STOCKBYTE

Molecules that are expressed exclusively on new vessels growing into a developing tumour are potentially important anchors for targeted tumour therapy. David Cheresh and colleagues have found that an integrin-targeted nanoparticle containing a chemotherapeutic drug can suppress the development of tumour metastases by affecting angiogenesis.

The integrin v3 is mostly expressed in endothelial cells that are actively involved in new vessel growth in diseased tissues, including tumours. Nanoparticles targeted at v3 have been used previously to mark angiogenic hot spots in the tumour vasculature, as well as delivering chemotherapeutic drugs and suicide genes. The authors built v3-targeted, fluorescent, liposomal based nanoparticles that contained doxorubicin (dox) and showed that these were internalized by human umbilical vein endothelial cells in culture and bound to newly forming tips of capillaries in tumours produced by implanted mouse melanoma cells. In a mouse orthotopic model of pancreatic cancer, intravenous injection of these nanoparticles resulted in their accumulation in the tumour vasculature and the induction of apoptosis in v3-positive vessels in the tumour margin, but not in the capillaries of healthy pancreatic tissue. Treatment of the mice with v3-targeted nanoparticles containing 1 mg/kg dox on days 5, 7 and 9 after orthotopic implant of mouse pancreatic tumour cells resulted in a modest reduction in the growth of the primary tumour. However, metastases in the draining lymph node were significantly reduced. Importantly, these effects were not seen in mice treated with control nanoparticles (non-targeted nanoparticles that contain dox), or with free dox at 1 mg/kg. Indeed, the authors found that a dose of 15 mg/kg of free dox was needed to achieve a similar effect and this caused severe weight loss. Further analyses in a mouse orthotopic model of kidney cancer also showed that treatment with 2 mg/kg dox in v3-targeted nanoparticles reduced the occurrence of metastasis and the total metastatic burden.

The authors conclude that the modest effects seen on the primary tumours might well reflect the fact that they had already established a blood supply and v3 integrin expression is restricted to the tumour margin under these conditions. Why and how v3-targeted dox-containing nanoparticles reduce metastasis is not clear, and further research is needed. However, these results clearly show that delivering dox to the angiogenic tumour vasculature in targeted nanoparticles significantly increases its effect at low doses and minimizes the side effects of this drug.

Author: Nicola McCarthy