Synthetic Nanoparticles That can Deliver Tumor Suppressors to Damaged Livers

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 United States, about 20,000 men and 8,000 women get liver cancer, and the 5-year survival rate is only 17%, according to the Centers for Disease Control and Prevention. The percentage of Americans who get liver cancer has been rising slowly for several decades, with higher rates in Asians and in Hispanic and African-American men. 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. UT Southwestern Medical Center chemists have successfully used synthetic nanoparticles to deliver tumor-suppressing therapies to diseased livers with cancer, an important hurdle scientists have been struggling to conquer.

UT Southwestern scientists crafted synthetic 'dendrimer' nanoparticles that are able to provide the tumor-suppressing effect without further damaging the liver or neighboring tissue. The findings appear in the Proceedings of the National Academy of Sciences.

Dr. Daniel Siegwart, Assistant Professor of Biochemistry and with the Harold C. Simmons Comprehensive Cancer Center, said, "We have synthesized highly effective dendrimer carriers that can deliver drugs to tumor cells without adverse side effects, even when the cancerous liver is consumed by the disease. 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."

Dr. Hao Zhu, Assistant Professor at the Children's Medical Center Research Institute at UT Southwestern, and a practicing oncologist, said, "Early-stage disease can be cured with surgery, but there are few options for cirrhotic patients with advanced liver cancers."

The recent failure of five phase III human clinical trials of small-molecule drugs to treat hepatocellular carcinoma - the most common form of liver cancer - prompted the authors to develop non-toxic carriers and explore 'miRNA' therapies as a promising alternative. MicroRNAs (miRNAs) are short nucleic acids that can function as natural tumor suppressors, but 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 synthesized 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," Dr. Siegwart said. This approach led to the identification of dendrimers to deliver miRNA to late-stage liver tumors with low liver toxicity.

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The study, conducted in genetic mouse models with a highly aggressive form of liver cancer, demonstrated that the miRNA nanoparticles inhibited tumor growth and dramatically extended survival.

Source-Eurekalert