Preliminary Results of Combining Low Frequency Low Intensity Ultrasound and Liposomal Drug Delivery to Treat Tumors in Rats

Abstract

Ultrasound is a convenient trigger for site-specific drug delivery in cancer therapy. Nano-sized liposomes formulated from soy phosphatidyl choline, cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] and alpha-tocopherol were loaded with Doxorubicin (Dox) using a pH gradient. The liposomal suspension was infused through the tail vein of BDIX rats possessing bilateral intradermal DHD/K12 tumors on their hind legs. Then 20-kHz ultrasound was applied to only one of the tumors for 15 minutes. This therapy was repeated weekly for 4 weeks. The results showed that in five of six rats, the tumors regressed to non-measurable size within 4 weeks. A paired comparison of the normalized size of the insonated and non-insonated tumors in the same rat indicated that the insonated tumors were smaller (p < 0.0001, n = 6 rats, 21 pairs). This observation has significant potential for non-invasive site-specific therapy of solid tumors.

Release of a Paramagnetic Magnetic Resonance Imaging Agent from Liposomes Triggered by Low Intensity Non-Focused Ultrasound

“…15 On the other hand, the lower release efficiency observed for cholesterol-containing liposomes and for polymersomes (which are exclusively made of amphiphilic di-block copolymers), it is likely the consequence of the higher stiffness of the resulting bilayers. Several publications correlated sonosensitivity with vesicles formulation, [37][38][39] but the different insonation setup, as well as some controversial results, makes difficult to find a general rationale.…”

“…To assess the role of the size of the encapsulated agent, the release of a paramagnetic agent bigger than Gadoteridol (the dimeric Gd-1 complex reported in Chart 1) 15 was investigated. The release of Gd-1 from DSPC/DSPE-PEG2000 liposomes was completely comparable with that one observed for Gadoteridol either at t ON 100 ms or at t ON at 250 ms (data not shown), thereby indicating that, at least for the agents here considered, the size of the encapsulated chemical does not influence the release properties.…”

Ultrasound Improves the Uptake and Distribution of Liposomal Doxorubicin in Prostate Cancer Xenografts

“…US, in combination with microbubbles, is reported to increase the permeability of blood vessels (Lin et al 2010) and cell membranes (Deckers et al 2008) and the release of drugs from carrier systems (Afadzi et al 2012;Husseini and Pitt 2008b;Kost and Langer 2001;Rapoport et al 2003;Suzuki et al 2008). Several in vivo studies have found that the combination of encapsulated cytotoxic drugs and therapeutic US delays tumor growth (Hagtvet et al 2011;Myhr and Moan 2006;Pitt et al 2011;Schroeder et al 2009a) and increases tumor concentrations of the cytotoxic drugs (Staples et al 2010) compared with non-insonated controls.…”

Low-frequency low-intensity ultrasound with contrast agent for the treatment of subcutaneous tumors in mice

“…Numerous studies have been conducted to investigate the targeted treatment using low-frequency ultrasound to date (Wu and Nyborg, 2008;Pitt et al, 2011;Reuter et al, 2010). The application of therapeutic ultrasound in combination with contrast agent is a new concept and has elicited interest in various medical fields (Postema and Gilja, 2011; Burke and Price, 2010).…”