HPMA–copolymer nanocarrier targets tumor-associated macrophages in primary and metastatic breast cancer Journal Article
| Authors: | Zimel, M. N.; Horowitz, C. B.; Rajasekhar, V. K.; Christ, A. B.; Wei, X.; Wu, J.; Wojnarowicz, P. M.; Wang, D.; Goldring, S. R.; Purdue, P. E.; Healey, J. H. |
| Article Title: | HPMA–copolymer nanocarrier targets tumor-associated macrophages in primary and metastatic breast cancer |
| 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. ©2017 AACR. |
| Keywords: | controlled study; primary tumor; nonhuman; flow cytometry; tumor associated leukocyte; animal cell; mouse; animal experiment; animal model; in vitro study; cd11b antigen; real time polymerase chain reaction; upregulation; folic acid; tumor growth; metastatic breast cancer; nanocarrier; chlordane; tumor microenvironment; macrophage activation; orthotopic transplantation; priority journal; article; n (2 hydroxypropyl)methacrylamide copolymer; 4t1 cell line; macrophage culture; mammary gland fat |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 16 |
| Issue: | 12 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-12-01 |
| Start Page: | 2701 |
| End Page: | 2710 |
| Language: | English |
| DOI: | 10.1158/1535-7163.mct-15-0995 |
| PROVIDER: | scopus |
| PUBMED: | 28830983 |
| PMCID: | PMC5847372 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
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