Targeted delivery of antisense inhibitor of miRNA for antiangiogenesis therapy using cRGD-functionalized nanoparticles.
MiRNAs are viable therapeutic targets for cancer therapy, but the targeted delivery of miRNA or its anti-miRNA antisense oligonucleotides (AMOs) remains a challenge. We report here a PEGylated LPH (liposome-polycation-hyaluronic acid) nanoparticle formulation modified with cyclic RGD peptide (cRGD) for specific and efficient delivery of AMO into endothelial cells, targeting α(v)β₃ integrin present on the tumor neovasculature. The nanoparticles effectively delivered anti-miR-296 AMO to the cytoplasm and downregulated the target miRNA in human umbilical vein endothelial cells (HUVECs), which further efficiently suppressed blood tube formulation and endothelial cell migration, owing to significant upregulation of hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), whereas nanoparticles without cRGD modification showed only little AMO uptake and miRNA silencing activity. In vivo assessment of angiogenesis using Matrigel plug assay also demonstrated that cRGD modified LPH nanoparticles have potential for antiangiogenesis in miRNA therapeutics. With the delivery of anti-miR-296 AMO by targeted nanoparticles, significant decrease in microvessel formulation within Matrigel was achieved through suppressing the invasion of CD31-positive cells into Matrigel and prompting HGS expression in angiogenic endothelial cells.
Key Laboratory of Brain Function and Diseases of Chinese Academy of Sciences, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
Xi-Qiu
XQ
Liu
Wen-Jing
WJ
Song
Tian-Meng
TM
Sun
Pei-Zhuo
PZ
Zhang
Jun
J
Wang
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008962:Models, Theoretical; D053758:Nanoparticles / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D009842:Oligopeptides / Q000737:chemistry*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism
D056827:Endosomal Sorting Complexes Required for Transport; D008081:Liposomes; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D010750:Phosphoproteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C047981:arginyl-glycyl-aspartic acid