Enhanced drug delivery in rabbit VX2 tumours using thermosensitive liposomes and MRI-controlled focused ultrasound hyperthermia

Abstract

Purpose: The efficacy of anticancer drugs in solid tumours is impaired by their inability to reach all cancer cells in sufficient concentration to cause cytotoxicity. Hyperthermia-triggered release of drugs from thermosensitive liposomes can increase tumour drug concentration, but tumour-specific drug delivery requires precise temperature control, and effects on microregional distribution of anticancer drugs in tumours are unknown. Here we evaluate thermally triggered release of doxorubicin in a rabbit tumour model by comparing free versus thermosensitive liposomal doxorubicin administered systemically during magnetic resonance imaging (MRI)-controlled focused ultrasound hyperthermia.

Materials and methods: Twelve rabbits with a transplanted VX2 tumour in each thigh had a 10 mm diameter region in one tumour heated to 43°C using focused ultrasound with temperature control by MRI thermometry. Delivery of doxorubicin to tumours and normal tissues was quantified by fluorescence in tissue homogenates, and by fluorescence microscopy.

Results: Using thermosensitive liposomal doxorubicin (2.5 mg/kg), doxorubicin concentrations in heated tumours were 26.7 times higher than in unheated tumours (n = 7, p = 0.017, two-sided Wilcoxon signed-rank test). There was no significant enhancement with free doxorubicin in heated versus unheated tumours (n = 3, p = 0.5). With thermosensitive liposomes (8.3 mg/kg), fluorescence microscopy demonstrated increased doxorubicin fluorescence in heated versus unheated tumours, co-localised with nuclear staining throughout the tumour.

Conclusions: Localised image-guided delivery of high concentrations of doxorubicin to cancer cells was achieved non-invasively in implanted tumours with temperature-sensitive drug carriers and a preclinical MRI-controlled focused ultrasound hyperthermia system.

• heat targeted drug delivery
• image-guided therapy
• focused ultrasound
• non-invasive thermometry
• magnetic resonance imaging