Tumor-specific delivery of therapeutic siRNAs by anti-EGFR immunonanoparticles

Abstract

Jung Seok Kim,1,* Min Woo Kim,1,* Seong Jae Kang,1,* Hwa Yeon Jeong,1 Sang Il Park,1 Yeon Kyung Lee,1 Hong Sung Kim,2 Keun Sik Kim,3 Yong Serk Park1 1Department of Biomedical Laboratory Science, Yonsei University, Wonju, Republic of Korea; 2Department of Biomedical Laboratory Science, Korea Nazarene University, Cheonan, Republic of Korea; 3Department of Biomedical Laboratory Science, Konyang University, Daejeon, Republic of Korea *These authors contributed equally to this work Background: Efficient target-specific siRNA delivery has always been a primary concern in the field of siRNA clinical application. Purpose: In this study, four different types of anti-epidermal growth factor receptor (EGFR) antibody-conjugated immunonanoparticles were prepared and tested for cancer cell-targeted therapeutic siRNA delivery. Materials and methods: The prepared nanoparticles encapsulating siRNAs were characterized by gel retardation and particle analysis using a Zetasizer. In vitro transfection and reduction of target genes, vimentin and JAK3, were determined using quantitative reverse transcription polymerase chain reaction. In vivo tumor targeting and antitumoral efficacies of the nanoparticles were evaluated in mice carrying tumors. Results: Among these immunonanoparticles, anti-EGFR immunolipoplexes and immunoviroplexes exhibited remarkable cell binding and siRNA delivery to EGFR-expressing tumor cells compared to immunoliposomes and immunovirosomes. Especially, the anti-EGFR immunoviroplexes exhibited the most efficient siRNA transfection to target tumor cells. Therefore, antitumoral vimentin and Janus kinase-3 siRNAs were loaded in the anti-EGFR immunolipoplexes and immunoviroplexes, which were tested in mice carrying SK-OV-3 tumor xenografts. In fact, the therapeutic siRNAs were efficiently delivered to the tumor tissues by both delivery vehicles, resulting in significant inhibition of tumor growth. Moreover, administration of doxorubicin in combination with anti-EGFR immunoviroplexes resulted in remarkable and synergistic tumor growth inhibition. Conclusion: This study provides experimental proof that cancer cell-targeted immunoviroplexes are an efficient siRNA delivery system for cancer therapy. Moreover, this study also suggests that a combination of conventional chemotherapy and tumor-directed anticancer siRNA therapy would be a better modality for cancer treatment. Keywords: EGFR, siRNA delivery, anti-EGFR immunonanoparticles, anti-EGFR immunoviroplexes, combinatorial therapy

Keywords

• EGFR
• siRNA delivery
• Anti-EGFR immunonanoparticles
• Anti-EGFR immunoviroplexes
• Combinatorial therapy