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

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• 作者：F. Piaggio^a ; ¹ ; V. Kondylis^b ; ⁱ ; ^j ; ¹ ; F. Pastorino^a ; D. Di Paolo^a ; P. Perri^a ; I. Cossu^a ; F. Schorn^b ; ⁱ ; ^j ; C. Marinaccio^c ; D. Murgia^d ; A. Daga^e ; F. Raggi^f ; M. Loi^a ; ² ; L. Emionite^g ; E. Ognio^g ; M. Pasparakis^b ; ⁱ ; ^j ; D. Ribatti^c ; ^h ; M. Ponzoni^a ; ³ ; ^{mircoponzoni@ospedale-gaslini.ge.it" class="auth_mail" title="E-mail the corresponding author} ; C. Brignole^a ; ³ ; ^{chiarabrignole@ospedale-gaslini.ge.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：TAMs ; Liposomal Clodronate ; Adjuvant therapy ; Melanoma
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：10 February 2016
• 年：2016
• 卷：223
• 期：Complete
• 页码：165-177
• 全文大小：3131 K

文摘

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 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 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-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.