Abstract 5398: Nanoparticles for image guided focused ultrasound drug delivery

Abstract

Abstract Thermally triggered, PEGylated drug- liposomes are currently in clinical trials. Conventional thermosensitive liposomes (TSLs) lack the labels that would allow tumor imaging upon intravenous injection and a better mark for tissue specific applied hyperthermia (image guidance). We suggest dual- labelled thermosensitive liposomes for focused ultrasound (FUS) induced hyperthermia, triggered-release and functional delivery of the therapeutic anti-cancer drugs to xenograft tumors in response to thermal stimuli in vivo. In addition to labeling for MR Imaging we introduce the use of near infrared (NIR) fluorophores that allow for real time imaging of nanoparticle behavior in the absence of any significant intrinsic tissue background fluorescence, with good to excellent transmission and reduced scattering throughout tissues. We have synthesized these labels as lipid-probe conjugates and using these labels and thermosensitive lipids we have prepared TSL nanoparticles. N`-XenoLight750-N,N-distearylamidomethylamine (XLA750.DSA) and Gadolinium(III) 2-{4,7-Bis-carboxymethyl-10-[(N,N-distearylamidomethyl-N′-amidomethyl]-1,4,7,10-tetraazacyclododec-1-yl}acetic Acid (Gd.DOTA.DSA) were synthesized and characterized. Both lipids were used to prepare TSL nanoparticles carrying the anticancer drugs at substantial encapsulation efficiency. Nanoparticles were tested for their biophysical characteristics (thermal drug release, stability in plasma, size) in vitro. MRI contrast enhancement ability and Near-IR signal were tested in vitro and in vivo. Nanoparticles carrying drugs were injected intravenously in mice bearing tumors. Nanoparticle kinetics in tumors were assessed with optical imaging and at defined time intervals (post injection), FUS (TIPS Phillips: 1.4MHz) was applied for 3-5 min to induce a small increase in temperature from 37°C to 41°C. Optical imaging revealed both substantial nanoparticle accumulation and drug release immediately after and only in tumors treated with focused ultrasound induced (focal) hyperthermia. Tumors treated with both nanoparticles and FUS post injection showed substantial growth inhibition compared to tumors treated with nanoparticles only. The applications of these multifunctional nanoparticles with short and mild hyperthermia could have a transformative effect on cancer chemotherapy. Citation Format: Maya Thanou, Michael Wright, Miguel Centelles. Nanoparticles for image guided focused ultrasound drug delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5398. doi:10.1158/1538-7445.AM2014-5398