UT Southwestern Medical Centre chemists have successfully used synthetic nanoparticles to deliver tumour-suppressing therapies to diseased livers with cancer, an important hurdle scientists have been struggling to surmount.
Since late-stage liver cancer is a major challenge for therapeutic intervention, drugs that show promise in healthy functioning livers can cause devastating toxicity in cirrhotic livers with cancer, the researchers said.
Scientists at the centre developed synthetic 'dendrimer' nanoparticles that are able to provide the tumour-suppressing effect without further damaging the liver or neighbouring tissue. The findings appear in the journal, Proceedings of the National Academy of Sciences.
'We found that efficacy required a combination of a small RNA drug that can suppress cancer growth and the carrier, thereby solving a critical issue in treating aggressive liver cancer and providing a guide for future drug development,' said Daniel Siegwart, Assistant Professor of Biochemistry and with the Harold C. Simmons Comprehensive Cancer Centre.
UTSW scientists chemically synthesised more than 1,500 different types of nanoparticles
Primary liver cancer, a chronic consequence of liver disease, is a leading cause of cancer death and a major global health problem. Each year in the US, about 20,000 men and 8,000 women get liver cancer, and the five-year survival rate is only 17%, according to the US Centres for Disease Control and Prevention.
Critical to understanding this problem, and developing the new therapy, was a collaboration between Siegwart and Hao Zhu, Assistant Professor at the Children’s Medical Centre Research Institute at UT Southwestern, and a practicing oncologist.
The recent failure of five Phase III human clinical trials of small-molecule drugs to treat hepatocellular carcinoma (HCC) – the most common form of liver cancer – prompted the authors to develop non-toxic carriers and explore miRNA therapies (short nucleic acids that can function as natural tumour suppressors as a promising alternative). miRNAs require delivery strategies to transport these large, anionic drugs into cells. To date, no existing carrier has been able to provide effective delivery to late-stage liver cancer without amplified toxicity, which negates the desired effect.
To address this problem, UTSW scientists chemically synthesised more than 1,500 different types of nanoparticles, which allowed discovery of lead compounds that could function in the heavily compromised cancerous liver. Synthetic, man-made nanoscale compounds called dendrimers provided an opportunity to screen different combinations of chemical groups, physical properties, and molecular size, Siegwart said. This approach led to the identification of dendrimers to deliver miRNA to late-stage liver tumours with low liver toxicity.
The study, conducted in genetic mouse models with a highly aggressive form of liver cancer, demonstrated that the miRNA nanoparticles inhibited tumour growth and dramatically extended survival.