Ultrasound-enhanced drug dispersion through solid tumours and its possible role in aiding ultrasound-targeted cancer chemotherapy
Introduction
Many cancer treatment modalities based on the use of chemotherapeutic drugs are relatively non-selective in terms of targeting the relevant tissues and this can lead to normal tissue dysfunction which, in turn, results in adverse side effects. This can occur as a result of conventional systemic administration of the therapeutic agent and saturation of normal tissues with that cytotoxic agent. It can also occur however as a result of inefficient uptake of the therapeutic agent by target tumour tissues. The latter usually results from the very atypical nature of the tumour vascular architecture and defective lymphatic drainage which in turn lead to the development of phenomena such as high interstitial fluid pressure in the tumour tissues [1], [2], [3]. Since the action of cancer chemotherapeutic drugs requires direct contact between the drug and target cell, such phenomena necessitate the use of increased therapeutic concentrations and this further exacerbates problems relating to non-specific toxicity. One suggested manner of addressing such a challenge has been to develop formulations of cancer chemotherapeutic agents that facilitate retention of the active agent within tumours and this has led to the development of formulations based on the use of liposome-based vehicles [3]. Such approaches however, still involve conventional systemic administration in order to establish a concentration gradient to force accumulation of the active agent into the target tumour tissues and challenges associated with the fate of excess drug remain.
Alternative strategies have involved the design of site-specific or targeted therapeutic regimes that strive to deliver the therapeutic agent specifically to the tumour. Some have reported the exploitation of isolated organ or target site perfusion with the chemotherapeutic agent [4], [5] whilst others have sought to exploit molecular targeting in the design of ‘homing’ vehicles that involve systemic administration but also facilitate specific accumulation at the relevant target tumour [6]. Other suggested strategies involve the use of physical stimuli to facilitate disruption of a drug-containing vehicles at the tumour site, thereby facilitating accumulation of that drug at the target site to which the stimulus has been directed [7]. In yet another approach involving the direction of an external stimulus to a target site in order to render that site more susceptible to a cancer chemotherapeutic drug, others have demonstrated enhanced drug toxicity during or following exposure of a tumour site to externally-applied ultrasound [8], [9]. In many of the studies relating to ultrasound-enhanced chemopotentiation, it has been suggested that ultrasound enhances cell membrane penetration by the relevant drug and such a suggestion is very well supported, at least for studies relating to the use of isolated cell populations in vitro[10], [11], [12]. Indeed, in the past, we have demonstrated that ultrasound could be employed to enhance the uptake of camptothecin by isolated tumour cells, thereby significantly reducing the LD50 of the drug in the presence of the stimulus in vitro[13]. The uptake of fluorogenic markers confirmed our suggestion that ultrasound-mediated transient cell membrane permeabilisation of the target cell population was responsible for the enhanced cytotoxicity of the overall treatment. In a more recent study in our laboratories, we demonstrated that electric fields could be exploited in order to facilitate the dispersion of a cancer chemotherapeutic drug through the relatively impermeable tissues of a solid tumour model [14]. It these studies it was confirmed, following surgical removal of treated tumours together with image analysis, that the drug was electrokinetically dispersed throughout the tumour tissues following exposure to the electric field and we suggested that this might play a beneficial role, particularly in the treatment of rather impermeable tumour tissues. In continuing our studies relating to the use of ultrasound to potentiate the cytotoxicity of cancer chemotherapeutic drugs in a site-specific manner, and cognisant of the outcomes from our previous studies with electric fields, we decided to extend our ultrasound-based studies to an in vivo pre-clinical tumour model. Here we report on those studies and we further report on the effectiveness of ultrasound in facilitating enhanced dispersion of the chemotherapeutic drug throughout the solid tumour model. We suggest that ultrasound-mediated chemopotentiation may not be solely due to a membrane permeabilising event, but may be supported by enhanced dispersion of the chemotherapeutic agent throughout the target tissues.
Section snippets
Cell culture and establishing tumours
In this study, the syngenic RIF-1 (radiation-induced fibrosarcoma) tumour model was employed in C3H/HeN (8 week-old) mice as a target for therapy. Cells were cultured in RPMI 1640 medium supplemented with glutamine (Gibco, UK) and 10% (v/v) foetal bovine serum. Cells that had been grown to 90% confluence were harvested by centrifugation after treatment with trypsin–EDTA solution. Following harvesting and washing in phosphate-buffered saline, 0.1 ml aliquots containing 1 × 106 cells were injected
Ultrasound-enhanced tumoricidal activity of camptothecin
The suggestion that ultrasound may be used to potentiate the cytotoxicity of cancer chemotherapeutics is not a new one and it has been indicated that such an approach could provide therapeutic benefit by achieving a degree of targeting of the therapeutic effect and by reducing the overall chemotherapeutic load [8], [9], [15], [16]. Although more recent publications are concerned with the use of ultrasound contrast agents to enhance transient ultrasound-mediated cell membrane permeabilisation to
Conflicts of interest
None declared.
Acknowledgements
Dr. Nomikou and Dr. Li wish to gratefully acknowledge receipt of partial funding for this work from the Vice Chancellors Research Scholarship Scheme at the University of Ulster. The authors gratefully acknowledge the assistance of Mr. P. O’Corragain and his colleagues at Sonidel Ltd, Ireland.
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Present address: School of Health Sciences, Department of Pharmacy, University of Patras, 26510, Greece.