BOSTON — A nanoparticle drug-delivery system that combines photodynamic and molecular therapies has been shown to suppress tumor progress and metastatic outgrowth in animal models. The complementary treatment could improve outcomes and mitigate toxicity for patients with pancreatic cancer and other treatment-resistant tumors.
3D rendering of a photoactivable multi-inhibitor nanolipsome encapsulating a nanoparticle from a cryoelectron microscopy tomogram. Courtesy of Elizabeth Villa, University of California, San Diego.
The research was conducted by the laboratory of professor Tayyaba Hasan, based at the Wellman Center. Hasan's lab focuses on photochemistry-based approaches for treatment and diagnosis of disease with the goal of developing molecular mechanisms and optical imaging-based combination treatment regimens.
"A broad challenge in cancer treatment is that tumor cells use a network of cellular signaling pathways to resist and evade treatment," said research fellow Bryan Spring of the Wellman Center for Photomedicine at Massachusetts General Hospital. "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."
Photodynamic therapy (PDT) uses chemicals called photosensitizers — activated by exposure to specific wavelengths of light — to release reactive molecules that can damage nearby cells. In cancer treatment, PDT damages both tumor cells and their blood supply, directly killing some tumor cells and starving those that remain of nutrients. However PDT can also stimulate molecular signaling pathways that support tumor survival.
The nanomedicine developed by Hasan's lab comprised photoactivable multi-inhibitor nanoliposomes (PMILs) enclosing a polymer nanoparticle that was loaded with a targeted molecular therapy drug. The lipid membrane of the PMILs contained a FDA-approved photosensitizer, BPD or benzoporphyrin derivative, and the nanoparticles were loaded with a molecular therapy drug called XL184 or cabozantinib.
XL184 inhibits two important treatment escape pathways, referred to VEGF and MET, but while it has FDA approval to treat thyroid cancer and is being tested against pancreatic cancer and several other tumors, it is quite toxic, which requires dose restrictions or treatment interruption, the researchers said. Since XL184 is delivered to every part of the body and not just to the tumor when administered orally, enclosing it in the PMIL could reduce toxicity by confining its action to the area of the tumor.
The investigators first confirmed in laboratory experiments that exposing PMILs to near-infrared (NIR) light both activated the antitumor action of BPD and, by disrupting the lipid membrane envelope, released the XL184-containing nanoparticles. In two mouse models of pancreatic cancer, a single treatment consisting of intravenous delivery of the PMILs followed by localized delivery of NIR light to the tumor site via optical fibers resulted in significantly greater reduction in tumor size than did either treatment with XL184 or PDT with BPD alone.
PMIL treatment also was significantly more effective than treatment with both XL184 and BPD-PDT given as separate agents. Along with prolonged tumor reduction, PMIL treatment also almost completely suppressed metastasis in the mouse models, the researchers reported.
While the VEGF treatment escape pathway is known to be induced and sensitized by PDT, the team found that PDT also induces signaling via the MET pathway. The ability to deliver XL184 and PDT almost simultaneously allowed the two therapeutics to cut off the rapid initiation of escape signaling that usually follows PDT. This was reflected in how much more efficient PMIL-delivered treatment was in the animal models compared to either treatment alone, since PDT simultaneously sensitized the tumor to the second therapy.
Delivery of XL184 directly to the tumor site produced these promising results at a dosage level less than one thousandth of what is used in oral therapy, with little or no toxicity, the researchers said.
"Right now we can say this approach has tremendous potential for patients with locally advanced pancreatic cancer, for whom surgery is not possible," said researcher Tayyaba Hasan. "In our Phase I/II clinical studies with PDT alone, tumor destruction was achieved in all cases, and we've seen at least one case where PDT alone induced enough tumor shrinkage to enable follow-up surgery.”
The team said they will continue to validate their nanoconstructs with the goal of clinical adoption of the treatment.
The study was published in Nature Nanotechnology (doi: 10.1038/nnano.2015.311).