Cited by 64RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryPancreatic and Hepatic Oncology Research

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

Open access
Ramot, Yuval, Rotkopf, Shay, Gabai, Rachel Malka, Zorde Khvalevsky, Elina, Muravnik, Sofia, Marzoli, Gabriela Alejandra, Domb, Abraham J., Shemi, Amotz +1 more·2016·Toxicologic Pathology

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.

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Crossref · 10.1177/0192623316645860

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Authors
Ramot, Y., Rotkopf, S., Gabai, R. M., Zorde Khvalevsky, E., Muravnik, S., Marzoli, G. A., Domb, A. J., Shemi, A., & Nyska, A.
Affiliations
  • Hadassah Medical Center (IL)
  • Silenseed Ltd, Modiin, Israel
  • Toxicology Department, Research Toxicology Centre, Pomezia, Italy
  • Hebrew University of Jerusalem (IL)
  • Tel Aviv University (IL)
Corresponding author
Nyska, Abraham
Venue
Toxicologic Pathology
Published
2016-07-11
Volume
44
Issue
6
Pages
856-865
ISSN
  • 0192-6233 (ISSN-L)
  • 1533-1601
OpenAlex
W2346795279
Cited by
64
References
50
Citations by year
2026: 2 · 2025: 4 · 2024: 5 · 2023: 11 · 2022: 7 · 2021: 11 · 2020: 9 · 2019: 9 · 2018: 2 · 2017: 3 · 2016: 1
FWCI
2.60
Type
journal article
Language
en
Open access
Locations
  • Toxicologic Pathology (publishedVersion)
  • PubMed (publishedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Keywords
pancreatic cancer, KRAS G12D mutation, RNA interference, biocompatibility, subcutaneous implantation, toxicity, macrophages, multinucleated giant cells
MeSH terms
Polylactic Acid-Polyglycolic Acid Copolymer, Animals, Antineoplastic Agents, Drug Carriers, Pancreatic Neoplasms, Polyglycolic Acid, Proto-Oncogene Proteins p21(ras), Rats, Sprague-Dawley, Lactic Acid, Carcinoma, Pancreatic Ductal, RNA, Small Interfering, Rats

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