Ligand-Targeted Delivery of Small Interfering RNAs to Malignant Cells and Tissues

• Published in: Annals of the New York Academy of Sciences 2009-09, Vol.1175 (1), p.32-39
• Main Authors: Thomas, Mini, Kularatne, Sumith A., Qi, Longwu, Kleindl, Paul, Leamon, Christopher P., Hansen, Michael J., Low, Philip S.
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Cancer; Carrier Proteins - metabolism; Conjugation; Drug delivery systems; Drugs; DUPA; endosomal escape; Female; folate receptor; Folate Receptors, GPI-Anchored; Folic Acid - administration & dosage; Folic Acid - chemistry; Folic Acid - metabolism; Glutarates - administration & dosage; Glutarates - chemistry; Glutarates - metabolism; HeLa Cells; Humans; In vitro testing; Ligands; Male; Mice; Mice, Mutant Strains; Neoplasms - therapy; PSMA; Receptors, Cell Surface - metabolism; Ribonucleic acids; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - chemistry; siRNA; siRNA targeting; Urea - administration & dosage; Urea - analogs & derivatives; Urea - chemistry; Urea - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/j.1749-6632.2009.04977.x

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.