CEB-01 membrane loaded with SN-38 for local post-resection control and metastasis reduction in preclinical pancreatic cancer models

Pancreatic cancer (PC) is an aggressive malignancy with extremely poor prognosis, in which resection surgery remains the only therapeutic option with curative intent. Patients often present with locoregional metastases in lymph nodes, peritoneum and liver at diagnosis (~ 50-60% of patients), precluding the possibility of surgical resection. In addition, majority of patients develop tumor recurrence after surgery, which can be local or metastatic, in both cases negatively affecting survival outcomes. Irinotecan has proven effective as an adjuvant setting after surgery and currently used in chemotherapeutic combination regimes for the management of PC. The extreme low solubility of irinotecan's active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), along with its instability at physiological pH, creates significant challenges for SN-38 systemic administration as a free drug, despite its much greater potency compared to irinotecan. CEB-01 is a novel formulation of SN-38 in the form of a biodegradable nanofiber Poly (Lactic-co-Glycolic Acid) (PLGA) membrane. Implanted in the PC surgical bed, CEB-01 releases SN-38 in a prolonged manner for tumor growth control.Using in vivo pancreatic models, CEB-01 shows statistically significant reduction of postoperative tumor growth at local concentrations of SN-38 between 25 and 50 µg/cm², both as monotherapy and in combination with chemotherapy (5-FU 30 mg/kg and 90 mg/kg leucovorin), in MIA PaCa-2 and metastatic Panc-1 pancreatic xenograft models. In addition, CEB-01 shows statistically significant effect on metastatic control, by reducing the number of metastases in liver, lymph nodes, and peritoneum in treated animals. Overall, no systemic toxic effects or changes in body weight were observed, confirming that CEB-01 shows a tolerable profile after post-surgical resection in in vivo models of PC. In conclusion, CEB-01 is a feasible drug delivery strategy for the local release of SN-38 as an add-on adjuvant to current PC treatments, strategy that could potentially reduce systemic side effects compared to intravenous administration of irinotecan.