Mannose Modified Co-Loaded Zoledronic Liposomes Deplete M2-tumor-associated Macrophages to Enhance Anti-Tumor Effect of Doxorubicin on TNBC

Abstract As the most numerous inflammatory cell group in tumor microenvironment, tumor-associated macrophages (TAMs) have an essential effect in tumor therapy and are potential therapeutic targets. M2 type tumor-associated macrophages (M2-TAMs) were involved in the entire process of tumor development, invasion, and metastasis, obstructing the anti-tumor effect of chemotherapy drugs and nano-medicine. This study aimed to construct a mannose modified co-loaded zoledronic acid and doxorubicin liposomes (Man-LP@ZOL/DOX) for improving the anti-tumor effect by suppressing M2-TAMs on triple-negative breast cancer (TNBC). The size, PDI, and Zeta-potential of Man-LP@ZOL/DOX liposomes were determined to be 212.80±7.74 nm, 0.1413±0.0232, -33.63±0.49 mV, respectively. The Man-LP@ZOL/DOX's EE% and DL% of ZOL as measured were 17.21±2.26% and 1.56±0.21%, while for DOX, they were 84.42±2.05% and 5.12±0.14%. The uptake of Man-LP into cells was increased when it was modified with a TAMs target ligand. The liposomes inhibited the invasion of MDA-MB-231 cells induced by M2-TAMs, and expression of biomarkers on M2-TAMs (Arg1 and CD206 in vitro, CD68, and CD206 in vivo) was apparent. Moreover, co-loaded drugs liposome system remarkably enhanced anticancer effects both in vitro and vivo combined with ZOL. In conclusion, all these results established that Man-LP@ZOL/DOX could enhance anti-tumor effect of DOX via depleting M2-TAMs on TNBC.