In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide

Dongzhi Yang, Liangzhu Feng, Casey A. Dougherty, Kathryn E. Luker, Daiqin Chen, Meagan A. Cauble, Mark M. Banaszak Holl, Gary D. Luker, Brian D. Ross, Zhuang Liu, Hao Hong

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. 64Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of 64Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates (64Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers with satisfactory drug loading capacity (e.g. for doxorubicin [DOX], 756 mg/g). Enhanced drug delivery efficiency in cbgLuc-MDA-MB-231 metastatic sites was demonstrated in DOX-loaded GO-FSHR-mAb by fluorescence imaging. This FSHR-targeted, GO-based nanoplatform can serve as a useful tool for early metastasis detection and targeted delivery of therapeutics.

Original languageEnglish
Pages (from-to)361-371
Number of pages11
JournalBiomaterials
Volume104
DOIs
Publication statusPublished - 1 Oct 2016
Externally publishedYes

Keywords

  • Angiogenesis
  • Breast cancer metastasis
  • Follicle-stimulating hormone receptor (FSHR)
  • Image-guided drug delivery
  • Nano-graphene oxide (GO)
  • Positron emission tomography (PET)

Cite this

Yang, D., Feng, L., Dougherty, C. A., Luker, K. E., Chen, D., Cauble, M. A., ... Hong, H. (2016). In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide. Biomaterials, 104, 361-371. https://doi.org/10.1016/j.biomaterials.2016.07.029
Yang, Dongzhi ; Feng, Liangzhu ; Dougherty, Casey A. ; Luker, Kathryn E. ; Chen, Daiqin ; Cauble, Meagan A. ; Banaszak Holl, Mark M. ; Luker, Gary D. ; Ross, Brian D. ; Liu, Zhuang ; Hong, Hao. / In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide. In: Biomaterials. 2016 ; Vol. 104. pp. 361-371.
@article{5b1e3cccaeb74fa4811d59bff7d4abc4,
title = "In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide",
abstract = "Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. 64Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of 64Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates (64Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers with satisfactory drug loading capacity (e.g. for doxorubicin [DOX], 756 mg/g). Enhanced drug delivery efficiency in cbgLuc-MDA-MB-231 metastatic sites was demonstrated in DOX-loaded GO-FSHR-mAb by fluorescence imaging. This FSHR-targeted, GO-based nanoplatform can serve as a useful tool for early metastasis detection and targeted delivery of therapeutics.",
keywords = "Angiogenesis, Breast cancer metastasis, Follicle-stimulating hormone receptor (FSHR), Image-guided drug delivery, Nano-graphene oxide (GO), Positron emission tomography (PET)",
author = "Dongzhi Yang and Liangzhu Feng and Dougherty, {Casey A.} and Luker, {Kathryn E.} and Daiqin Chen and Cauble, {Meagan A.} and {Banaszak Holl}, {Mark M.} and Luker, {Gary D.} and Ross, {Brian D.} and Zhuang Liu and Hao Hong",
year = "2016",
month = "10",
day = "1",
doi = "10.1016/j.biomaterials.2016.07.029",
language = "English",
volume = "104",
pages = "361--371",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier",

}

Yang, D, Feng, L, Dougherty, CA, Luker, KE, Chen, D, Cauble, MA, Banaszak Holl, MM, Luker, GD, Ross, BD, Liu, Z & Hong, H 2016, 'In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide' Biomaterials, vol. 104, pp. 361-371. https://doi.org/10.1016/j.biomaterials.2016.07.029

In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide. / Yang, Dongzhi; Feng, Liangzhu; Dougherty, Casey A.; Luker, Kathryn E.; Chen, Daiqin; Cauble, Meagan A.; Banaszak Holl, Mark M.; Luker, Gary D.; Ross, Brian D.; Liu, Zhuang; Hong, Hao.

In: Biomaterials, Vol. 104, 01.10.2016, p. 361-371.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide

AU - Yang, Dongzhi

AU - Feng, Liangzhu

AU - Dougherty, Casey A.

AU - Luker, Kathryn E.

AU - Chen, Daiqin

AU - Cauble, Meagan A.

AU - Banaszak Holl, Mark M.

AU - Luker, Gary D.

AU - Ross, Brian D.

AU - Liu, Zhuang

AU - Hong, Hao

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. 64Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of 64Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates (64Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers with satisfactory drug loading capacity (e.g. for doxorubicin [DOX], 756 mg/g). Enhanced drug delivery efficiency in cbgLuc-MDA-MB-231 metastatic sites was demonstrated in DOX-loaded GO-FSHR-mAb by fluorescence imaging. This FSHR-targeted, GO-based nanoplatform can serve as a useful tool for early metastasis detection and targeted delivery of therapeutics.

AB - Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. 64Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of 64Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates (64Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers with satisfactory drug loading capacity (e.g. for doxorubicin [DOX], 756 mg/g). Enhanced drug delivery efficiency in cbgLuc-MDA-MB-231 metastatic sites was demonstrated in DOX-loaded GO-FSHR-mAb by fluorescence imaging. This FSHR-targeted, GO-based nanoplatform can serve as a useful tool for early metastasis detection and targeted delivery of therapeutics.

KW - Angiogenesis

KW - Breast cancer metastasis

KW - Follicle-stimulating hormone receptor (FSHR)

KW - Image-guided drug delivery

KW - Nano-graphene oxide (GO)

KW - Positron emission tomography (PET)

UR - http://www.scopus.com/inward/record.url?scp=84989313955&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2016.07.029

DO - 10.1016/j.biomaterials.2016.07.029

M3 - Article

VL - 104

SP - 361

EP - 371

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

ER -