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