Date: 12th February 2021
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and the 5 year survival prognosis is unfortunately poor. Despite intense efforts, current therapies have not greatly altered survival rates although, it has now been established that liver transplants offer favourable and even curable outcomes. However, availability of liver transplants is limited and therefore there is an urgent need for alternative treatments to be identified especially for those that can halt disease progression whilst a suitable organ can be found. Now, scientists have developed a novel ionic liquid which functions as a drug carrier and can induce local tumour ablation in the liver.
In clinical practice, every effort is made to maintain HCC patients within the transplant criteria until a liver becomes available. If possible HCC lesion resections are performed, however cirrhosis and other comorbidities may hinder this approach. An alternative is percutaneous locoregional therapies (LRTs), such as such as thermal ablation, which are used as a bridge to transplantation. However, the location, size and existence of multiple lesions may preclude the use of LRT, and the proximity of adjacent tissues to the tumour may also limit this strategy.
Now, scientists from the Mayo Clinic and Harvard University, US, led by Rahmi Oklu and Samir Mitragotri have developed an ionic liquid–ablative agent that was locally injected under image guidance, delivering uniformly distributed chemotherapy drugs which ablated tumours in rat and rabbit livers, and in human liver tumour tissue samples ex vivo.
The team hypothesised that an ionic liquid could offer a means to induce local tumour ablation, the ionic composition could alter the local osmotic conditions – ablating tumour cells, and enhance diffusion through the tissue. Additional, it could act as a targeted delivery system for chemotherapy drugs thereby, circumventing systemic toxicity.
They started by preparing the novel ionic liquid–based composition, called Locally-active Agent for Tumour Treatment and Eradication (LATTE), and mixed it with fluorescent dye. To assess the distribution, LATTE was delivered into the livers of healthy mice. The diffusion capability was measured by various imaging technologies. The ionic liquid mixture spread rapidly within the liver in a concentration-dependent manner and remained visible at 24 hours without breaching the liver.
Whilst these results were encouraging the real test would be whether LATTE could inhibit or ablate tumour growth. So it was injected intratumourally into immunocompetent rat livers bearing a highly malignant HCC cell line tumour. At 2 weeks post treatment the LATTE-tumours were significantly smaller than in the control group, the smaller tumours had enhanced fluorescence which also extended beyond the tumour margins. The tumours showed complete necrosis, and were infiltrated with a variety of immune cells.
Next the team wanted to assess LATTE in combination with a chemotherapy drug, doxorubicin (Dox). The two were mixed and again injected into rats’ livers bearing HCC tumours. Dox was retained in the livers for up to 28 days, which is important to prevent tumour reoccurrence. There was a well-demarcated area of tissue necrosis a few days after treatment, which subsequently underwent remodelling.
The team also went on to show that LATTE facilitated internalisation of Dox and synergistically enhanced cytotoxicity in a human HCC cell lines, and was also functional in other types of cancer cells lines, such as pancreatic carcinoma.
Finally, the team wanted to test the system in preclinical models so they injected the LATTE-Dox mixture into a rabbit VX2 tumour model and into 12 human resected tumours. Here, they once again saw consistent tumour ablation and uniform distribution within the tumour ablation zone. The feasibility of LATTE was also demonstrated in a large animal model supporting its translation into humans.
The work here has demonstrated that the novel ionic liquid agent, LATTE, designed for the percutaneous ablation of solid tumours, produced a uniform, reproducible tumour ablation in rat, rabbit and pig livers in vivo. Furthermore, experiments in cell culture indicated synergistic effects with chemotherapy drugs, such as Dox, which enhanced its ablation capabilities, and targetted delivery of these therapeutics.
The team are planning on focusing their future investigations into the functional mechanism that LATTE has on the cell, in particular how it induces cancer cell death. They will also examine the delivery of other drugs such as protein-based anticancer therapies. As LATTE was also functional in a variety of cancer cell types, it will interesting to evaluate its efficacy against tumours in other organs.
Whilst, LATTE alone efficiently ablated tissue, its effectiveness as drug carrier was also demonstrated. The team envisage it could be used as a drug carrier solvent or even within nanoparticles to deliver chemotherapy or other therapeutics. The use of nanoparticles for treating disease is expanding at an incredible rate, whether it is for the treatment of osteoarthritis, traumatic brain disease, genetic disease in utero, or cancer, the ability to enhance the persistence of drugs within a specific (ablation) zone period for an extended would be hugely beneficial for many therapeutics.
For more information please see the press release from the Mayo Clinic
Albadawi, H., Z. Zhang, I. Altun, J. Hu, L. Jamal, K. N. Ibsen, E. E. L. Tanner, S. Mitragotri and R. Oklu (2021). “Percutaneous liquid ablation agent for tumor treatment and drug delivery.” Science Translational Medicine 13(580): eabe3889.