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Cancer-Targeting Peptides Functionalized With Polyarginine Enables GRP78-Dependent Cell Uptake and siRNA Delivery
George Hilan1, Grace Daniel2,3, Filiz Collak1,2
1Department of Biology, Carleton University, Ottawa, ON, Canada.
Summary
Researchers developed a novel peptide strategy for targeted delivery of short-interfering RNA (siRNA) in prostate cancer cells. This GRP78-targeting peptide facilitates efficient cellular uptake and gene silencing, paving the way for innovative cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Nanotechnology
Background:
- Targeted delivery of therapeutic agents like short-interfering RNA (siRNA) is crucial for effective cancer treatment.
- The GRP78 receptor is overexpressed on various cancer cells, making it a promising target for cancer-specific therapies.
- Developing efficient and safe delivery vehicles for nucleic acid-based therapeutics remains a significant challenge.
Purpose of the Study:
- To investigate a novel peptide-based strategy for GRP78-targeting siRNA delivery in cancer cells.
- To evaluate the efficiency and mechanism of cellular uptake of GRP78-targeting peptides.
- To assess the potential of peptide:siRNA complexes for RNA interference (RNAi) and their impact on cancer cell fate under stress.
Main Methods:
- Synthesis of fluorescein-labeled amphiphilic peptides combining GRP78-targeting and cell-penetrating domains.
- Assessment of GRP78-dependent cellular uptake in DU145 prostate cancer and WI-38 fibroblast cells.
- Mechanistic studies using endocytosis inhibitors to elucidate the uptake pathway.
- Formation and characterization of peptide:siRNA nanoparticles, with calcium as a stabilizer.
- Preliminary siRNA transfections in DU145 cells to evaluate GRP78 knockdown effects under ER stress.
Main Results:
- GRP78-targeting peptides demonstrated GRP78-dependent cell uptake in DU145 cells, with lower uptake in WI-38 cells.
- Energy-dependent, GRP78 receptor-mediated endocytosis was identified as the primary uptake mechanism.
- Peptide:siRNA complexes formed stable nanoparticles, and calcium promoted endosomal escape for RNAi.
- GRP78 knockdown in DU145 cells under ER stress induced a complex interplay between cell survival and cell death pathways.
Conclusions:
- The GRP78-targeting polyarginine peptides enable efficient and specific siRNA delivery into DU145 cancer cells.
- This peptide-based system shows potential for targeted gene delivery and cancer therapy innovation.
- The findings highlight the importance of synthetic bioactive peptides in advancing cancer research and therapeutic strategies.
