PDGFR-α shRNA-polyplex for uveal melanoma treatment via EMT mediated vasculogenic mimicry interfering.

Abstract

Up to 50% of individuals with uveal melanoma (UM), a frequent cancer of the eye, pass away from metastases. One of the major challenges in treating UM is the role of receptor tyrosine kinases (RTKs), which mediate the epithelial-mesenchymal transition (EMT) of tumors. RTKs are involved in binding multiple growth factors, leading to angiogenesis and vasculogenic mimicry (VM) phenomena. Currently, most anti-angiogenic drugs have shown a tendency to increase the VM of tumors in clinical trials, resulting in limited efficacy. The existing gap in UM treatment lies in the lack of effective strategies to target RTK-mediated EMT and VM. While some approaches have been attempted, there is still a need for novel therapeutic interventions that can specifically interfere with these processes. This research employed the gene vector PEI-g-PEG to interfere with the platelet derived growth factor-alpha receptor (PDGFR-α)-mediated EMT process, thereby retarding the growth of UM. The cell experiments demonstrated that the gene polyplex exhibited favorable cell uptake and lysosome escape properties, effectively suppressing the expression of PDGFR-α protein and EMT marker proteins and the occurrence of VM phenomenon. In vivo animal studies also inhibited the growth of UM, and PAS assays showed that the treatment reduced the generation of VM in tumor tissue. This study broadens the application of PEI-g-PEG while interfering with the RTK-mediated tumor EMT process with the help of RNAi technology, providing a new idea for tumor reduction research.