HPMA–copolymer nanocarrier targets tumor-associated macrophages in primary and metastatic breast cancer

Melissa N. Zimel, Chloe B. Horowitz, Vinagolu K. Rajasekhar, Alexander B. Christ, Xin Wei, Jianbo Wu, Paulina M. Wojnarowicz, Dong Wang, Steven R. Goldring, P. Edward Purdue, John H. Healey

Research output: Contribution to journalArticle

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Abstract

Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development.

Original languageEnglish (US)
Pages (from-to)2701-2710
Number of pages10
JournalMolecular cancer therapeutics
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Macrophages
Breast Neoplasms
Neoplasms
Tumor Microenvironment
Macrophage Activation
Cell Transplantation
Folic Acid
N-(2-hydroxypropyl)methacrylamide
Adipose Tissue
Breast
Bone Marrow
Inflammation
Drug Therapy
Cell Line
Injections
Alexa Fluor 647
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zimel, M. N., Horowitz, C. B., Rajasekhar, V. K., Christ, A. B., Wei, X., Wu, J., ... Healey, J. H. (2017). HPMA–copolymer nanocarrier targets tumor-associated macrophages in primary and metastatic breast cancer. Molecular cancer therapeutics, 16(12), 2701-2710. https://doi.org/10.1158/1535-7163.MCT-15-0995

HPMA–copolymer nanocarrier targets tumor-associated macrophages in primary and metastatic breast cancer. / Zimel, Melissa N.; Horowitz, Chloe B.; Rajasekhar, Vinagolu K.; Christ, Alexander B.; Wei, Xin; Wu, Jianbo; Wojnarowicz, Paulina M.; Wang, Dong; Goldring, Steven R.; Purdue, P. Edward; Healey, John H.

In: Molecular cancer therapeutics, Vol. 16, No. 12, 01.12.2017, p. 2701-2710.

Research output: Contribution to journalArticle

Zimel, MN, Horowitz, CB, Rajasekhar, VK, Christ, AB, Wei, X, Wu, J, Wojnarowicz, PM, Wang, D, Goldring, SR, Purdue, PE & Healey, JH 2017, 'HPMA–copolymer nanocarrier targets tumor-associated macrophages in primary and metastatic breast cancer', Molecular cancer therapeutics, vol. 16, no. 12, pp. 2701-2710. https://doi.org/10.1158/1535-7163.MCT-15-0995
Zimel, Melissa N. ; Horowitz, Chloe B. ; Rajasekhar, Vinagolu K. ; Christ, Alexander B. ; Wei, Xin ; Wu, Jianbo ; Wojnarowicz, Paulina M. ; Wang, Dong ; Goldring, Steven R. ; Purdue, P. Edward ; Healey, John H. / HPMA–copolymer nanocarrier targets tumor-associated macrophages in primary and metastatic breast cancer. In: Molecular cancer therapeutics. 2017 ; Vol. 16, No. 12. pp. 2701-2710.
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AU - Christ, Alexander B.

AU - Wei, Xin

AU - Wu, Jianbo

AU - Wojnarowicz, Paulina M.

AU - Wang, Dong

AU - Goldring, Steven R.

AU - Purdue, P. Edward

AU - Healey, John H.

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N2 - Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development.

AB - Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development.

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