Nanoparticle formulations of toll-like receptor agonists and oxaliplatin for local intraperitoneal delivery to treat colorectal peritoneal metastasis

01 November 2022 → 31 October 2024
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Cancer therapy
    • Biopharmaceutics
    • Pharmaceutical technology
Colorectal peritoneal metastasis TLR agonists and oxaliplatin nanoparticles intraperitoneal injection or nebulization
Project description

1 in 4 patients diagnosed with colorectal cancer will develop peritoneal metastasis (PM), characterized by the spread of numerous tumor nodules in the peritoneal cavity. Despite cytoreductive surgery and local or IV chemotherapy, 80% of patients develop disease recurrence. Most peritoneal metastases correspond to the CMS4 subtype, which is immune suppressive and characterized by the worst overall survival. Toll-like receptor (TLR) agonists, however, can stimulate the patient's own immune system and revert the CMS4 subtype into an immune-responsive subtype. TLR7/8 and 9 agonists will be formulated into liposomes which may also be formulated into a hydrogel to maximize their retention in the peritoneal cavity. Furthermore, an oxaliplatin containing poly-arginine hyaluronic acid nanoparticle (oxa pARG-HA NP) will be evaluated to treat colorectal PM, after promising results in the treatment of PM from ovarian origin. Finally, as the administration method can also determine treatment effectiveness, peritoneal injection will be compared to nebulization of the formulations in the intraperitoneal cavity under high pressure. Antitumor effects will be assessed in a mouse model of colorectal PM, while immunohistochemistry and multicolor flow cytometry will be used to characterize the changes in the tumor microenvironment during therapy of TLR agonists, oxa pARG-HA NPs or a combination of both.