Photodynamic Enhancement of Drug Delivery to Tumors

Pancreatic cancer is associated with one of the poorest prognosis of all malignancies, with an unchanged five- year survival rate of 5% or less. The complex desmoplastic microenvironment impeding effective drug delivery to pancreatic tumors and the compensatory ability of cancer cells to adapt alternative survival pathways suggest that treatments will need to attack several targets. Photodynamic therapy (PDT) may have a specific role in enhancing drug delivery to pancreatic tumors and ameliorating drug resistance mechanisms by the targeted destruction of specific pathways. We have developed a bi-directionally cooperative combination regimen of PDT and irinotecan for pancreatic cancer using two clinically approved, nanotechnology-enabled therapies with a clear molecular basis. In an orthotopic pancreatic cancer mouse model, a combination of photodynamic therapy (PDT) and FDA-approved liposomal irinotecan (nal-IRI, MM-398) synergistically reduced the primary and metastatic tumor burden, and prolonged animal survival. This presentation will discuss how PDT increases tumor permeability and irinotecan transport by several mechanisms including disruption of efflux pumps, vascular and stromal integrity. Our findings provide a framework for the translation of mechanistic insights into rational new therapies for several cancers. This study is supported by the following NIH grants: 1K99CA194269 (HH); 5K99CA175292/ 4R00CA175292 (IR); 4R01CA15841505, 5R01CA16099805 5P01CA08420312 (TH). JL was supported by the Herchel Smith fellowship and Harvard College Research Program.