Targeted drug delivery and image-guided therapy of heterogeneous ovarian cancer using HER2-targeted theranostic nanoparticles

Minati Satpathy, Liya Wang, Rafal J. Zielinski, Weiping Qian, Y. Andrew Wang, Aaron M. Mohs, Brad A. Kairdolf, Xin Ji, Jacek Capala, Malgorzata Lipowska, Shuming Nie, Hui Mao, Lily Yang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Cancer heterogeneity and drug resistance limit the efficacy of cancer therapy. To address this issue, we have developed an integrated treatment protocol for effective treatment of heterogeneous ovarian cancer. Methods: An amphiphilic polymer coated magnetic iron oxide nanoparticle was conjugated with near infrared dye labeled HER2 affibody and chemotherapy drug cisplatin. The effects of the theranostic nanoparticle on targeted drug delivery, therapeutic efficacy, non-invasive magnetic resonance image (MRI)-guided therapy, and optical imaging detection of therapy resistant tumors were examined in an orthotopic human ovarian cancer xenograft model with highly heterogeneous levels of HER2 expression. Results: We found that systemic delivery of HER2-targeted magnetic iron oxide nanoparticles carrying cisplatin significantly inhibited the growth of primary tumor and peritoneal and lung metastases in the ovarian cancer xenograft model in nude mice. Differential delivery of theranostic nanoparticles into individual tumors with heterogeneous levels of HER2 expression and various responses to therapy were detectable by MRI. We further found a stronger therapeutic response in metastatic tumors compared to primary tumors, likely due to a higher level of HER2 expression and a larger number of proliferating cells in metastatic tumor cells. Relatively long-time retention of iron oxide nanoparticles in tumor tissues allowed interrogating the relationship between nanoparticle drug delivery and the presence of resistant residual tumors by in vivo molecular imaging and histological analysis of the tumor tissues. Following therapy, most of the remaining tumors were small, primary tumors that had low levels of HER2 expression and nanoparticle drug accumulation, thereby explaining their lack of therapeutic response. However, a few residual tumors had HER2-expressing tumor cells and detectable nanoparticle drug delivery but failed to respond, suggesting additional intrinsic resistant mechanisms. Nanoparticle retention in the small residual tumors, nevertheless, produced optical signals for detection by spectroscopic imaging. Conclusion: The inability to completely excise peritoneal metastatic tumors by debulking surgery as well as resistance to chemotherapy are the major clinical challenges for ovarian cancer treatment. This targeted cancer therapy has the potential for the development of effective treatment for metastatic ovarian cancer.

Original languageEnglish (US)
Pages (from-to)778-795
Number of pages18
JournalTheranostics
Volume9
Issue number3
DOIs
StatePublished - Jan 1 2019

Fingerprint

Ovarian Neoplasms
Nanoparticles
Pharmaceutical Preparations
Neoplasms
Therapeutics
Residual Neoplasm
Theranostic Nanomedicine
Heterografts
Cisplatin
Magnetic Resonance Spectroscopy
Drug Therapy
Molecular Imaging
Optical Imaging
Clinical Protocols
Drug Resistance
Nude Mice
Polymers
Coloring Agents
Cell Count

Keywords

  • MR image-guided cancer therapy
  • Resistant mechanism
  • Spectroscopic imaging
  • Targeted drug delivery
  • Theranostic nanoparticles

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Cite this

Targeted drug delivery and image-guided therapy of heterogeneous ovarian cancer using HER2-targeted theranostic nanoparticles. / Satpathy, Minati; Wang, Liya; Zielinski, Rafal J.; Qian, Weiping; Wang, Y. Andrew; Mohs, Aaron M.; Kairdolf, Brad A.; Ji, Xin; Capala, Jacek; Lipowska, Malgorzata; Nie, Shuming; Mao, Hui; Yang, Lily.

In: Theranostics, Vol. 9, No. 3, 01.01.2019, p. 778-795.

Research output: Contribution to journalArticle

Satpathy, M, Wang, L, Zielinski, RJ, Qian, W, Wang, YA, Mohs, AM, Kairdolf, BA, Ji, X, Capala, J, Lipowska, M, Nie, S, Mao, H & Yang, L 2019, 'Targeted drug delivery and image-guided therapy of heterogeneous ovarian cancer using HER2-targeted theranostic nanoparticles', Theranostics, vol. 9, no. 3, pp. 778-795. https://doi.org/10.7150/thno.29964
Satpathy, Minati ; Wang, Liya ; Zielinski, Rafal J. ; Qian, Weiping ; Wang, Y. Andrew ; Mohs, Aaron M. ; Kairdolf, Brad A. ; Ji, Xin ; Capala, Jacek ; Lipowska, Malgorzata ; Nie, Shuming ; Mao, Hui ; Yang, Lily. / Targeted drug delivery and image-guided therapy of heterogeneous ovarian cancer using HER2-targeted theranostic nanoparticles. In: Theranostics. 2019 ; Vol. 9, No. 3. pp. 778-795.
@article{c0ae3f293f0f453dbb9b1a1b31cb8efd,
title = "Targeted drug delivery and image-guided therapy of heterogeneous ovarian cancer using HER2-targeted theranostic nanoparticles",
abstract = "Cancer heterogeneity and drug resistance limit the efficacy of cancer therapy. To address this issue, we have developed an integrated treatment protocol for effective treatment of heterogeneous ovarian cancer. Methods: An amphiphilic polymer coated magnetic iron oxide nanoparticle was conjugated with near infrared dye labeled HER2 affibody and chemotherapy drug cisplatin. The effects of the theranostic nanoparticle on targeted drug delivery, therapeutic efficacy, non-invasive magnetic resonance image (MRI)-guided therapy, and optical imaging detection of therapy resistant tumors were examined in an orthotopic human ovarian cancer xenograft model with highly heterogeneous levels of HER2 expression. Results: We found that systemic delivery of HER2-targeted magnetic iron oxide nanoparticles carrying cisplatin significantly inhibited the growth of primary tumor and peritoneal and lung metastases in the ovarian cancer xenograft model in nude mice. Differential delivery of theranostic nanoparticles into individual tumors with heterogeneous levels of HER2 expression and various responses to therapy were detectable by MRI. We further found a stronger therapeutic response in metastatic tumors compared to primary tumors, likely due to a higher level of HER2 expression and a larger number of proliferating cells in metastatic tumor cells. Relatively long-time retention of iron oxide nanoparticles in tumor tissues allowed interrogating the relationship between nanoparticle drug delivery and the presence of resistant residual tumors by in vivo molecular imaging and histological analysis of the tumor tissues. Following therapy, most of the remaining tumors were small, primary tumors that had low levels of HER2 expression and nanoparticle drug accumulation, thereby explaining their lack of therapeutic response. However, a few residual tumors had HER2-expressing tumor cells and detectable nanoparticle drug delivery but failed to respond, suggesting additional intrinsic resistant mechanisms. Nanoparticle retention in the small residual tumors, nevertheless, produced optical signals for detection by spectroscopic imaging. Conclusion: The inability to completely excise peritoneal metastatic tumors by debulking surgery as well as resistance to chemotherapy are the major clinical challenges for ovarian cancer treatment. This targeted cancer therapy has the potential for the development of effective treatment for metastatic ovarian cancer.",
keywords = "MR image-guided cancer therapy, Resistant mechanism, Spectroscopic imaging, Targeted drug delivery, Theranostic nanoparticles",
author = "Minati Satpathy and Liya Wang and Zielinski, {Rafal J.} and Weiping Qian and Wang, {Y. Andrew} and Mohs, {Aaron M.} and Kairdolf, {Brad A.} and Xin Ji and Jacek Capala and Malgorzata Lipowska and Shuming Nie and Hui Mao and Lily Yang",
year = "2019",
month = "1",
day = "1",
doi = "10.7150/thno.29964",
language = "English (US)",
volume = "9",
pages = "778--795",
journal = "Theranostics",
issn = "1838-7640",
publisher = "Ivyspring International Publisher",
number = "3",

}

TY - JOUR

T1 - Targeted drug delivery and image-guided therapy of heterogeneous ovarian cancer using HER2-targeted theranostic nanoparticles

AU - Satpathy, Minati

AU - Wang, Liya

AU - Zielinski, Rafal J.

AU - Qian, Weiping

AU - Wang, Y. Andrew

AU - Mohs, Aaron M.

AU - Kairdolf, Brad A.

AU - Ji, Xin

AU - Capala, Jacek

AU - Lipowska, Malgorzata

AU - Nie, Shuming

AU - Mao, Hui

AU - Yang, Lily

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Cancer heterogeneity and drug resistance limit the efficacy of cancer therapy. To address this issue, we have developed an integrated treatment protocol for effective treatment of heterogeneous ovarian cancer. Methods: An amphiphilic polymer coated magnetic iron oxide nanoparticle was conjugated with near infrared dye labeled HER2 affibody and chemotherapy drug cisplatin. The effects of the theranostic nanoparticle on targeted drug delivery, therapeutic efficacy, non-invasive magnetic resonance image (MRI)-guided therapy, and optical imaging detection of therapy resistant tumors were examined in an orthotopic human ovarian cancer xenograft model with highly heterogeneous levels of HER2 expression. Results: We found that systemic delivery of HER2-targeted magnetic iron oxide nanoparticles carrying cisplatin significantly inhibited the growth of primary tumor and peritoneal and lung metastases in the ovarian cancer xenograft model in nude mice. Differential delivery of theranostic nanoparticles into individual tumors with heterogeneous levels of HER2 expression and various responses to therapy were detectable by MRI. We further found a stronger therapeutic response in metastatic tumors compared to primary tumors, likely due to a higher level of HER2 expression and a larger number of proliferating cells in metastatic tumor cells. Relatively long-time retention of iron oxide nanoparticles in tumor tissues allowed interrogating the relationship between nanoparticle drug delivery and the presence of resistant residual tumors by in vivo molecular imaging and histological analysis of the tumor tissues. Following therapy, most of the remaining tumors were small, primary tumors that had low levels of HER2 expression and nanoparticle drug accumulation, thereby explaining their lack of therapeutic response. However, a few residual tumors had HER2-expressing tumor cells and detectable nanoparticle drug delivery but failed to respond, suggesting additional intrinsic resistant mechanisms. Nanoparticle retention in the small residual tumors, nevertheless, produced optical signals for detection by spectroscopic imaging. Conclusion: The inability to completely excise peritoneal metastatic tumors by debulking surgery as well as resistance to chemotherapy are the major clinical challenges for ovarian cancer treatment. This targeted cancer therapy has the potential for the development of effective treatment for metastatic ovarian cancer.

AB - Cancer heterogeneity and drug resistance limit the efficacy of cancer therapy. To address this issue, we have developed an integrated treatment protocol for effective treatment of heterogeneous ovarian cancer. Methods: An amphiphilic polymer coated magnetic iron oxide nanoparticle was conjugated with near infrared dye labeled HER2 affibody and chemotherapy drug cisplatin. The effects of the theranostic nanoparticle on targeted drug delivery, therapeutic efficacy, non-invasive magnetic resonance image (MRI)-guided therapy, and optical imaging detection of therapy resistant tumors were examined in an orthotopic human ovarian cancer xenograft model with highly heterogeneous levels of HER2 expression. Results: We found that systemic delivery of HER2-targeted magnetic iron oxide nanoparticles carrying cisplatin significantly inhibited the growth of primary tumor and peritoneal and lung metastases in the ovarian cancer xenograft model in nude mice. Differential delivery of theranostic nanoparticles into individual tumors with heterogeneous levels of HER2 expression and various responses to therapy were detectable by MRI. We further found a stronger therapeutic response in metastatic tumors compared to primary tumors, likely due to a higher level of HER2 expression and a larger number of proliferating cells in metastatic tumor cells. Relatively long-time retention of iron oxide nanoparticles in tumor tissues allowed interrogating the relationship between nanoparticle drug delivery and the presence of resistant residual tumors by in vivo molecular imaging and histological analysis of the tumor tissues. Following therapy, most of the remaining tumors were small, primary tumors that had low levels of HER2 expression and nanoparticle drug accumulation, thereby explaining their lack of therapeutic response. However, a few residual tumors had HER2-expressing tumor cells and detectable nanoparticle drug delivery but failed to respond, suggesting additional intrinsic resistant mechanisms. Nanoparticle retention in the small residual tumors, nevertheless, produced optical signals for detection by spectroscopic imaging. Conclusion: The inability to completely excise peritoneal metastatic tumors by debulking surgery as well as resistance to chemotherapy are the major clinical challenges for ovarian cancer treatment. This targeted cancer therapy has the potential for the development of effective treatment for metastatic ovarian cancer.

KW - MR image-guided cancer therapy

KW - Resistant mechanism

KW - Spectroscopic imaging

KW - Targeted drug delivery

KW - Theranostic nanoparticles

UR - http://www.scopus.com/inward/record.url?scp=85064181714&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064181714&partnerID=8YFLogxK

U2 - 10.7150/thno.29964

DO - 10.7150/thno.29964

M3 - Article

C2 - 30809308

AN - SCOPUS:85064181714

VL - 9

SP - 778

EP - 795

JO - Theranostics

JF - Theranostics

SN - 1838-7640

IS - 3

ER -