Study on Synergistic Treatment of Pancreatic Cancer by Multiple Small Interfering Ribonucleic Acid Lipid
Rongrong Wang1,2, Yiying Zeng1,2, Zhaowu Zeng1,2
1School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China.
Abstract:
Background/Objective: This study aimed to use multiple disk domain receptor 1 (DDR1), transforming growth factor β1 (TGFβ-1), tumor-associated calcium signal transduction protein 2 (TACSTD2), and polyligand proteoglycan 1 (SDC1) siRNA to treat pancreatic cancer with the goals of high specificity, significant therapeutic efficacy, and relatively low toxicity. Methods: (1) A microfluidic method was used to prepare siRNA-LNPs with different formulations. (2) Quantitative PCR (qPCR) and Western blot assays were used to detect the inhibitory effect of different-prescription siRNA-LNP formulations on mRNA and protein expression levels of related genes in PaTu 8988 pancreatic cells. (3) The anti-pancreatic cancer effect of multiple siRNAs combined with LNPs in vivo was evaluated using the BALB/c nude mouse model with subcutaneous pancreatic cancer xenografts. Results: (1) Three siRNA-LNP formulations, DMG, CE 1.5, and CE 0.75, were successfully prepared, exhibiting small particle sizes and uniform distribution. (2) qPCR and Western blot results indicated that DDR1, TGFβ-1, TACSTD2, and SDC1 siRNA-LNP significantly inhibited related genes' mRNA and protein expression in pancreatic cancer PaTu 8988 cells. (3) Efficacy studies in animals indicated that multiple siRNA combined with LNPs in each group exhibited significant antitumor effects on pancreatic cancer tumor-bearing nude mice. The therapeutic efficacy of the combined siRNAs was superior to that of single siRNA treatments, indicating a clear combined effect, especially with three- and four-siRNA combinations. Conclusions: The prepared DDR1/TGFβ-1/TACSTD2/SDC1 siRNA-loaded LNP demonstrated a small particle size, high gene inhibition efficiency, and a significant therapeutic effect in treating pancreatic cancer. Its safety is generally acceptable, but attention should be paid to the toxicity caused by LNP excipients, especially cationic lipids.
Insights
This study developed novel siRNA-loaded lipid nanoparticles (LNPs) targeting DDR1, TGFβ-1, TACSTD2, and SDC1 to treat pancreatic cancer. Combined siRNA treatments showed superior antitumor efficacy in vivo with acceptable safety.
Area of Science:
- Biomedical Engineering
- Molecular Oncology
- Nanomedicine
Background:
- Pancreatic cancer presents significant therapeutic challenges.
- Targeting specific genes like DDR1, TGFβ-1, TACSTD2, and SDC1 offers potential therapeutic strategies.
- Developing effective delivery systems for gene silencing agents is crucial.
Purpose of the Study:
- To develop and evaluate siRNA-loaded lipid nanoparticles (siRNA-LNPs) for pancreatic cancer treatment.
- To assess the gene inhibition efficiency and therapeutic efficacy of combined siRNAs targeting DDR1, TGFβ-1, TACSTD2, and SDC1.
- To investigate the in vivo antitumor effects and safety profile of the developed siRNA-LNPs.
Main Methods:
- Preparation of siRNA-LNPs using a microfluidic method with various formulations.
- Quantitative PCR (qPCR) and Western blot assays to determine gene and protein expression inhibition in pancreatic cancer cells (PaTu 8988).
- Evaluation of in vivo anti-pancreatic cancer efficacy in a BALB/c nude mouse model with subcutaneous xenografts.
Main Results:
- Successfully prepared three siRNA-LNP formulations (DMG, CE 1.5, CE 0.75) with optimal particle characteristics.
- Demonstrated significant inhibition of DDR1, TGFβ-1, TACSTD2, and SDC1 mRNA and protein expression in pancreatic cancer cells.
- Observed significant antitumor effects in vivo, with combined siRNA treatments outperforming single siRNA therapies, particularly three- and four-siRNA combinations.
Conclusions:
- The developed DDR1/TGFβ-1/TACSTD2/SDC1 siRNA-LNPs exhibit small particle size and high gene inhibition efficiency.
- These siRNA-LNPs demonstrate significant therapeutic efficacy against pancreatic cancer in vivo.
- The formulation shows generally acceptable safety, though potential toxicity from LNP excipients requires consideration.
