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

Toxicologic Pathology - Tập 44 Số 6 - Trang 856-865 - 2016
Yuval Ramot1, Shay Rotkopf2, Rachel Malka Gabai2, Elina Zorde Khvalevsky2, Sofia Muravnik2, Gabriela Alejandra Marzoli3, Abraham J. Domb4, Amotz Shemi2, Abraham Nyska5,6
1Hadassah Hebrew University Medical Center, Jerusalem, Israel
2Silenseed Ltd, Modiin, Israel
3Toxicology Department, Research Toxicology Centre, Pomezia, Italy
4Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel
5Consultant in Toxicologic Pathology, Timrat, Israel
6Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Tóm tắt

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 (LODERTM) 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.

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Toxicologic Pathology

Tập 44 Số 6

856-865

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