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 accessAbstract
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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siG12D-LODER is a mutant-specific siRNA-polymeric nanoparticle against KRASG12D developed to treat advanced pancreatic cancer.
“siG12D-LODER (238) is a mutant-specific siRNA-polymeric nanoparticles against KRASG12D developed by Silenseed Ltd. to treat advanced pancreatic cancer.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [571]
Preclinical trials showed that KRASG12D suppressed the growth of pancreatic tumors in rat models with local and systemic safety and tolerability.
“Preclinical trials showed that KRASG12D suppressed the growth of pancreatic tumors in rat models with local and systemic safety and tolerability.571”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [571]
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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
- Publisher
- SAGE Publications
- 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
- bronze
- doi.org
- 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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