A novel liposomal Clodronate depletes tumor-associated macrophages in primary and metastatic melanoma: Anti-angiogenic and anti-tumor effects

Francesca Piaggio, V. Kondylis, Fabio Pastorino, Daniela Di Paolo, Patrizia Perri, Irene Cossu, F. Schorn, Christian Marinaccio, Daniele Murgia, Antonio Daga, Federica Raggi, Monica Loi, Laura Emionite, Emanuela Ognio, M. Pasparakis, Domenico Ribatti, Mirco Ponzoni, Chiara Brignole

Research output: Contribution to journalArticle

Abstract

The depletion of tumor-associated macrophages (TAMs), involved in different stages of cancer development and progression, is an appealing strategy in cancer therapy. Wedeveloped novel Clodronate-containing liposomes (Clo-Lipo-DOTAP) presenting physicochemical 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-positive 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 subcutaneous melanoma-bearing mice, Clo-Lipo-DOTAP significantly reduced the volume of primary tumors (P <0.001). Within the tumors, the expression F4/80 and a-SMA was significantly lowered. Plasma levels of IL-10, Mo KC, TNF-a, 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 b 0.05). F4/ 80-positive cells and microvessel density 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.

Original languageEnglish
Pages (from-to)165-177
Number of pages13
JournalJournal of Controlled Release
Volume223
DOIs
Publication statusPublished - Feb 10 2016

Keywords

  • Adjuvant therapy
  • Liposomal Clodronate
  • Melanoma
  • TAMs

ASJC Scopus subject areas

  • Pharmaceutical Science

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