MRI GUIDED DOXORUBICIN RELEASE FROM LIPOSOMES BY NON-FOCUSED ULTRASOUND IN MICE BEARING TUMORS

CUTRIN JC; RIZZITELLI S.; GIUSTETTO P; MENCHISE V.; DELLI CASTELLI D; BOFFA C; RUZZA M; OTERO-LOSADA M.; AIME S.; TERRENO E.

Torino

Congreso; European Molecular Imaging Meeting EMIM 2013; 2013

European Society for Molecular Imaging

Doxorubicin (Dox) has been used for treating cancer for over 30 years. While providing a cure in select cases, Dox causes toxicity to most organs. Over the years, many studies have been conducted to devise a drug delivery system that would eliminate these adverse effects, including liposomes. However, despite the excellent clinical success of the formulation, the ability of liposomes to diffuse freely in the tumour is still debated. For this reason, it is important to find alternative strategies able to increase the dose released into the cancer. Accordingly, we have explored the use of Non Focused Ultrasound (NFUS) to induce a local drug release from liposomes. MRI has been selected to offer an imaging support to visualise the release process as well as to provide a very accurate tool to follow the therapeutic outcome. Methods Stealth liposomes mimicking Doxyl® formulation was prepared encapsulatingi Dox and Gadoteridol (Gad) in them. The liposomes were injected in the tail vein of Balb/C mice grafted with a syngenic TSA-cancer cells in order to obtain 5mg/kg of Dox and 0.1 mmol/kg of Gad when the tumour reached 40-60 mm3. Subcutaneous tumour was exposed to a single shot of NFSU (duty cycle pilot modulation) after the liposomal injection to maximise the local release of the drug and its diffusion in the tumour mass. The mice received a single dose of Dox (5 mg/kg) per week for three weeks and the ?US-group? was insonated after each injection. Mice were monitored by MRI over the three weeks and T1 and T2 contrast was measured in tumour, kidneys, liver, spleen and bladder. Furthermore, MRI was also used to monitor the tumour growth. The US device used was a 3 MHz probe. Tumours and organs were removed at different time-points and analysed by histology and immunohistochemistry in order to evaluate the specific form of cell death, namely Bcl-2/Bax apoptosis pathway and necrosis induced by ROS over production, as well as to localise the diffusion of the released material in the tumour. Results Tumours exposed to NFUS showed a good T1 contrast due to release of Gad from liposomes. It is to stand out that the NFUS-induced release led to significant cell death index and delay tumour growth over the time course of observation. Conclusions The application of NFU can induce a mechanical non-heat mediated release from liposomal carriers containing a chemoterapic drug. MRI is an optimal technique to visualise and quantify the release process and this method opens new opportunities to develop innovative MRI-guided theranostic protocols for tumour pathologies decreasing drug doses and collateral adverse effects.