Researchers at Massachusetts General Hospital are now reporting that the tumor microenvironment itself can be therapeutically primed to facilitate accumulation of multiple clinically relevant therapeutic nanoparticles to tumors.
Researchers at Massachusetts General Hospital (MGH) are now reporting that the tumor microenvironment itself can be therapeutically primed to facilitate accumulation of multiple clinically relevant therapeutic nanoparticles (TNPs) to tumors. Writing in Science Translational Medicine, they report on a new method of vascular permeability that may enhance drug delivery to tumors.
In animal models, they have demonstrated that combining radiation and cyclophosphamide enhances vascular bursting and significantly increasing tumoral TNP concentration. The researchers have found that macrophages can improve the effectiveness of nanoparticle-delivered cancer therapies. They theorize that appropriately timed radiation therapy can improve the delivery of cancer nanomedicines by as much as 600% by attracting macrophages to tumor blood vessels. By attracting macrophages, there is a transient "burst" of leakage from capillaries into the tumor.
"Rather than focusing on the nanoparticles themselves, we used in vivo microscopy to discover how to rewire the structure of the tumor itself to more efficiently accumulate a variety of nanomedicines already in clinical use,” said says lead study author Miles Miller, PhD, of the MGH Center for Systems Biology in Boston.
Encapsulating cancer drugs in nanoparticles can improve pharmacokinetics by extending a drug's presence in the circulation and avoiding the toxic solvents used in infusion chemotherapy. However, delivering nanoencapsulated drugs into patients' tumors in clinical practice has been challenging. High pressures within tumors and low permeability of tumor blood vessels limit the passage of any drugs from the circulation into tumor cells.
A 2015 study by Miller and his colleagues showed that tumor-associated macrophages can improve delivery of nanoparticle-based therapies to tumor cells, and radiation therapy is known to increase the permeability of tumor vessels. Experiments in mouse models of cancer revealed that radiation therapy produced important changes in the tumor microenvironment, including greater blood vessel size and permeability, and an increase in the number of macrophages relative to tumor cells.
The investigators discovered that these changes did not appear until 3 to 4 days after administration of radiation therapy and disappeared by day 11. Analysis of patient biopsy samples taken before and several days after radiation therapy for breast or cervical cancer revealed significant macrophage expansion in post-radiation samples, with the greatest increases in patients receiving the highest radiation dosage.
Additional mouse studies showed that beginning 3 days after radiation therapy the uptake of nanoparticles but not of solvent-delivered drugs approximately doubled. High-resolution in vivo microscopy revealed that increases in vascular permeability occurred erratically, with periods of low permeability interrupted by a bursting of vascular contents, including nanoparticles, into the tumors.
The rate of bursting increased 3 days after radiation and was higher on larger blood vessels with adjacent macrophages. Removal of macrophages prevented the radiation-induced changes and the increased uptake of nanoparticles. Combining radiation therapy with cyclophosphamide led to even greater nanoparticle uptake.
Miller said most of the treatments and nanomedicines employed in this study were already approved by the US Food and Drug Administration for cancer treatment, so this combination treatment strategy could be tested in clinical trials relatively quickly. He said there is great interest in combining tumor irradiation and nanomedicine with immuno-oncology therapies.