Nanoparticle targets primary tumours and brain metastases

Scientists at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have developed a nanoparticle that can penetrate the blood-brain barrier (BBB) to kill primary breast cancer tumours and brain metastases in one treatment.

Brain metastases most commonly arise from solid tumours like breast, lung and colon cancer. They are often associated with a poor prognosis, as when cancer breaches the brain it can be challenging for treatment to follow, partly due to the BBB, a near-impenetrable membrane separating the brain from the rest of the body.

Dr Shanta Dhar, associate professor of Biochemistry and Molecular Biology and assistant director of Technology and Innovation at Sylvester, led the study. According to her, the team’s nanoparticle could be used to treat the metastases with the added benefit of treating the primary tumour at the same time.

The nanoparticle is made of a biodegradable polymer, previously developed by Dhar’s team, paired with two drugs that target mitochondria that were also developed in her lab. Compared to healthy cells, cancer cells often have a different form of metabolism, so suppressing their metabolism can be an effective way to kill tumours without harming other tissues. One of the drugs used is a modified version of a classic chemotherapy drug, cisplatin, which kills cancer cells by damaging their DNA. However, tumour cells can repair their DNA, sometimes leading to cisplatin resistance.

The team modified the drug to shift its target from nuclear DNA to mitochondrial DNA. Mitochondria contain their own, much smaller genomes. Notably, for cancer therapeutic purposes, they do not have the same DNA-repair machinery that our larger genomes do. They combined their modified cisplatin, named Platin-M which attacks the process of oxidative phosphorylation, with another drug they developed, Mito-DCA, that specifically targets a kinase, and inhibits glycolysis.

Dr Dhar stated that it was a long route to develop a nanoparticle that can access the brain. Having studied nanoparticles for her whole independent career, in a previous project she studied different forms of polymers and noticed that a fraction of some of these nanoparticles reached the brain in preclinical studies. Therefore, the team further honed the polymers to develop a nanoparticle that can cross the BBB and the outer membrane of mitochondria. “There have been a lot of ups and downs to figuring this out, and we’re still working to understand the mechanism by which these particles cross the blood-brain barrier,” Dr Dhar commented.

The specialised drug-loaded nanoparticle was then tested in preclinical studies. The scientists found that they work to shrink both breast tumours and breast cancer cells that were seeded in the brain to form tumours there. The nanoparticle-drug combination appeared to be nontoxic and significantly extended survival in lab studies.

Moving forwards, the team aim to test their method in the lab to replicate human brain metastases more closely, potentially using patient-derived cancer cells. Also, they want to test the drug in laboratory models of glioblastoma.

This study was published in Proceedings of the National Academy of Science.