Nature Nanotechnology, an online manual, has published a report outlining the concept of combining nanoparticles with molecular and photodynamic therapies in order to deliver anticancer treatment, and obtain improved results for patients with pancreatic cancer and other treatment-resistant tumors. The concept has been developed by a team of researchers from the Wellman Center for Photomedicine at Massachusetts General Hospital (MGH).
The team demonstrated how the new concept can help to reduce the dosage of the molecular therapy drug used to control the growth of tumors, and metastatic outgrowth in animal models.
A broad challenge in cancer treatment is that tumor cells use a network of cellular signaling pathways to resist and evade treatment. 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.
Bryan Spring, PhD, The Wellman Center
Photosensitizers used in photodynamic therapy (PDT) are exposed to particular light wavelengths in order to release reactive molecules, capable of damaging the surrounding cells. PDT, used in the treatment of cancer, damages the blood supply of the tumor cells and the tumor cells themselves, directly eliminating some of the tumor cells and starving those that remain. Like other tumor-treating options, the usage of PDT could help stimulate molecular signaling pathways that support tumor survival.
The Wellman-based team’s nanomedicine is developed from nanoliposomes, lipid membrane spherical structures covering a polymer nanoparticle loaded with a targeted molecular therapy drug. The lipid membrane of the photoactivable multi-inhibitor nanoliposomes (PMILs) comprises of benzoporphyrin derivative (BPD), and the nanoparticles that are loaded with cabozantinib or XL184, which is a molecular therapy drug. BPD is a FDA-approved photosensitizer.
MET and VEGF are two vital treatment escape pathways inhibited by XL184. XL184 is currently being tested against a number of tumors, including pancreatic cancer., though it is still found to be toxic, requiring treatment interruption or dose restrictions. In treating tumors, XL184 is introduced to all parts of the body instead of focusing only on the tumor. XL184, enclosed in the PMIL, may reduce toxicity when its action to the tumor site is restricted.
A team of investigators led by Tayyaba Hasan, PhD, of the Wellman Center, conducted laboratory experiments and highlighted that PMILs, when exposed to near-infrared light, activated BPD’s antitumor action by interrupting the lipid membrane envelope and then releasing the XL184 comprising nanoparticles. On delivering PMILs in two mouse models with pancreatic cancer, and then locally introducing near-infrared light to the tumor site, the team discovered the size of the tumor reduced tremendously, compared with the reduction resulting from the treatment with BPD, XL184 and PDT. PMIL treatment was considered to be more effective in the treatment of pancreatic tumors as it prolonged tumor reduction, and almost totally reduced metastasis occurring in the two mouse models.
The research team also discovered that PDT generated signaling through the MET pathway, and that it sensitized and induced the VEGF treatment escape pathway. PMIL-delivered treatment seems to be more efficient in the mouse models, as the tumor was simultaneously sensitized to the second therapy. The direct delivery of XL184 to the tumor area resulted in good results when compared with the dosage level used in oral therapy.
Right now we can say this approach has tremendous potential for patients with locally advanced pancreatic cancer, for whom surgery is not possible. 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 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.
Tayyaba Hasan, PhD, The Wellman Center
Previously, a research fellow in Dermatology at the Wellman Center, Spring is now an assistant professor of Physics at Northeastern University. Hasan is a professor of Dermatology and of Health Sciences and Technology at Harvard Medical School. Bryan Sears and Lei Zak Zheng of the Wellman Center are also first co-authors of the Nature Nanotechnology paper. Additional co-authors are Zhiming Mai, PhD, and Margaret Sherwood, Wellman Center; Reika Watanab and Elizabeth Villa, PhD, University of California San Diego; David Schoenfeld, PhD, MGH Biostatistics; Brian Pogue, PhD, Dartmouth College; and Stephen Pereira, PhD, University College London. National Institutes of Health grants RC1-CA146337, R01-CA160998, P01-CA084203, and F32-CA144210 supported the study.