Fusogenic-oligoarginine peptide-mediated silencing of the CIP2A oncogene suppresses oral cancer tumor growth in vivo

JOURNAL OF CONTROLLED RELEASE

卷:218

Article

Alexander-Bryant, Angela A.^1,2,3  Dumitriu, Anca⁴  Attaway, Christopher C.^1,2  Yu, Hong^1,2  Jakymiw, Andrew^1,2,3 

[1] Med Univ S Carolina, Dept Oral Hlth Sci, Hollings Canc Ctr, Charleston, SC 29425 USA

[2] Med Univ S Carolina, Ctr Oral Hlth Res, Hollings Canc Ctr, Charleston, SC 29425 USA

[3] Clemson Univ, Dept Bioengn, Clemson, SC 29634 USA

[4] Med Univ S Carolina, Dept Pediat, Div Hematol Oncol, Charleston, SC 29425 USA

关键词: Fusogenic peptide;    Cell-penetrating peptide;    Oral cancer;    CIP2A;    siRNA delivery;    RNAi;   

DOI  :  10.1016/j.jconrel.2015.09.026

来源: Elsevier

【 摘 要 】

Intracellular delivery and endosomal escape of functional small interfering RNAs (siRNAs) remainmajor barriers limiting the clinical translation of RNA interference (RNAi)-based therapeutics. Recently, we demonstrated that a cell-penetrating endosome-disruptive peptide we synthesized, termed 599, enhanced the intracellular delivery and bioavailability of siRNAs designed to target the CIP2A oncoprotein (siCIP2A) into oral cancer cells and consequently inhibited oral cancer cell invasiveness and anchorage-independent growth in vitro. Thus, to further assess the therapeutic potential of the 599 peptide in mediating RNAi-based therapeutics for oral cancer and its prospective applicability in clinical settings, the objective of the current study was to determine whether intratumoral dosing of the 599 peptide-siCIP2A complex could induce silencing of CIP2A and consequently impair tumor growth using a xenograft oral cancer mousemodel. Our results demonstrate that the 599 peptide is able to protect siRNAs from degradation by serum and ribonucleases in vitro and upon intratumoral injection in vivo, confirming the stability of the 599 peptide-siRNA complex and its potential for therapeutic utility. Moreover, 599 peptide-mediated delivery of siCIP2A to tumor tissue induces CIP2A silencing without any associated toxicity, consequently resulting in reduction of themitotic index and significant inhibition of tumor growth. Together, these data suggest that the 599 peptide carrier is a clinically effective mediator of RNAi-based cancer therapeutics. (C) 2015 Elsevier B. V. All rights reserved.

【 授权许可】

Free