Ligand-targeted delivery of small interfering RNAs to malignant cells and tissues

Mini Thomas; Sumith A. Kularatne; Longwu Qi; Paul Kleindl; Christopher P. Leamon; Michael J. Hansen; Philip S. Low

doi:10.1111/j.1749-6632.2009.04977.x

Ligand-targeted delivery of small interfering RNAs to malignant cells and tissues

Mini Thomas, Sumith A. Kularatne, Longwu Qi, Paul Kleindl, Christopher P. Leamon, Michael J. Hansen, Philip S. Low

Research output: Chapter in Book/Report/Conference proceeding › Conference contribution

68 Scopus citations

Abstract

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.

Original language	English (US)
Title of host publication	Oligonucleotide Therapeutics Fourth Annual Meeting
Publisher	Blackwell Publishing Inc.
Pages	32-39
Number of pages	8
ISBN (Print)	9781573317580
DOIs	https://doi.org/10.1111/j.1749-6632.2009.04977.x
State	Published - Sep 1 2009

Publication series

Name	Annals of the New York Academy of Sciences
Volume	1175
ISSN (Print)	0077-8923
ISSN (Electronic)	1749-6632

Keywords

DUPA
Endosomal escape
Folate receptor
PSMA
SiRNA
SiRNA targeting

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1111/j.1749-6632.2009.04977.x

Cite this

Thomas, M., Kularatne, S. A., Qi, L., Kleindl, P., Leamon, C. P., Hansen, M. J., & Low, P. S. (2009). Ligand-targeted delivery of small interfering RNAs to malignant cells and tissues. In Oligonucleotide Therapeutics Fourth Annual Meeting (pp. 32-39). (Annals of the New York Academy of Sciences; Vol. 1175). Blackwell Publishing Inc.. https://doi.org/10.1111/j.1749-6632.2009.04977.x

Ligand-targeted delivery of small interfering RNAs to malignant cells and tissues. / Thomas, Mini; Kularatne, Sumith A.; Qi, Longwu et al.
Oligonucleotide Therapeutics Fourth Annual Meeting. Blackwell Publishing Inc., 2009. p. 32-39 (Annals of the New York Academy of Sciences; Vol. 1175).

Research output: Chapter in Book/Report/Conference proceeding › Conference contribution

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abstract = "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.",

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AU - Qi, Longwu

AU - Kleindl, Paul

AU - Leamon, Christopher P.

AU - Hansen, Michael J.

AU - Low, Philip S.

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N2 - 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.

AB - 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.

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KW - SiRNA targeting

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Ligand-targeted delivery of small interfering RNAs to malignant cells and tissues

Abstract

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Keywords

ASJC Scopus subject areas

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