Conventional chemotherapy treatments for pancreatic cancer are mainly 
palliative. RNA interference (RNAi)-based drugs present the potential for a new 
targeted treatment. LOcal Drug EluteR (LODER(TM)) is a novel biodegradable 
polymeric matrix that shields drugs against enzymatic degradation and releases 
small interfering RNA (siRNA) against G12D-mutated KRAS (siG12D). siG12D-LODER 
has successfully passed a phase 1/2a clinical trial. Such a formulation 
necessitates biocompatibility and safety studies. We describe the safety and 
toxicity studies with siG12D-LODER in 192 Hsd:Sprague Dawley rats, after 
repeated subcutaneous administrations (days 1, 14, and 28). Animals were 
sacrificed on days 29 and 42 (recovery phase). In all groups, no adverse effects 
were noted, and all animals showed favorable local and systemic tolerability. 
Histopathologically, LODER implantation resulted in the expected capsule 
formation, composed of a thin fibrotic tissue. On the interface between the 
cavity and the capsule, a single layer composed of macrophages and 
multinucleated giant cells was observed. No difference was noted between the 
placebo and siG12D-LODER groups. These findings provide valuable information for 
future preclinical studies with siRNA-bearing biodegradable polymers and for the 
safety aspects of RNAi-based drugs as a targeted therapy.