Combination therapy with chitosan/siRNA nanoplexes targeting PDGF‐D and PDGFR‐β reveals anticancer effect in breast cancer

• Published in: The journal of gene medicine 2023-02, Vol.25 (2), p.e3465-n/a
• Main Authors: Şalva, Emine, Özbaş, Suna, Alan, Saadet, Özkan, Naziye, Ekentok‐Atıcı, Ceyda, Kabasakal, Levent, Akbuğa, Jülide
• Format: Article
• Language: English
• Subjects: Apoptosis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cancer therapies; Cell proliferation; Chitosan; Chitosan - therapeutic use; Combination therapy; Female; Gene expression; Gene silencing; Gene therapy; Humans; mRNA; Nanostructures - therapeutic use; PDGFR‐β; PDGF‐D; Platelet-derived growth factor; Receptor, Platelet-Derived Growth Factor beta - genetics; Receptor, Platelet-Derived Growth Factor beta - metabolism; RNA Interference; RNA, Small Interfering - genetics; RNA, Small Interfering - therapeutic use; RNA-mediated interference; RNAi; Signal transduction; siRNA; Tumors
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/jgm.3465

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. The suppression of Platelet derived growth factors (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. The downregulation of PDGF‐D and PDGFR‐β with chitosan/siRNA nanoplex formulations reduced proliferation and invasion in breast cancer cells and markedly decreased in tumor volume in the in vivo breast tumor model.