Abstract

Small interfering RNA (siRNA) can specifically silence disease gene expression. This project investigated the overexpression of programmed death receptor ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) on the surface of tumor cells. However, the main obstacle to the development of gene therapy drugs is the lack of an efficient delivery vector, which should be able to overcome multiple delivery barriers and protect siRNA to enter the target cells. Therefore, a novel fluorine-modified endogenous molecular carrier TFSPEI was constructed by linking fluorinated groups with hydrophobic and hydrophilic characteristics on the surface of PEI and spermine. The results showed that lower toxicity, higher endocytosis, and silencing efficiency were achieved. We found that the inhibition of VEGF targets can indirectly activate the immune response to promote the tumor-killing and invasion effects of T cells. The combined delivery of anti-VEGF siRNA and anti-PD-L1 siRNA could inhibit the expression of corresponding proteins, restore the anti-tumor function of T cells and inhibit the growth of neovascularization, and obtained significant anti-tumor effects. Therefore, this safe and efficient fluorinated spermine and small molecule PEI-based anti-PD-L1 and anti-VEGF siRNA delivery system is expected to provide a new strategy for gene therapy of tumors.

Highlights

  • TFSPEI was synthesized by condensing PEI 1.8 kDa and spermine with 2,3,5,6tetrafluoroterephthaldehyde through imine linkage

  • The positive signal density was significantly reduced in the TFSPEI-anti-vascular endothelial growth factor (VEGF) group and the TFSPEI-combination group, and the difference between the two groups was not significant. These results show that anti-VEGF Small interfering RNA (siRNA) delivered by TFSPEI can effectively inhibit tumor angiogenesis, and there is no relevant pathway for anti-programmed death receptor ligand 1 (PD-L1) siRNA

  • Fluoride TFSPEI was successfully constructed by forming an imine linkage between PEI 1.8 kDa, spermine, and the aldehyde group

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Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The incidence of tumors has been increasing year by year, seriously threatening human health. The drugs used to treat tumors are still concentrated on traditional small-molecule chemical drugs and macromolecular protein drugs [1], but the targets of these drugs only account for 2–5% of the whole genome [2], and more than 90%. Of the remaining genome requires gene drugs to achieve target druggability. By the end of 2017, nearly 2600 gene therapy clinical trials were underway or have been approved globally, 65% of which are used for the treatment of cancer [3,4]

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