Ultrasound-enhanced drug dispersion through solid tumours and its possible role in aiding ultrasound-targeted cancer chemotherapy.

It has been demonstrated that inadequate dispersion of cancer chemotherapeutic drugs throughout the tissues of larger, relatively poorly vascularised tumours compromises the therapeutic effectiveness of such drugs. Recently we demonstrated that electric fields could be exploited to achieve dispersion of a cancer chemotherapeutic drug through relatively impermeable tissues of a poorly vascularised solid tumour model. Using a modified Sonidel SP100 sonoporator we demonstrate that ultrasound may enhance the toxicity of a cancer chemotherapeutic drug by dispersing the drug through relatively impermeable tissues of a non-vascularised tumour model in vivo. We suggest that such a phenomenon may play a significant role in ultrasound targeting of cancer chemotherapeutic drugs, particularly in the treatment of solid tumours.

Optimising ultrasound-mediated gene transfer (sonoporation) in vitro and prolonged expression of a transgene in vivo: potential applications for gene therapy of cancer.

Therapeutic approaches using gene-based medicines promise alternatives or adjuncts to conventional cancer treatment. Because of its non-invasive nature, ultrasound, as a membrane-permeabilising stimulus has the potential to be highly competitive with viral gene delivery and existing non-viral alternatives. In optimising ultrasound-mediated, microbubble-assisted (MB101) gene tranfection in vitro, we demonstrate efficiencies of up to 18% using ultrasound at 1 MHz at a duty cycle of 25% at intensities ranging from 1 to 4 W cm(-2). Using ultrasound-mediated transfection together with an episomal plasmid-based gene expression system, we demonstrate prolonged functional gene expression of luciferase in mouse hind leg muscle and in tumours in vivo.

Enhancing ultrasound-mediated cell membrane permeabilisation (sonoporation) using a high frequency pulse regime and implications for ultrasound-aided cancer chemotherapy.

Delivering ultrasound to HeLa cells at 1MHz using a high frequency pulse regime (40kHz) and at a maximum energy density of 270Jcm(-2) resulted in significant cell membrane permeabilisation. Using FITC-dextran as a fluorogenic marker, optimally up to 64% of treated populations were permeabilised with cell viability remaining above 80%. Although cell membrane permeabilisation was observed in the presence of the microbubble-based ultrasound contrast agent, SonoVue, cell viability was severely compromised. Using the high frequency pulse regime in the absence of microbubbles, the LD50 of the cancer chemotherapeutic agent, camptothecin, was reduced from 58 to 18nM.