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Combination therapy with chitosan/siRNA nanoplexes targeting PDGF-D and PDGFR-β reveals anticancer effect in breast
Emine Şalva1, Suna Özbaş2, Saadet Alan3
1Department of Pharmaceutical Biotechnology, İnönü University, Faculty of Pharmacy, Malatya, Turkey.
Background:
Platelet derived growth factors (PDGF)-D and the expression of its receptor increase in neoplastic progression of cancer. Co-silencing of growth factor and receptor can be suggested as an important strategy for effective cancer therapy. In the present study, we hypothesized that suppression of PDGF-D signaling pathway with small interfering RNAs (siRNAs) targeting both PDGF-D and PDGF receptor (PDGFR)-β is a promising strategy for anticancer therapy.
Methods:
Chitosan nanoplexes containing dual and single siRNA were prepared at different weight ratios and controlled by gel retardation assay. Characterization, cellular uptake, gene silencing and invasion studies were performed. The effect of nanoplexes on breast tumor growth, PDGF expression and apoptosis was investigated.
Results:
We have shown that downregulation of PDGF-D and PDGFR-β with chitosan/siRNA nanoplex formulations reduced proliferation and invasion in breast cancer cells. In the in vivo breast tumor model, it was determined that the intratumoral administration of chitosan/siPDGF-D/siPDGFR-β nanoplexes markedly decreased the tumor volume and PDGF-D and PDGFR-β mRNA and protein expression levels and increased apoptosis.
Conclusions:
According to the results obtained, we evaluated the effect of PDGF-D and PDGFR-β on breast tumor development and showed that RNAi-mediated inhibition of this pathway formulated with chitosan nanoplexes can be considered as a new breast cancer therapy strategy.
Insights
This study shows that dual siRNA targeting Platelet-Derived Growth Factor (PDGF)-D and its receptor (PDGFR)-β, delivered via chitosan nanoplexes, effectively inhibits breast cancer growth. This RNA interference strategy significantly reduces tumor volume and promotes apoptosis in vivo.
Area of Science:
- Oncology
- Biotechnology
- Molecular Biology
Background:
- Platelet-Derived Growth Factor (PDGF)-D and its receptor (PDGFR)-β expression increase during cancer progression.
- Co-silencing of PDGF-D and PDGFR-β is a potential therapeutic strategy for cancer.
- This study investigates the suppression of the PDGF-D signaling pathway for anticancer therapy.
Purpose of the Study:
- To evaluate the efficacy of small interfering RNAs (siRNAs) targeting both PDGF-D and PDGFR-β for breast cancer therapy.
- To develop chitosan nanoplexes for co-delivery of dual siRNAs against PDGF-D and PDGFR-β.
- To assess the impact of this targeted therapy on breast cancer cell proliferation, invasion, tumor growth, and apoptosis.
Main Methods:
- Chitosan nanoplexes encapsulating single and dual siRNAs were prepared and characterized.
- In vitro studies assessed cellular uptake, gene silencing, and invasion inhibition in breast cancer cells.
- In vivo studies in a breast tumor model evaluated the effect of nanoplex administration on tumor volume, gene expression, and apoptosis.
Main Results:
- Chitosan/siRNA nanoplex formulations effectively reduced breast cancer cell proliferation and invasion.
- Intratumoral administration of chitosan/siPDGF-D/siPDGFR-β nanoplexes significantly decreased tumor volume in vivo.
- The treatment led to reduced PDGF-D and PDGFR-β mRNA and protein expression, alongside increased apoptosis.
Conclusions:
- RNAi-mediated inhibition of the PDGF-D/PDGFR-β pathway using chitosan nanoplexes is a promising strategy for breast cancer treatment.
- Dual silencing of PDGF-D and PDGFR-β demonstrates significant therapeutic potential.
- This approach offers a novel therapeutic avenue for managing breast tumor development.
