Peptide-guided JC polyomavirus-like particles specifically target bladder cancer cells for gene therapy

Wei-Hong Lai,Deching Chang,Chiung-Yao Fang,Chun-Nun Chao,Cheng-Huang Shen,Meilin Wang,Ming-Chieh Chou,Mien-Chun Lin,Yeong‐Chin Jou

doi:10.1038/s41598-021-91328-7

Abstract

The ultimate goal of gene delivery vectors is to establish specific and effective treatments for human diseases. We previously demonstrated that human JC polyomavirus (JCPyV) virus-like particles (VLPs) can package and deliver exogenous DNA into susceptible cells for gene expression. For tissue-specific targeting in this study, JCPyV VLPs were conjugated with a specific peptide for bladder cancer (SPB) that specifically binds to bladder cancer cells. The suicide gene thymidine kinase was packaged and delivered by SPB-conjugated VLPs (VLP-SPBs). Expression of the suicide gene was detected only in human bladder cancer cells and not in lung cancer or neuroblastoma cells susceptible to JCPyV VLP infection in vitro and in vivo, demonstrating the target specificity of VLP-SPBs. The gene transduction efficiency of VLP-SPBs was approximately 100 times greater than that of VLPs without the conjugated peptide. JCPyV VLPs can be specifically guided to target particular cell types when tagged with a ligand molecule that binds to a cell surface marker, thereby improving gene therapy.

Highlights

Abbreviations GCV Ganciclovir specific peptide for bladder cancer (SPB) Specific peptide for bladder cancer TAMRA Tetramethylrhodamine tk Thymidine kinase virus-like particles (VLPs) Virus-like particle
JC polyomavirus (JCPyV) VLP-SPBs effectively delivered the tk suicide gene, which is cytotoxic to bladder cancer cells, only to bladder cancer cell lines and not to cell lines originally demonstrated to be susceptible to JCPyV VLPs, such as lung cancer and neuroblastoma cell lines
The xenograft mouse model showed that JCPyV VLP-SPB only inhibited the growth of bladder tumors, while the growth of lung cancer cells on the contralateral side was unaffected

Summary

Introduction

Abbreviations GCV Ganciclovir SPB Specific peptide for bladder cancer TAMRA Tetramethylrhodamine tk Thymidine kinase VLP Virus-like particle. Exogenous genes of interest can be packaged by the VLPs without requiring viral genetic material, which can be subsequently delivered into tissues susceptible to JCPyV to enable gene transduction and gene therapy. These VLPs were successfully used to package and deliver exogenous DNA into human kidney cells for e xpression[9]. The VLPs were used to successfully deliver a BK polyomavirus (BKPyV) LT peptidespecific small hairpin RNA to inhibit BKPyV replication in human kidney cells[20] and to deliver an interleukin (IL)-10 RNA interference vector into macrophage cells to reduce IL-10 e xpression[21] as a possible gene therapy for systemic lupus erythematosus. This SPB was conjugated with JCPyV VLPs for the investigation of bladder cancer-specific targeting

Methods

Results

Conclusion