Clo-Lipo-DOTAP

The depletion of tumor-associated macrophages (TAMs), involved in different stages of cancer development and progression, is an appealing strategy in cancer therapy.We developed novel Clodronate-containing liposomes (Clo-Lipo-DOTAP) presenting physicochem. properties (size distribution, polydispersity index and Z-potential) suited for safe storage and injections.In vitro, Clo-Lipo-DOTAP inhibited proliferation, reduced viability and induced apoptosis of a macrophage-like cell line in a dose- and time-dependent manner.In proof of functionality experiments, Clo-Lipo-DOTAP depleted macrophages in a genetic mouse model of chronic hepatitis and hepatocellular carcinoma leading to a significant reduction of F4/80-pos. cells in the liver and spleen of treated mice compared to PBS-treated controls.The number of granulocytes, B and T lymphocytes was not affected.In B16/F10 s.c. melanoma-bearing mice, Clo-Lipo-DOTAP significantly reduced the volume of primary tumors (P < 0.001).Within the tumors, the expression F4/80 and α-SMA was significantly lowered.Plasma levels of IL-10, Mo KC, TNF-α, VEGF and PDGF-bb were statistically decreased.In B16/F10 lung metastatic melanoma model, treatment with Clo-Lipo-DOTAP significantly reduced the number of pulmonary nodules (P < 0.05).F4/80-pos. cells and microvessel d. were statistically decreased.In conclusion, the depletion of TAMs in primary and metastatic melanoma presents anti-tumor efficacy via inhibition of angiogenesis and modulation of inflammation related cytokines.