ABS 019: Photodynamic Targeted Priming of Tumor Microenvironment to Improve Irinotecan Chemotherapy

Ibrahim Janjua ¹ ² , Jose Quilez Alburquerque ² , Fernanda Viana Cabral ² , Tayyaba Hasan ²

¹ Dana-Farber/ Harvard Cancer Institute Boston, MA
² Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA

Van Wickle (2025) Volume 1, ABS 019

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis, largely due to its complex tumor microenvironment (TME) that resists conventional therapies. One significant challenge in treating pancreatic cancer is desmoplasia, which is characterized by the growth of dense fibrous or connective tissue around the tumor. This dense stroma acts as a physical barrier and reduces the effectiveness of chemotherapy and immunotherapy delivery to tumor cells. This research addresses the problem of inadequate irinotecan delivery, a common chemotherapy approved for the treatment of metastatic PDAC, by exploring the potential of targeted photodynamic therapy (PDT). PDT involves the use of a nontoxic photosensitizer that, upon light absorption, converts molecular oxygen into reactive oxygen species (ROS), leading to cell death. In this study, the photoactive agent benzoporphyrin derivative (BPD) was conjugated to the Arginylglycylaspartic acid (RGD), which targets integrin αVβ5 overexpressed in PDAC, with the aim of disrupting the TME and improving irinotecan delivery.

Methods: To mimic the TME, heterotypic spheroids of MiaPaca-2 human pancreatic cancer cells and pancreatic cancer-associated fibroblasts (CAFs) were co-cultured in 20/80 and 80/20 ratios, respectively. The spheroids were then subjected to PDT at various light doses ranging from 0 J/cm² to 20 J/cm² to determine whether PDT is affected by the TME.

Results: The study demonstrates that the BPD-RGD conjugate achieves higher accumulation and photoactivity, independent of the enriched CAF microenvironment. Moreover, using a subtherapeutic light dose (5 J/cm²) before irinotecan incubation enhances its uptake within the spheroids by 2-fold.

Discussion: These findings lay the groundwork for future studies focused on enhancing irinotecan chemotherapy's delivery and effectiveness by precisely targeting and disrupting the TME. This approach has the potential to significantly improve treatment outcomes for pancreatic cancer by overcoming the immunosuppressive barriers within the TME and offering a more targeted therapeutic strategy.