Photoactivated Nanoparticles Block Pancreatic Cancer Growth and Metastasis in Mouse Models

A nanoparticle delivery system was used for the safe transport a photodynamic therapy (PDT) agent together with a highly toxic anti-cancer drug for the pinpoint treatment of pancreatic cancer.

Few nanoparticle drug delivery schemes have proven effective because cancer cells develop ways to resist and evade treatment. In order to "outsmart" the cancer cells, investigators at Harvard Medical School (Boston, MA, USA) developed a photoactivable multi-inhibitor nanoliposome (PMIL) delivery technique that imparted light-induced cytotoxicity together with a photo-initiated and sustained release of inhibitors that suppressed tumor re-growth and treatment escape signaling pathways.

The PMIL consisted of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing the drug cabozantinib (XL184) - a multikinase inhibitor - encapsulated inside. Cabozantinib is a small molecule inhibitor of the tyrosine kinases Met (MET proto-oncogene, receptor tyrosine kinase) and VEGFR2 (vascular endothelial growth factor receptor 2), and has been shown to reduce tumor growth, metastasis, and angiogenesis. This drug is quite toxic requiring dose restrictions or treatment interruption.

Met is a receptor tyrosine kinase that stimulates cell scattering, invasion, protection from apoptosis, and angiogenesis. Mutations that cause deregulation of Met activity can cause a wide variety of different cancers, such as renal, gastric and small cell lung carcinomas, central nervous system tumors, as well as several sarcomas. VEGF is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from preexisting vasculature). When VEGF is overexpressed, it can contribute to the growth and spread of solid tumors.

In the current study, the investigators worked with two mouse pancreatic cancer models. Following intravenous PMIL administration the mice were treated with near-infrared tumor irradiation applied directly to the tumor sites via optical fibers.

The investigators reported in the January 18, 2016, online edition of the journal Nature Nanotechnology that the near-infrared light treatment triggered photodynamic damage of tumor cells and microvessels, and simultaneously initiated release of cabozantinib inside the tumor. A single PMIL treatment achieved prolonged tumor reduction in the two mouse pancreatic cancer models and also suppressed metastatic escape.

These results were obtained using cabozantinib at a dosage level less than one thousandth of what is normally used in oral therapy, with little or no toxicity.

"Right now we can say this approach has tremendous potential for patients with locally advanced pancreatic cancer, for whom surgery is not possible," said senior author Dr. Tayyaba Hasan, professor of dermatology at Harvard Medical School. "In our Phase I/II clinical studies with PDT alone, tumor destruction was achieved in all cases, and we have seen at least one case where PDT alone induced enough tumor shrinkage to enable follow-up surgery. The more robust tumor reduction and suppression of escape pathways possible with PMILs might enable curative surgery or improve the outcome of chemotherapy to enhance patient survival. But while we are encouraged by these results, this combination in a new nanoconstruct needs more validation before becoming a clinical treatment option."

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