title: 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 pretreated with zoledronic acid to nonselectively 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 pretreated with zoledronic acid, the TAM-targeting DOX-AS-M-PLGA-NPs were significantly more effective than the nontargeting DOX-AS-PLGA-NPs in controlling the tumor growth. The AS-M-PLGA-NPs or other nanoparticles surface-functionalized similarly, when loaded with a chemotherapeutic agent commonly used in adjuvant therapy of TNBC, may be developed into targeted therapy for TNBC.
authors.affiliation: The University of Texas at Austin , College of Pharmacy, Pharmaceutics Division, Austin, Texas 78712, United States.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Niu
authors.affiliation: The University of Texas at Austin , College of Pharmacy, Pharmaceutics Division, Austin, Texas 78712, United States.
authors.forename: Solange
authors.initials: S
authors.lastname: Valdes
authors.affiliation: The University of Texas at Austin , College of Pharmacy, Pharmaceutics Division, Austin, Texas 78712, United States.
authors.forename: Youssef W
authors.initials: YW
authors.lastname: Naguib
authors.affiliation: University of North Carolina , Gillings School of Global Public Health, Chapel Hill, North Carolina 27599, United States.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
authors.affiliation: The University of Texas at Austin , College of Pharmacy, Pharmaceutics Division, Austin, Texas 78712, United States.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Nanoparticles; macrophage depletion; tumor growth inhibition