title: 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.
abstract: 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.
authors.affiliation: Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Ramot
authors.affiliation: Silenseed Ltd, Modiin, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Rotkopf
authors.affiliation: Silenseed Ltd, Modiin, Israel.
authors.forename: Rachel Malka
authors.initials: RM
authors.lastname: Gabai
authors.affiliation: Silenseed Ltd, Modiin, Israel.
authors.forename: Elina
authors.initials: E
authors.lastname: Zorde Khvalevsky
authors.affiliation: Silenseed Ltd, Modiin, Israel.
authors.forename: Sofia
authors.initials: S
authors.lastname: Muravnik
authors.affiliation: Toxicology Department, Research Toxicology Centre, Pomezia, Italy.
authors.forename: Gabriela Alejandra
authors.initials: GA
authors.lastname: Marzoli
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel.
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Domb
authors.affiliation: Silenseed Ltd, Modiin, Israel.
authors.forename: Amotz
authors.initials: A
authors.lastname: Shemi
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Consultant in Toxicologic Pathology, Timrat, Israel anyska@bezeqint.net.
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D004337:Drug Carriers / Q000494:pharmacology*; D019344:Lactic Acid / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011100:Polyglycolic Acid / Q000494:pharmacology*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; C528430:Kras protein, rat; D034741:RNA, Small Interfering; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS; RNAi; biocompatibility; biodegradability; biodegradable materials; drug release; oligonucleotides; pancreatic cancer; safety studies; siRNA