Ligand-targeted delivery of small interfering RNAs to malignant cells and tissues.
Potential clinical applications of small interfering RNA (siRNA) are hampered primarily by delivery issues. We have successfully addressed the delivery problems associated with off-site targeting of highly toxic chemotherapeutic agents by attaching the drugs to tumor-specific ligands that will carry the attached cargo into the desired cancer cell. Indeed, several such tumor-targeted drugs are currently undergoing human clinical trials. We now show that efficient targeting of siRNA to malignant cells and tissues can be achieved by covalent conjugation of small-molecular-weight, high-affinity ligands, such as folic acid and DUPA (2-[3-(1, 3-dicarboxy propyl)-ureido] pentanedioic acid), to siRNA. The former ligand binds a folate receptor that is overexpressed on a variety of cancers, whereas the latter ligand binds to prostate-specific membrane antigen that is overexpressed specifically on prostate cancers and the neovasculature of all solid tumors. Using these ligands, we show remarkable receptor-mediated targeting of siRNA to cancer tissues in vitro and in vivo.
Thomas
Mini
M
Department of Chemistry, Purdue University, West Lafayette, Indiana, USA.
Kularatne
Sumith A
SA
Qi
Longwu
L
Kleindl
Paul
P
Leamon
Christopher P
CP
Hansen
Michael J
MJ
Low
Philip S
PS
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D005977:Glutarates / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000378:metabolism; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C544380:2-(3-(1,3-dicarboxypropyl)ureido)pentanedioic acid; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D005977:Glutarates; D008024:Ligands; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D014508:Urea; D005492:Folic Acid