Dual peptide-mediated targeted delivery of bioactive siRNAs to oral cancer cells in vivo

作者：Alexander Bryant Angela A; Zhang Haiwen; Attaway Christopher C; Pugh William; Eggart Laurence; Sansevere Robert M; Andino Lourdes M; Lu Dinh; Cantini Liliana P; Jakymiw Andrew^*

来源：Oral Oncology, 2017, 72: 123-131.

DOI：10.1016/j.oraloncology.2017.07.004

• Peptide
• Homing/targeting
• Cell-penetrating
• Endosome-disruptive
• Oral cancer
• OSCC
• siRNA
• RNAi
• EGFR
• CIP2A

Objectives: Despite significant advances in cancer treatment, the prognosis for oral cancer remains poor in comparison to other cancer types, including breast, skin, and prostate. As a result, more effective therapeutic modalities are needed for the treatment of oral cancer. Consequently, in the present study, we examined the feasibility of using a dual peptide carrier approach, combining an epidermal growth factor receptor (EGFR)-targeting peptide with an endosome-disruptive peptide, to mediate targeted delivery of small interfering RNAs (siRNAs) into EGFR-overexpressing oral cancer cells and induce silencing of the targeted oncogene, cancerous inhibitor of protein phosphatase 2A (CIP2A).
Materials and methods: Fluorescence microscopy, real-time PCR, Western blot analysis, and in vivo bioimaging of mice containing orthotopic xenograft tumors were used to examine the ability of the dual peptide carrier to mediate specific delivery of bioactive siRNAs into EGFR-overexpressing oral cancer cells/tissues.
Results: Co-complexation of the EGFR-targeting peptide, GE11R9, with the endosome-disruptive 599 peptide facilitated the specific uptake of siRNAs into oral cancer cells overexpressing EGFR in vitro with optimal gene silencing observed at a 60: 30: 1 (GE11R9: 599: siRNA) molar ratio. Furthermore, when administered systemically to mice bearing xenograft oral tumors, this dual peptide complex mediated increased targeted delivery of siRNAs into tumor tissues in comparison to the 599 peptide alone and significantly enhanced CIP2A silencing.
Conclusion: Herein we provide the first report demonstrating the clinical potential of a dual peptide strategy for siRNA-based therapeutics by synergistically mediating the effective targeting and delivery of bioactive siRNAs into EGFR-overexpressing oral cancer cells.

• 出版日期2017-9