A tumor-targeting cRGD-EGFR siRNA conjugate and its anti-tumor effect on glioblastoma in vitro and in vivo.
The epidermal growth factor receptor (EGFR) is an important anti-tumor target. The development of novel molecular-targeted anti-tumor drugs that can target the interior of tumor cells and specifically silence EGFR expression is valuable and promising. In this work, a promising anti-tumor conjugate comprising methoxy-modified EGFR siRNA and cyclic arginine-glycine-aspartic acid (cRGD) peptides, which selectively bind to αvβ3 integrins, was synthesized and examined. To prepare cRGD-EGFR siRNA (cRGD-siEGFR), cRGD was covalently conjugated to the 5'-end of an siRNA sense strand using a thiol-maleimide linker. The cellular uptake and cytotoxicity of cRGD-siEGFR in vitro were tested using an αvβ3-positive U87MG cell line. In vivo bio-distribution, anti-tumor activity, immunogenicity and toxicity were investigated in a nude mouse tumor model through repeated i.v. administration of cRGD-siEGFR (7 times over a 48 h interval). Analyses of in vitro data showed that cRGD-siEGFR silenced EGFR expression effectively, with high tumor targeting ability. Administration of cRGD-siEGFR to tumor-bearing nude mice led to significant inhibition of tumor growth, obvious reduction of EGFR expression and down-regulation of EGFR mRNA and protein in tumor tissue. Furthermore, serum biochemistry and pathological section evaluation did not indicate any serious toxicity of cRGD-siEGFR in vivo. cRGD-siEGFR is likely a promising candidate with high targeting ability, substantial anti-tumor effects and low toxicity in vitro and in vivo.
a Department of Pharmacy, Zhujiang Hospital of Southern Medical University , Guangzhou , China and.|b Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou , China.
Shuai
S
He
a Department of Pharmacy, Zhujiang Hospital of Southern Medical University , Guangzhou , China and.
Bohong
B
Cen
a Department of Pharmacy, Zhujiang Hospital of Southern Medical University , Guangzhou , China and.
Lumin
L
Liao
a Department of Pharmacy, Zhujiang Hospital of Southern Medical University , Guangzhou , China and.
Zhen
Z
Wang
a Department of Pharmacy, Zhujiang Hospital of Southern Medical University , Guangzhou , China and.
Yixin
Y
Qin
a Department of Pharmacy, Zhujiang Hospital of Southern Medical University , Guangzhou , China and.
Zhuomin
Z
Wu
a Department of Pharmacy, Zhujiang Hospital of Southern Medical University , Guangzhou , China and.
Wenjie
W
Liao
a Department of Pharmacy, Zhujiang Hospital of Southern Medical University , Guangzhou , China and.
Zhongyi
Z
Zhang
a Department of Pharmacy, Zhujiang Hospital of Southern Medical University , Guangzhou , China and.|b Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou , China.
Aimin
A
Ji
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008024:Ligands; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010456:Peptides, Cyclic / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D000067492:RNAi Therapeutics / Q000379:methods*; D013997:Time Factors; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D039302:Integrin alphaVbeta3; D008024:Ligands; D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; C507169:cyclic arginine-glycine-aspartic acid peptide; C512478:EGFR protein, human; D066246:ErbB Receptors
conjugate system; gene silencing; glioblastoma; siRNA delivery; tumor targeting