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 (TAMs) 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 co-stained 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.

Molecular Perspective of Nanoparticle Mediated Therapeutic Targeting in Breast Cancer: An Odyssey of Endoplasmic Reticulum Unfolded Protein Response (UPRER) and Beyond

“…Its magnetic core makes it possible for utilization in the diagnosis as it is detected by MRI on injection to tissues. On one side, where Poly-L-glutamic acid (PLGA; a synthetic biodegradable polymer) is employed for conjugate synthesis, polyethylene glycol (PEG) and N-(2-hydroxypropyl)-methacryl amide copolymer (HPMA) are the most widely used non-biodegradable polymers of synthetic origin [40][41][42][43]. PLGA (Poly-(lactic-co-glycolic acid) nanoencapsulated with Callistemon citrinus phenolics exhibited anticancer properties against BC cell lines viz.…”

Polymer Therapeutics: Biomarkers and New Approaches for Personalized Cancer Treatment

“…Therefore, routine ferumoxytol assessments in cancer patients may provide predictive data regarding passive targeting and tumor cell/TAM uptake (see below) and therefore, allow the stratification of patients for PT treatment. Interestingly, a study has described TAM-specific targeting in primary and metastatic breast cancer using HPMA-copolymer nanocarriers as a possible therapeutic approach [ 117 ].…”

Anti-tumor effects of an ID antagonist with no observed acquired resistance

“…MDA-MB-231 cells used in xenograft studies were obtained from NCI NIH (Bethesda, MD). Luciferase-labeled 4T1 cells were described previously 80 , as were luciferase- and GFP-labeled 4T1 cells 81 . The 4T1 cells’ overexpression Id1 were derived by transducing cells with pBabe- Id1 plasmids as described previously 47 .…”