Triple-targeted Photonanomedicine: A Strategy to Treat Heterogeneous Tumors
Mentor: Tayyaba Hasan, Ph.D. (Massachusetts General Hospital)
Intra-tumor heterogeneity in humans facilitates tumor progression. During the course of disease, cancers tend to become heterogeneous, resulting in a nonuniform distribution of distinct tumor cell subpopulations within the bulk tumor, demonstrating differential levels of sensitivity or resistance to treatment (Dagogo-Jack and Shaw, 2017). Heterogeneity in the expression of several molecular markers has been extensively reported in many cancers including human glioblastoma (Liu et. Al 2017), breast cancer (Turashvili and Brogi, 2017), and pancreatic ductile adenocarcinoma (Cros et. Al 2017). Despite the advancements and the great promises brought by antibody-based therapies, single-targeted cancer therapy is challenged partially due to the distinct surface features of an antigen, therapeutic resistance, and non-uniformity in marker expression (Yan, et. al 2019). This heterogeneity is a major challenge for an optimal treatment because even if one tumor subpopulation is successfully targeted, other subpopulations may persist and continue to proliferate. Near-infrared (NIR) light-activated photosensitizer–antibody photo‐immunoconjugates (PICs) for photo‐immunotherapy (PIT) are a unique approach that could further broaden the utility of photodynamic therapy (PDT). The immunotherapy aspect involves using an antibody while the PDT aspect involves cell death induced by photochemically generated reactive molecular species using a photosensitizer (PS), light, and cellular oxygen (Kobayashi, 2019). The Hasan Lab has established antibody targeted nanoconstructs to destroy tumors selectively (Obaid et. al 2019). They developed the photoimmuno-nanoconstructs (PINs) incorporating benzoporphyrin derivative (BPD), which is a PS and is activated by near-infrared (NIR) light irradiation. An FDA approved antibody cetuximab (Cet, anti-EGFR mAb) is chemically conjugated on the surface of these PINs for targeting. This strategy can be improved by increasing the selectivity of the established nanoconstructs, since heterogeneous tumors overexpress various biomarkers that present challenges to effective therapies. The overarching goal of this project is to develop a flexible platform for cancer cell-specific intracellular delivery of photodynamic agents, by targeting three different receptors simultaneously on the surface of tumor cells to successfully kill the different subpopulations within the same bulk tumor.
Figure 1: Photodynamic activation of specificity tuned photoimmuno-nanoconstructs in 3D heterotypic organoids of pancreatic ductal adenocarcinoma (PDAC) and pancreatic cancer associated fibroblasts. Source: