Tissue-Penetrating Delivery of Compounds and Nanoparticles into Tumors

Kazuki N. Sugahara; Tambet Teesalu; Priya Prakash Karmali; Venkata Ramana Kotamraju; Lilach Agemy; Olivier M. Girard; Douglas Hanahan; Robert F. Mattrey; Erkki Ruoslahti

doi:10.1016/j.ccr.2009.10.013

Tissue-Penetrating Delivery of Compounds and Nanoparticles into Tumors

Kazuki N. Sugahara, Tambet Teesalu, Priya Prakash Karmali, Venkata Ramana Kotamraju, Lilach Agemy, Olivier M. Girard, Douglas Hanahan, Robert F. Mattrey, Erkki Ruoslahti

Research output: Contribution to journal › Article › peer-review

939 Scopus citations

Abstract

Poor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compounds deep into the tumor parenchyma that uses a tumor-homing peptide, iRGD (CRGDK/RGPD/EC). Intravenously injected compounds coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. iRGD homes to tumors through a three-step process: the RGD motif mediates binding to αv integrins on tumor endothelium and a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor-imaging agents and enhanced the activity of an antitumor drug.

Original language	English (US)
Pages (from-to)	510-520
Number of pages	11
Journal	Cancer Cell
Volume	16
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2009.10.013
State	Published - Dec 8 2009

Keywords

CELLCYCLE

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2009.10.013

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title = "Tissue-Penetrating Delivery of Compounds and Nanoparticles into Tumors",

abstract = "Poor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compounds deep into the tumor parenchyma that uses a tumor-homing peptide, iRGD (CRGDK/RGPD/EC). Intravenously injected compounds coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. iRGD homes to tumors through a three-step process: the RGD motif mediates binding to αv integrins on tumor endothelium and a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor-imaging agents and enhanced the activity of an antitumor drug.",

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author = "Sugahara, {Kazuki N.} and Tambet Teesalu and Karmali, {Priya Prakash} and Kotamraju, {Venkata Ramana} and Lilach Agemy and Girard, {Olivier M.} and Douglas Hanahan and Mattrey, {Robert F.} and Erkki Ruoslahti",

note = "Funding Information: We thank M.J. Sailor and J.-H. Park for advice on the synthesis of iron oxide nanoworms, D.A. Cheresh for the M21 and R.M. Hoffman for the GFP-PC-3 cell lines, E. Engvall for comments on the manuscript, and L. Zhang and T. J{\"a}rvinen for advice on the phage display screens. We also thank E. Allen and E. Drori for support with transgenic mice, J. Corbeil for help with MRI, and R. Varghese for editing. This work was supported by National Cancer Institute grants CA104898, CA115410, CA119414, CA119335, and CA30199 (Cancer Center Support Grant) and grants W81XWH-08-1-0727 and W81XWH-08-BCRP-CIA from the Department of Defense. ",

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doi = "10.1016/j.ccr.2009.10.013",

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pages = "510--520",

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T1 - Tissue-Penetrating Delivery of Compounds and Nanoparticles into Tumors

AU - Sugahara, Kazuki N.

AU - Teesalu, Tambet

AU - Karmali, Priya Prakash

AU - Kotamraju, Venkata Ramana

AU - Agemy, Lilach

AU - Girard, Olivier M.

AU - Hanahan, Douglas

AU - Mattrey, Robert F.

AU - Ruoslahti, Erkki

N1 - Funding Information: We thank M.J. Sailor and J.-H. Park for advice on the synthesis of iron oxide nanoworms, D.A. Cheresh for the M21 and R.M. Hoffman for the GFP-PC-3 cell lines, E. Engvall for comments on the manuscript, and L. Zhang and T. Järvinen for advice on the phage display screens. We also thank E. Allen and E. Drori for support with transgenic mice, J. Corbeil for help with MRI, and R. Varghese for editing. This work was supported by National Cancer Institute grants CA104898, CA115410, CA119414, CA119335, and CA30199 (Cancer Center Support Grant) and grants W81XWH-08-1-0727 and W81XWH-08-BCRP-CIA from the Department of Defense.

PY - 2009/12/8

Y1 - 2009/12/8

N2 - Poor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compounds deep into the tumor parenchyma that uses a tumor-homing peptide, iRGD (CRGDK/RGPD/EC). Intravenously injected compounds coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. iRGD homes to tumors through a three-step process: the RGD motif mediates binding to αv integrins on tumor endothelium and a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor-imaging agents and enhanced the activity of an antitumor drug.

AB - Poor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compounds deep into the tumor parenchyma that uses a tumor-homing peptide, iRGD (CRGDK/RGPD/EC). Intravenously injected compounds coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. iRGD homes to tumors through a three-step process: the RGD motif mediates binding to αv integrins on tumor endothelium and a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor-imaging agents and enhanced the activity of an antitumor drug.

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Tissue-Penetrating Delivery of Compounds and Nanoparticles into Tumors

Abstract

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