Study: Regulating tumor blood vessel stability can improve drug delivery
A new way to regulate the leakiness of blood vessels by blocking TGF beta surrounding blood vessels in mice can enhance delivery of molecular imaging agents and drugs to tumors, according to research published in the March online issue of Disease Models and Mechanisms.
Lisa M. Coussens, PhD, professor of pathology at the University of California, San Francisco and colleagues identified a novel pathway regulating vessel stability in tissues that involves matrix metalloproteinase 14 (MMP14) and transforming growth factor beta 1 (TGF beta1).
The researchers found that short-term treatment of mice in vivo with broad-spectrum inhibitors of MMP14, and TGF beta1 significantly enhanced vessel leakage. By contrast, when MMP14 activity and TGF beta bioavailability are chronically elevated cutaneous vessels are resistant to acute leakage and are reinstated if the fibrotic mice are pretreated with metalloproteinase inhibitors or TGF beta signaling antagonists.
After injecting different sizes of fluorescent molecules into mice with different types of tumors, Coussens and colleagues found that around 30 percent of the larger molecules leaked out into the tumor tissue after blocking the pathway, compared to only five percent without blockade while smaller molecules leaked out at the same rate as in untreated vessels but stayed in the tissue longer.
“If scientists can mimic this effect in humans, the compounds could be given along with chemotherapy drugs or molecular imaging reagents to more effectively deliver them into tumor tissues,” explained Coussens.
“The delivery of standard therapeutic agents or diagnostic molecular imaging agents to tumor tissue may be enhanced by transient blockade of the TGF beta pathway. If so, this could advance disease therapy and/or diagnostic imaging, not only in cancer medicine, but also in fibrotic disorders such as scleroderma and kidney failure,” concluded Coussens and colleagues.
Lisa M. Coussens, PhD, professor of pathology at the University of California, San Francisco and colleagues identified a novel pathway regulating vessel stability in tissues that involves matrix metalloproteinase 14 (MMP14) and transforming growth factor beta 1 (TGF beta1).
The researchers found that short-term treatment of mice in vivo with broad-spectrum inhibitors of MMP14, and TGF beta1 significantly enhanced vessel leakage. By contrast, when MMP14 activity and TGF beta bioavailability are chronically elevated cutaneous vessels are resistant to acute leakage and are reinstated if the fibrotic mice are pretreated with metalloproteinase inhibitors or TGF beta signaling antagonists.
After injecting different sizes of fluorescent molecules into mice with different types of tumors, Coussens and colleagues found that around 30 percent of the larger molecules leaked out into the tumor tissue after blocking the pathway, compared to only five percent without blockade while smaller molecules leaked out at the same rate as in untreated vessels but stayed in the tissue longer.
“If scientists can mimic this effect in humans, the compounds could be given along with chemotherapy drugs or molecular imaging reagents to more effectively deliver them into tumor tissues,” explained Coussens.
“The delivery of standard therapeutic agents or diagnostic molecular imaging agents to tumor tissue may be enhanced by transient blockade of the TGF beta pathway. If so, this could advance disease therapy and/or diagnostic imaging, not only in cancer medicine, but also in fibrotic disorders such as scleroderma and kidney failure,” concluded Coussens and colleagues.