Sunitinib-Loaded Chondroitin Sulfate Hydrogels as a Novel Drug-Delivery Mechanism for the Treatment of Pancreatic Neuroendocrine Tumors

Abstract

Background

Pancreatic neuroendocrine tumors (PanNETs) are increasingly common. Experts debate whether small tumors should be resected. Tumor destruction via injection of cytotoxic agents could offer a minimal invasive approach to this controversy. We hypothesize that a new drug delivery system comprising chondroitin sulfate (CS) hydrogels loaded with sunitinib (SUN) suppresses tumor growth in PanNET cells.

Methods

Injectable hydrogels composed of CS modified with methacrylate groups (MA) were fabricated and loaded with SUN. Loading target was either 200 µg (SUN200-G) or 500 µg (SUN500-G) as well as sham hydrogel with no drug loading (SUN0-G). SUN release from hydrogels was monitored in vitro over time and cytotoxicity induced by the released SUN was evaluated using QGP-1 and BON1 PanNET cell lines. QGP-1 xenografts were developed in 35 mice and directly injected with 25 µL of either SUN200-G, SUN500-G, SUN0-G, 100 µL of Sunitinib Malate (SUN-inj), or given 40 mg/kg/day oral sunitinib (SUN-oral).

Results

SUN-loaded CSMA hydrogel retained complete in vitro cytotoxicity toward the QGP-1 PanNET and BON-1 PanNET cell lines for 21 days. Mouse xenograft models with QGP-1 PanNETs showed a significant delay in tumor growth in the SUN200/500-G, SUN-inj and SUN-oral groups compared with SUN0-G (p = 0.0014). SUN500-G hydrogels induced significantly more tumor necrosis than SUN0-G (p = 0.04). There was no difference in tumor growth delay between SUN200/500G, SUN-inj, and SUN-oral.

Conclusions

This study demonstrates that CSMA hydrogels loaded with SUN suppress PanNETs growth. This drug delivery could approach represents a novel way to treat PanNETs and other neoplasms via intratumoral injection.

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Funding

This work was supported in part by the Neuroendocrine Tumor SPORE grant P50 CA174521 (XK) from the University of Iowa.

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XK: Manuscript writing and review, conduction and design of experiments (animal), KO: Conduction and design of experiments (hydrogel), AV: Conduction and design of experiments (animal), OL: Conduction and design of experiments (animal), JW: Conduction and design of experiments, statistical analysis (animal), PM: Conduction and design of experiments, statistical analysis (animal), KM: Conduction and design of experiments (hydrogel), NS: Pathology review and analysis, RW: Manuscript review, design of experiments, JC: Manuscript writing and review, design of experiments

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Correspondence to Xavier M. Keutgen or Jeannine M. Coburn.

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Presented in part at the Americas Hepato-Pancreato-Biliary Association (AHPBA) Annual Meeting, March 2019, Miami Beach, FL.

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Keutgen, X.M., Ornell, K.J., Vogle, A. et al. Sunitinib-Loaded Chondroitin Sulfate Hydrogels as a Novel Drug-Delivery Mechanism for the Treatment of Pancreatic Neuroendocrine Tumors. Ann Surg Oncol (2021). https://doi.org/10.1245/s10434-021-10245-1

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