Targeted nanoparticles deliver siRNA to melanoma.
Melanoma is a severe skin cancer that often leads to death. To examine the potential of small interfering RNA (siRNA) therapy for melanoma, we have developed anisamide-targeted nanoparticles that can systemically deliver siRNA into the cytoplasm of B16F10 murine melanoma cells, which express the sigma receptor. A c-Myc siRNA delivered by the targeted nanoparticles effectively suppressed c-Myc expression in the tumor and partially inhibited tumor growth. More significant tumor growth inhibition was observed with nanoparticles composed of N,N-distearyl-N-methyl-N-2-(N'-arginyl) aminoethyl ammonium chloride (DSAA), a guanidinium-containing cationic lipid, than with a commonly used cationic lipid, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). Three daily injections of c-Myc siRNA formulated in the targeted nanoparticles containing DSAA could impair tumor growth, and the ED(50) of c-Myc siRNA was about 0.55  mg  kg(-1). The targeted DSAA nanoparticles containing c-Myc siRNA sensitized B16F10 cells to paclitaxel (Taxol), resulting in a complete inhibition of tumor growth for 1 week. Treatments of c-Myc siRNA in the targeted nanoparticles containing DSAA also showed significant inhibition on the growth of MDA-MB-435 tumor. The enhanced anti-melanoma activity is probably related to the fact that DSAA, but not DOTAP, induced reactive oxygen species, triggered apoptosis, and downregulated antiapoptotic protein Bcl-2 in B16F10 melanoma cells. Thus, the targeted nanoparticles containing c-Myc siRNA may serve as an effective therapeutic agent for melanoma.
Chen
Yunching
Y
Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Bathula
Surendar R
SR
Yang
Qi
Q
Huang
Leaf
L
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D016259:Genes, myc / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008081:Liposomes / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane