Evaluation of folate-PAMAM for the delivery of antisense oligonucleotides to rat C6 glioma cells in vitro and in vivo.
In the current study, we evaluated the efficiency of folate-polyamidoamine dendrimers conjugates (FA-PAMAM) for the in situ delivery of therapeutic antisense oligonucleotides (ASODN) that could inhibit the growth of C6 glioma cells. Folic acid was coupled to the surface amino groups of G5-PAMAM dendrimer (G5D) through a 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide bond, and ASODNs corresponding to rat epidermal growth factor receptor (EGFR) were then complexed with FA-PAMAM. At an ASODN to PAMAM ratio of 16:1, agarose electrophoresis indicated that antisense oligonucleotides were completely complexed with PAMAM or FA-PAMAM. The ASODN transfection rates mediated by FA-PAMAM and PAMAM were superior to oligofectamine, resulting in greater suppression of EGFR expression and glioma cell growth. Stereotactic injection of EGFR ASODN:FA-PAMAM complexes into established rat C6 intracranial gliomas resulted in greater suppression of tumor growth and longer survival time of tumor-bearing rats compared with PAMAM and oligofectamine-mediated EGFR-ASODN therapy. The current study demonstrates the suitability of folate-PAMAM dendrimer conjugates for efficient EGFR ASODN delivery into glioma cells, wherein they release the ASODN from the FA-PAMAM to knock down EGFR expression in C6 glioma cells, both in vitro and in vivo. FA-PAMAM may thus represent a novel delivery system for short oligonucleotides in glioma-targeted therapy.
Kang
Chunsheng
C
Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin 300052, People's Republic of China.
Yuan
Xubo
X
Li
Fei
F
Pu
Peiyu
P
Yu
Shizhu
S
Shen
Changhong
C
Zhang
Zhiyong
Z
Zhang
Yunting
Y
D000818:Animals; D017209:Apoptosis; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005910:Glioma / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008422:Materials Testing; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D001672:Biocompatible Materials; D050091:Dendrimers; D016376:Oligonucleotides, Antisense; C104700:PAMAM Starburst; D005492:Folic Acid; D066246:ErbB Receptors