Preclinical safety study of a gemcitabine-controlled release polymer for locoregional administration in pancreatic cancer

There is a subpopulation of pancreatic tumor pluripotent cells with mechanisms of drug resistance that favor the locoregional recurrence and poor prognosis of the disease. In this work, the preclinical study of the safety of gemcitabine (GEM) impregnated in polymeric foams designed for intraoperative administration in pancreatic cancer (PC) is introduced. GEM impregnated in Poly Lactic-co-Glycolic Acid (PLGA) foams (at doses of 2.6, 20.5, and 170 mg GEM/g PLGA) were prepared by supercritical CO2 technology, and their morphology, structure, and thermal properties were characterized. The average cell size of the foams was 100 μm, achieving a GEM impregnation efficiency higher than 90% and a homogeneous distribution over the foams. An experimental trial was carried out to study the safety of foams by means of a murine model in 4 groups implanting control foams or impregnated with different doses of GEM. Distal pancreatectomy was performed, and the polymer was implanted together in the pancreatic, periesply, and retrogastric stump. Locoregional and systemic toxicity were discarded with the lower dose of GEM tested (2.6 mg GEM/g PLGA, corresponding to 0.45 mg GEM). Furthermore, GEM quantification was performed in pancreatic tissue, and plasma obtained a maximum concentration at 72 h (0.7 ng/mg and 7.87 ng/ml, respectively, for the safe GEM-PLGA foams). Also, it can be observed that after 7 days, the GEM-PLGA foam has been completely absorbed. The results are encouraging and push us to continue the second phase of the clinical study to determine its safety and efficacy in patients with PC. [Display omitted]