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. 2021 Dec 17;71(9):1843–1855. doi: 10.1136/gutjnl-2021-325180

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© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Delivery of TRAIL and NO by tumour stroma-targeted nanogels reduced collagen I production, increased apoptosis induction and suppressed tumour growth in both murine and human orthotopic PDAC models. (A) Schematic illustration of the LQT-TRAIL-NO@Nanogel treatment protocol. After the implantation of PDAC cells, mice were treated intravenously with various NP formulations encapsulating the NO donor DNIC and/or TRAIL on days 3, 5, 7, 9, 11, 13 and 15; tumour volume was measured on day 16. (B) Representative H&E, Masson’s trichrome staining and immunofluorescence images showing the results of collagen I, α-SMA and TUNEL staining in orthotopic murine PDAC (AK4.4) tumours after treatment with various formulations. Blue, nuclei (DAPI). Scale bars, 50 µm. (C–D) LQT-TRAIL-NO@Nanogel significantly reduced collagen I production (C) and α-SMA expression (D) in orthotopic PDAC tumours, as indicated by immunofluorescence staining for collagen I and α-SMA (n=7 section images from four mice). (E) Volumes of orthotopic PDAC tumours 16 days after implantation in treated and untreated (control) mice (AK4.4 PDAC model, n=10; AsPC-1 PDAC model, n=5). (F) LQT-TRAIL-NO@Nanogel significantly enhanced the induction of apoptosis in orthotopic PDAC tumours, as indicated by TUNEL staining (AK4.4 PDAC model, n=7 section images from four mice; AsPC-1 PDAC model, n=6 section images from three mice). (G) LQT-TRAIL-NO@Nanogel significantly prolonged the overall survival in orthotopic AK4.4 PDAC tumour model (n=8). ****P<0.0001 compared with untreated (control) mice, *p=0.0118 compared with LQT-NO@Nanogel, *p=0.0161 compared with LQT-TRAIL@Nanogel and *p=0.0340 compared with TRAIL-NO@Nanogel. Comparison of survival curves was performed using a log-rank Mantel-Cox test (two-sided). All data are shown as the mean±SEM. *P<0.05, **p<0.01, ***p<0.001. DNIC, dinitrosyl iron complexes; NO, nitric oxide; NP, nanoparticle; PDAC, pancreatic ductal adenocarcinoma; SMA, smooth muscle actin; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand.