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Ligand‐Targeted Delivery of Small Interfering RNAs to Malignant Cells and Tissues
Author(s) -
Thomas Mini,
Kularatne Sumith A.,
Qi Longwu,
Kleindl Paul,
Leamon Christopher P.,
Hansen Michael J.,
Low Philip S.
Publication year - 2009
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2009.04977.x
Subject(s) - folate receptor , small interfering rna , in vivo , cancer research , ligand (biochemistry) , in vitro , chemistry , receptor , cancer , prostate cancer , cancer cell , folic acid , rna , biochemistry , biology , medicine , gene , microbiology and biotechnology
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 .