Lectin‐based phototherapy targeting cell surface glycans for pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is resistant to current treatments but lectin‐based therapy targeting cell surface glycans could be a promising new horizon. Here, we report a novel lectin‐based phototherapy (Lec‐PT) that combines the PDAC targeting ability of rBC2LCN lectin to a photoabsorber, IRDye700DX (rBC2‐IR700), resulting in a novel and highly specific near‐infrared, light‐activated, anti‐PDAC therapy. Lec‐PT cytotoxicity was first verified in vitro with a human PDAC cell line, Capan‐1, indicating that rBC2‐IR700 is only cytotoxic upon cellular binding and exposure to near‐infrared light. The therapeutic efficacy of Lec‐PT was subsequently verified in vivo using cell lines and patient‐derived, subcutaneous xenografting into nude mice. Significant accumulation of rBC2‐IR700 occurs as early as 2 hours postintravenous administration while cytotoxicity is only achieved upon exposure to near‐infrared light. Repeated treatments further slowed tumor growth. Lec‐PT was also assessed for off‐target toxicity in the orthotopic xenograft model. Shielding of intraperitoneal organs from near‐infrared light minimized off‐target toxicity. Using readily available components, Lec‐PT specifically targeted pancreatic cancer with high reproducibility and on‐target, inducible toxicity. Rapid clinical development of this method is promising as a new modality for treatment of pancreatic cancer.

Novel positron emission tomography imaging targeting cell surface glycans for pancreatic cancer: 18F‐labeled rBC2LCN lectin

“…sufficiently compensates for lower binding affinity as evidenced by tumoricidal activity. 27,29 Thus, while maintaining high-contrast tumor delineation in our in vivo work, [ 18 F]FB-rBC2LCN's lower binding affinity is compensated for by the larger number of binding sites, potentially increasing whole-tumor imaging resolution. 48 Despite the fact that glycans should be attractive targets due to their specificity, development of probes targeting glycans for in vivo imaging has been limited.…”

“…27 Therefore, any potential rBC2LCN lectin harm would depend on the chosen payload and not the molecule itself. 29 An immediate concern is the fact that the F I G U R E 5 Graphic summary of positron emission tomography (PET) imaging targeting cell surface glycans for pancreatic cancer by using 18 F-labeled rBC2LCN lectin.…”

“…However, we previously reported that rBC2LCN lectin alone showed no toxicity to any organ, including kidneys and liver 27 . Therefore, any potential rBC2LCN lectin harm would depend on the chosen payload and not the molecule itself 29 . An immediate concern is the fact that the kidney is in physical proximity to the pancreas and thus may mask signal from the PDAC.…”

“…27 Exploiting these unique properties, we previously employed rBC2LCN to deliver cytocidal drugs to PDAC cells. 27,29 By combining rBC2LCN specificity toward PDAC cells in concert with conjugated payloads, such as exotoxins 27 and/or theragnostic dyes, 29 we now seek to explore the potential application of an rBC2LCN-fluorine-18 ( 18 F) conjugate as a PET probe.…”

“…Importantly, rBC2LCN does not induce hemagglutination (induced when exogenous lectins are introduced into the blood), 28 allowing it to be harmlessly administered intravenously 27 . Exploiting these unique properties, we previously employed rBC2LCN to deliver cytocidal drugs to PDAC cells 27,29 . By combining rBC2LCN specificity toward PDAC cells in concert with conjugated payloads, such as exotoxins 27 and/or theragnostic dyes, 29 we now seek to explore the potential application of an rBC2LCN–fluorine‐18 ( 18 F) conjugate as a PET probe.…”