Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic

Kin Man Au; Andrew Satterlee; Yuanzeng Min; Xi Tian; Young Seok Kim; Joseph M Caster; Longzhen Zhang; Tian Zhang; Leaf Huang; Andrew Z Wang

doi:10.1016/j.biomaterials.2015.12.018

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Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic

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Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic

Kin Man Au, Andrew Satterlee, Yuanzeng Min, Xi Tian, Young Seok Kim, Joseph M Caster, Longzhen Zhang, Tian Zhang, Leaf Huang and Andrew Z Wang

Biomaterials, Vol.82, pp.178-193

03/2016

DOI: 10.1016/j.biomaterials.2015.12.018

PMID: 26763733

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Abstract

Zoledronate (Zol) is a third-generation bisphosphonate that is widely used as an anti-resorptive agent for the treatment of cancer bone metastasis. While there is preclinical data indicating that bisphosphonates such as Zol have direct cytotoxic effects on cancer cells, such effect has not been firmly established in the clinical setting. This is likely due to the rapid absorption of bisphosphonates by the skeleton after intravenous (i.v.) administration. Herein, we report the reformulation of Zol using nanotechnology and evaluation of this novel nanoscale metal-organic frameworks (nMOFs) formulation of Zol as an anticancer agent. The nMOF formulation is comprised of a calcium zoledronate (CaZol) core and a polyethylene glycol (PEG) surface. To preferentially deliver CaZol nMOFs to tumors as well as facilitate cellular uptake of Zol, we incorporated folate (Fol)-targeted ligands on the nMOFs. The folate receptor (FR) is known to be overexpressed in several tumor types, including head-and-neck, prostate, and non-small cell lung cancers. We demonstrated that these targeted CaZol nMOFs possess excellent chemical and colloidal stability in physiological conditions. The release of encapsulated Zol from the nMOFs occurs in the mid-endosomes during nMOF endocytosis. In vitro toxicity studies demonstrated that Fol-targeted CaZol nMOFs are more efficient than small molecule Zol in inhibiting cell proliferation and inducing apoptosis in FR-overexpressing H460 non-small cell lung and PC3 prostate cancer cells. Our findings were further validated in vivo using mouse xenograft models of H460 and PC3. We demonstrated that Fol-targeted CaZol nMOFs are effective anticancer agents and increase the direct antitumor activity of Zol by 80–85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis. [Display omitted]

Chemotherapy

Folate-targeted nanoscale metal-organic frameworks

Drug delivery

Zoledronate

Cancer

Details

Title: Subtitle: Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic
Creators: Kin Man Au - Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Andrew Satterlee - Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Yuanzeng Min - Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Xi Tian - Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Young Seok Kim - Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Joseph M Caster - Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Longzhen Zhang - Department of Radiation Oncology, Xuzhou Medical College, Xuzhou, China
Tian Zhang - Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham NC 27710, USA
Leaf Huang - Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Andrew Z Wang - Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Resource Type: Journal article
Publication Details: Biomaterials, Vol.82, pp.178-193
DOI: 10.1016/j.biomaterials.2015.12.018
PMID: 26763733
NLM abbreviation: Biomaterials
ISSN: 0142-9612
eISSN: 1878-5905
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/100006808, name: University of North Carolina, award: R01CA178748, R01CA149387; DOI: 10.13039/100000002, name: National Institutes of Health Center, award: U54-CA151652
Language: English
Date published: 03/2016
Academic Unit: Radiation Oncology
Record Identifier: 9984047694502771

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