Urokinase plasminogen activator system-Targeted delivery of nanobins as a novel ovarian cancer therapy

Yilin Zhang, Hilary A. Kenny, Elden P. Swindell, Anirban K. Mitra, Patrick L. Hankins, Richard W. Ahn, Katja Gwin, Andrew P. Mazar, Thomas V. O'Halloran, Ernst Lengyel

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The urokinase system is overexpressed in epithelial ovarian cancer cells and is expressed at low levels in normal cells. To develop a platform for intracellular and targeted delivery of therapeutics in ovarian cancer, we conjugated urokinase plasminogen activator (uPA) antibodies to liposomal nanobins. The arsenic trioxide- loaded nanobins had favorable physicochemical properties and the ability to bind specifically to uPA. Confocal microscopy showed that the uPA-targeted nanobins were internalized by ovarian cancer cells, whereas both inductively coupled plasma optical mass spectrometry (ICP-MS) and fluorescence-activated cell sorting (FACS) analyses confirmed more than four-fold higher uptake of targeted nanobins when compared with untargeted nanobins. In a coculture assay, the targeted nanobins showed efficient uptake in ovarian cancer cells but not in the normal primary omental mesothelial cells. Moreover, this uptake could be blocked by either downregulating uPA receptor expression in the ovarian cancer cells using short-hairpin RNA (shRNA) or by competition with free uPA or uPA antibody. In proof-of-concept experiments, mice bearing orthotopic ovarian tumors showed a greater reduction in tumor burdenwhentreated with targeted nanobins than with untargeted nanobins (47% vs. 27%; P < 0.001). The targeted nanobins more effectively inhibited tumor cell growth both in vitro and in vivo compared with untargeted nanobins, inducing caspase-mediated apoptosis and impairing stem cell marker, aldehyde dehydrogenase-1A1 (ALDH1A1), expression. Ex vivo fluorescence imaging of tumors and organs corroborated these results, showing preferential localization of the targeted nanobins to the tumor. These findings suggest that uPA-targeted nanobins capable of specifically and efficiently delivering payloads to cancer cells could serve as the foundation for a new targeted cancer therapy using protease receptors.

Original languageEnglish (US)
Pages (from-to)2628-2639
Number of pages12
JournalMolecular cancer therapeutics
Volume12
Issue number12
DOIs
StatePublished - Dec 1 2013

Fingerprint

Plasminogen Activators
Urokinase-Type Plasminogen Activator
Ovarian Neoplasms
Neoplasms
Therapeutics
Urokinase Plasminogen Activator Receptors
Aldehyde Dehydrogenase
Antibodies
Optical Imaging
Caspases
Coculture Techniques
Confocal Microscopy
Small Interfering RNA
Mass Spectrometry
Flow Cytometry
Peptide Hydrolases
Stem Cells
Down-Regulation
Apoptosis
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Urokinase plasminogen activator system-Targeted delivery of nanobins as a novel ovarian cancer therapy. / Zhang, Yilin; Kenny, Hilary A.; Swindell, Elden P.; Mitra, Anirban K.; Hankins, Patrick L.; Ahn, Richard W.; Gwin, Katja; Mazar, Andrew P.; O'Halloran, Thomas V.; Lengyel, Ernst.

In: Molecular cancer therapeutics, Vol. 12, No. 12, 01.12.2013, p. 2628-2639.

Research output: Contribution to journalArticle

Zhang, Y, Kenny, HA, Swindell, EP, Mitra, AK, Hankins, PL, Ahn, RW, Gwin, K, Mazar, AP, O'Halloran, TV & Lengyel, E 2013, 'Urokinase plasminogen activator system-Targeted delivery of nanobins as a novel ovarian cancer therapy', Molecular cancer therapeutics, vol. 12, no. 12, pp. 2628-2639. https://doi.org/10.1158/1535-7163.MCT-13-0204
Zhang, Yilin ; Kenny, Hilary A. ; Swindell, Elden P. ; Mitra, Anirban K. ; Hankins, Patrick L. ; Ahn, Richard W. ; Gwin, Katja ; Mazar, Andrew P. ; O'Halloran, Thomas V. ; Lengyel, Ernst. / Urokinase plasminogen activator system-Targeted delivery of nanobins as a novel ovarian cancer therapy. In: Molecular cancer therapeutics. 2013 ; Vol. 12, No. 12. pp. 2628-2639.
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