Thermal combination therapies for local drug delivery by magnetic resonance-guided high-intensity focused ultrasound

Abstract

Several thermal-therapy strategies such as thermal ablation, hyperthermia-triggered drug delivery from temperature-sensitive liposomes (TSLs), and combinations of the above were investigated in a rhabdomyosarcoma rat tumor model ( = 113). Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) was used as a noninvasive heating device with precise temperature control for image-guided drug delivery. For the latter, TSLs were prepared, coencapsulating doxorubicin (dox) and [Gd(HPDO3A)(HO)], and injected in tumor-bearing rats before MR-HIFU treatment. Four treatment groups were defined: hyperthermia, ablation, hyperthermia followed by ablation, or no HIFU. The intratumoral TSL and dox distribution were analyzed by single-photon emission computed tomography (SPECT)/computed tomography (CT), autoradiography, and fluorescence microscopy. Dox biodistribution was quantified and compared with that of nonliposomal dox. Finally, the treatment efficacy of all heating strategies plus additional control groups (saline, free dox, and Caelyx) was assessed by tumor growth measurements. All HIFU heating strategies combined with TSLs resulted in cellular uptake of dox deep into the interstitial space and a significant increase of tumor drug concentrations compared with a treatment with free dox. Ablation after TSL injection showed [Gd(HPDO3A)(HO)] and dox release along the tumor rim, mirroring the TSL distribution pattern. Hyperthermia either as standalone treatment or before ablation ensured homogeneous TSL, [Gd(HPDO3A)(HO)], and dox delivery across the tumor. The combination of hyperthermia-triggered drug delivery followed by ablation showed the best therapeutic outcome compared with all other treatment groups due to direct induction of thermal necrosis in the tumor core and efficient drug delivery to the tumor rim.

Image-guided thermosensitive liposomes for focused ultrasound drug delivery: Using NIRF-labelled lipids and topotecan to visualise the effects of hyperthermia in tumours

“…In recent studies using doxorubicin TSLs, FUS ablation was suggested as a new strategy to be combined with drug delivery systems (thermosensitive or not) [31,69]. Both presented studies show an impressive efficacy of this method of FUS treatments (ablation / hyperthermia) in combination with thermosensitive liposomes.…”

“…followed by ablation showed the best therapeutic outcome compared with other treatments. This appeared to be due to direct induction of thermal necrosis in the tumour core and efficient drug delivery to the surrounding rim [31].…”

Thermosensitive Nanosystems Associated with Hyperthermia for Cancer Treatment

“…thermosensitive liposome infusion during MRI-HIFU light hyperthermia reduced tumor growth compared to tumors treated with liposome without hyperthermia [108]. Hijnen et al, also investigated the use of MRI-HIFU with the intravascular release of DOX encapsulated in TSLs in a preclinical setting using a rhabdomyosarcoma mouse tumor model [109]. All HIFU heating strategies combined with TSL resulted in increased DOX cell uptake in the interstitial space and a significant increase in drug concentrations in the tumor compared to a free DOX treatment [109].…”

High-intensity focused ultrasound enhances the cisplatin sensitivity to human non-small cell lung cancer in vitro and in vivo

“…Recently, HIFU has been widely used in benign and malignant tumors such as uterine broids, breast cancer, liver cancer, pancreatic cancer, bone tumors, and kidney cancer [11]. Previous studies have suggested that magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) has the great potential for localized heat-mediated drug delivery of temperature-sensitive liposomes (TSL), which affects drug uptake and distribution [12].…”