Tumor-Associated Macrophage-Mediated Targeted Therapy of Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer. TNBC is often infiltrated with a large number of macrophages, which in turn promote tumor growth and metastasis. In this study, tumor-associated macrophages (TAMs) were exploited as a target to deliver doxorubicin (DOX), a chemotherapeutic agent, to TNBC using nanoparticles surface-functionalized by i) acid-sensitive sheddable PEGylation and ii) modifying with mannose (i.e. DOX-AS-M-PLGA-NPs). In mice with orthotopic M-Wnt triple-negative mammary tumors, a single intravenous injection of DOX-AS-M-PLGA-NPs significantly reduced macrophage population in tumors within 2 days, and the density of the macrophages recovered slowly. Repeated injections of DOX-AS-M-PLGA-NPs can help maintain the population of the macrophages at a lower level. In M-Wnt tumor-bearing mice that were pre-treated with zoledronic acid to non-selectively deplete macrophages, the TAM-targeting DOX-AS-M-PLGA-NPs were not more effective than the DOX-AS-PLGA-NPs that were not surface-modified with mannose, and thus do not target TAMs, in controlling tumor growth. However, in M-Wnt tumor-bearing mice that were not pre-treated with zoledronic acid, the TAM-targeting DOX-AS-M-PLGA-NPs were significantly more effective than the non-targeting DOX-AS-PLGA-NPs in controlling the tumor growth. The AS-M-PLGA-NPs or other nanoparticles surface-functionalized similarly, when loaded with chemotherapeutic agents commonly used in adjuvant therapy of TNBC, may be developed into targeted therapy of TNBC.

Nanomedicines for dysfunctional macrophage-associated diseases

“…Recently, the same group applied the combination of mannose modification and acid-sensitive sheddable PEGylation to deliver doxorubicin to TAMs in triple-negative breast cancer. They reported that a single intravenous injection of such functionalized nanoparticles significantly reduced macrophage population in tumors within 2 days, and the repeated injections kept the macrophage population at a lower level for 9 days [132]. …”

Reverse Microemulsion-Based Synthesis of (Bis)phosphonate–Metal Materials with Controllable Physical Properties: An Example Using Zoledronic Acid–Calcium Complexes

“…Such tumor contains a high population of tumor-associated macrophages (TAMs). 28 M-Wnt cells were cultured in RPMI 1640 containing 10% FBS and 1% P/S. All cell culture media and reagents were from Invitrogen (Carlsbad, CA).…”

Tumor-Associated Macrophages: Implications in Cancer Immunotherapy

“…As TNBC is often infiltrated with high numbers of TAMs, Niu et al showed that doxorubicin-containing nanoparticles targeting TAMs via mannose-mannose receptor recognition reduced TAM density and inhibited tumor growth in an orthotopic mouse model of TNBC. In addition, the effectiveness of these nanoparticles is found to be dependent on their ability to target TAMs within TNBC stroma [96]. Other novel approaches to target TAMs in vivo include the use of DNA vaccines against TAM-derived protein legumain in several murine cancer models [97] as well as the success of using clodronate/liposome to delete TAMs as an adjuvant therapy to boost antitumor immunity induced by a TLR agonist-conjugated peptide Pam2IDG [98].…”