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Injectable nanoparticles deliver cancer therapy in mice

Accumulation of pDox nanoparticles, highlighted by green arrow, in lung metastatic tumors from a treated mouse. Xu et al., Nature Biotechnology

Many drugs for treating cancer work by slowing or stopping the growth of cancerous cells. However, there are numerous barriers that can hinder a drug’s ability to work successfully. A drug needs to reach and get inside cancerous cells—whether they’re in the liver, breast, or lung. The drug must also avoid damaging healthy, non-cancerous tissues—such as the heart and kidneys—to prevent side effects.

A team led by Drs. Mauro Ferrari and Haifa Shen at Houston Methodist Research Institute has been working to overcome the many hurdles to successful cancer treatment by harnessing nanotechnology to deliver drugs directly into cancerous cells. The group set out to develop and test an injectable carrier of nanoparticles that contain a chemotherapy drug. The work was funded in part by NIH’s National Cancer Institute. Results were published on March 14, 2016, in Nature Biotechnology.

The scientists turned to doxorubicin (dox), a drug used to treat many cancer types. They attached dox to string-like molecules, known as poly(L-glutamic acid), through a pH-sensitive link. This formed a drug complex called pDox. The team made disk-shaped, micrometer-sized silicon particles to serve as a carrier for the pDox. The pDox was loaded into the particles through nanometer-sized pores.

Scanning electron micrograph of an empty silicon disk-shaped microparticle (2.5 μm in diameter × 700 nm thick).Xu et al., Nature Biotechnology

When the researchers injected pDox-containing silicon particles intravenously into mice with cancerous tumors, the particles traveled through the blood stream and accumulated at the site of tumors, where blood vessels are leakier. The silicon, which was designed to degrade, released pDox molecules at the tumor site. These molecules spontaneously formed nanoparticles, which were then taken up by tumor cells.

Once inside cancerous cells, the pDox was transported to the area around the nucleus through vesicular transport. Due to the acidic environment near the nucleus, the dox was cleaved from its attachment to the poly(L-glutamic acid). This resulted in a high concentration of dox within the nuclei of the cancerous cells.

In contrast, when the researchers injected the drug dox alone, high levels appeared in non-cancerous tissues, such as the heart, leading to damage.

The team tested the therapy in several mouse cancer models, including triple-negative breast cancer, which is difficult to treat. Mice treated with the pDox-containing particles had much smaller and fewer tumors. They also had a longer survival time than mice given a saline control. The group found that 40-50% of cancer-bearing mice given the treatment showed no signs of metastatic tumors 8 months later.

“We invented a method that actually makes the nanoparticles inside the cancer and releases the drug particles at the site of the cellular nucleus,” Ferrari says.

The silicon-based carrier could transport other chemicals, or combinations of chemicals, besides dox. The team plans to begin safety and efficacy studies in humans in the future.

—by Carol Torgan, Ph.D.