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.
Drug resistance represents an obstacle in colorectal cancer (CRC) treatment because of its association with poor prognosis. rBC2LCN is a lectin isolated from Burkholderia that binds cell surface glycans that have fucose moieties. Because fucosylation is enhanced in many types of cancers, this lectin could be an efficient drug carrier if CRC cells specifically present such glycans. Therefore, we examined the therapeutic efficacy and toxicity of lectin drug conjugate therapy in CRC mouse xenograft models. The affinity of rBC2LCN for human CRC cell lines HT‐29, LoVo, LS174T, and DLD‐1 was assessed in vitro. The cytocidal efficacy of a lectin drug conjugate, rBC2LCN‐38 kDa domain of pseudomonas exotoxin A (PE38) was evaluated by MTT assay. The therapeutic effects and toxicity for each CRC cell line‐derived mouse xenograft model were compared between the intervention and control groups. LS174T and DLD‐1 cell lines showed a strong affinity for rBC2LCN. In the xenograft model, the tumor volume in the rBC2LCN‐PE38 group was significantly reduced compared with that using control treatment alone. However, the HT‐29 cell line showed weak affinity and poor therapeutic efficacy. No significant toxicities or adverse responses were observed. In conclusion, we demonstrated that rBC2LCN lectin binds CRC cells and that rBC2LCN‐PE38 significantly suppresses tumor growth in vivo. In addition, the efficacy of the drug conjugate correlated with its binding affinity for each CRC cell line. These results suggest that lectin drug conjugate therapy has potential as a novel targeted therapy for CRC cell surface glycans.
A 62-year-old woman had developed polymyositis 12 years previously and had taken oral steroids. Chest and abdominal computed tomography showed pneumomediastinum and free air in the abdominal cavity. Although a colon perforation was suspected, the perforation site could not be identified on the image. In addition, a diagnosis of oesophageal rupture could not be excluded from the findings of pneumomediastinum. After general anaesthesia, an upper gastrointestinal endoscopy was performed before surgery. Because there was no obvious perforation in the oesophagus, a laparotomy approach was used. A perforation was found on the mesentery side of the sigmoid colon, and a perforation of the sigmoid colon’s diverticulum towards the mesentery was diagnosed. A Hartmann’s procedure was performed. Colon perforations are rarely associated with pneumomediastinum. Preoperative endoscopy is useful to help diagnose and determine the surgical procedure if an obvious perforation cannot be identified.
Pancreatic ductal adenocarcinoma (PDAC) has abundant immunosuppressive regulatory T cells (Tregs), which contribute to a microenvironment resistant to immunotherapy. Here, we report that Tregs in the PDAC tissue, but not those in the spleen, express the αvβ5 integrin in addition to neuropilin-1 (NRP-1), which makes them susceptible to the iRGD tumor-penetrating peptide, which targets cells positive for αv integrin- and NRP-1. As a result, long-term treatment of PDAC mice with iRGD leads to tumor-specific depletion of Tregs and improved efficacy of immune checkpoint blockade. αvβ5 integrin+ Tregs are induced from both naïve CD4+ T cells and natural Tregs upon T cell receptor stimulation, and represent a highly immunosuppressive subpopulation of CCR8+ Tregs. This study identifies the αvβ5 integrin as a marker for activated tumor-resident Tregs, which can be targeted to achieve tumor-specific Treg depletion and thereby augment anti-tumor immunity for PDAC therapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.