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

Area of Science:

• Biomedical Engineering
• Oncology
• Nanotechnology

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis.
• Tumor-associated macrophages (TAMs) within the tumor microenvironment promote TNBC growth and metastasis.
• Targeting TAMs presents a potential therapeutic strategy for TNBC.

Purpose of the Study:

• To develop and evaluate mannose-functionalized, acid-sensitive nanoparticles for targeted doxorubicin delivery to TAMs in TNBC.
• To assess the efficacy of these nanoparticles in reducing TAMs and controlling tumor growth in a TNBC mouse model.

Main Methods:

• Synthesized doxorubicin-loaded nanoparticles with acid-sensitive sheddable PEGylation and mannose functionalization (DOX-AS-M-PLGA-NPs).
• Administered nanoparticles intravenously to mice with orthotopic M-Wnt TNBC tumors.
• Evaluated nanoparticle effects on macrophage populations and tumor growth, with and without prior zoledronic acid treatment to deplete macrophages.

Main Results:

• A single injection of DOX-AS-M-PLGA-NPs significantly reduced tumor macrophage populations within 2 days, with slow recovery.
• Repeated injections maintained lower macrophage levels.
• TAM-targeting nanoparticles were significantly more effective in controlling tumor growth than non-targeting nanoparticles in untreated mice, but not in macrophage-depleted mice.

Conclusions:

• Surface-functionalized nanoparticles effectively target and reduce TAMs in TNBC.
• Targeted delivery of doxorubicin via these nanoparticles demonstrates significant efficacy in controlling TNBC growth.
• This approach holds potential for developing novel targeted therapies for TNBC.