ANTISENSE OLIGONUCLEOTIDES ADSORBED TO POLYALKYLCYANOACRYLATE NANOPARTICLES SPECIFICALLY INHIBIT MUTATED HA-RAS-MEDIATED CELL-PROLIFERATIONAND TUMORIGENICITY IN NUDE-MICE

ras oncogenes owe their transforming properties to single point mutati ons in the sequence coding for the active site of the p21 protein. The se mutations lead to changes in cellular proliferation and induce tumo rigenic properties. Point mutations represent a well-defined target fo r antisense oligonucleotides that can specifically suppress the transl ation of the targeted mutant mRNA. We show that the stability and cell ular disponibility of antisense oligonucleotides can be markedly impro ved by adsorption to polyalkylcyanoacrylate nanoparticles. Nanoparticl e-adsorbed antisense oligonucleotides directed to a point mutation (G --> U) in codon 12 of the Ha-ras mRNA selectively inhibited the prolif eration of cells expressing the point-mutated Ha-ras gene at a concent ration 100 times lower than free oligonucleotides. In addition they ma rkedly inhibited Ha-ras-dependent tumor growth in nude mice after subc utaneous injection. These experiments show that inhibition of ras onco genes by antisense oligonucleotides can block tumor development even t hough ras oncogenic activation might be an early event in tumor progre ssion.