Nanoparticle Drug Delivery Aims to Control Pancreatic Tumor and Inhibit Escape Pathways

Use of a nanoparticle to deliver drugs may reduce tumors and suppress metastatic escape, according to initial research in a mouse model of pancreatic cancer. These efforts to control drug release over space and time while reducing systemic drug exposure and the associated side effects were described in Nature Nanotechnology (doi:10.1038/nnano.2015.311).

This nanoparticle drug-delivery system combines 2 complementary types of anticancer treatment, and may improve outcomes for patients with highly treatment-resistant tumors, such as pancreatic cancer, and decrease toxicity. This study describes a nanomedicine that uses photodynamic therapy, meaning light is used to trigger a chemical reaction, along with a molecular therapy drug. The drug portion of the nanomedicine is targeted against common treatment resistance pathways, and targeting allowed for a 1000-fold reduction in the dose required to suppress tumor progression and metastatic outgrowth in an animal model.

"A broad challenge in cancer treatment is that tumor cells use a network of cellular signaling pathways to resist and evade treatment," said co-lead author Bryan Spring, PhD, of the Wellman Center for Photomedicine at Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. "The new optically active nanoparticle we have developed is able both to achieve tumor photodamage and to suppress multiple escape pathways, opening new possibilities for synchronized multidrug combination therapies and tumor-focused drug release."

Nanoliposomes were used in this nanomedicine. These spherical lipid membrane structures enclose a polymer nanoparticle loaded with a targeted molecular therapy drug. The lipid membrane of these photoactivable multi-inhibitor nanoliposomes (PMILs) contains the FDA-approved photosensitizer benzoporphyrin derivative (BPD), and the nanoparticles are loaded with the molecular therapy drug XL184 (cabozantinib).

XL184 currently has FDA approval for treating thyroid cancer and is being tested for other tumors, including pancreatic cancer. Notably, XL184 is quite toxic, so it requires dose restrictions or treatment interruptions. Enclosing XL184 in the PMIL could reduce its toxicity since its action would be confined to the area of the tumor.

Initial tests in mouse models of pancreatic cancer found that intravenous delivery of the PMILs followed by localized delivery of near-infrared light to the tumor site via optical fibers resulted in significantly greater reduction in tumor size than did treatment with XL184 or photodynamic therapy with the photosensitizer BPD alone. The PMILs led to both prolonged tumor reduction and almost complete suppression of metastasis in the mouse models.

"Right now we can say this approach has tremendous potential for patients with locally advanced pancreatic cancer, for whom surgery is not possible," said corresponding author Tayyaba Hasan, PhD, also of the Wellman Center. "But while we are encouraged by these results, this combination in a new nanoconstruct needs more validation before becoming a clinical treatment option."

The study was supported by grants from the National Institutes of Health.

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