Effect of Liposome-Encapsulated Zoledronic Acid on Microenvironment of Hepatocellular Carcinoma May Depend on the Ratio
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ome-Encapsulated Zoledronic Acid on Microenvironment of Hepatocellular Carcinoma May Depend on the Ratio Between M1 and M2 Polarized Macrophages S. Wu1, X. Lin2, and X. Cui1
Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 170, No. 7, pp. 84-90, July, 2020 Original article submitted April 12, 2020 We studied the effect of zoledronic acid encapsulated into liposomes (L-ZOL) on tumorassociated macrophages in the stroma of hepatocellular carcinoma xenograft. Liposomes were prepared from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-snglycero-3-phospho-sn-1-glycerol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[carboxy(polyethylene glycol)-2000] using thin film method and loaded with zoledronic acid. It was shown that L-ZOL promoted apoptosis of RAW264.7 cells, eliminate much more protumoral M2 macrophages than antitumoral M1 macrophages in the tumor xenograft, and did not significantly reduce the size of xenograft in 6 days. Thus, the effect of treatment depends on the ratio between antitumoral M1 and protumoral M2 polarized macrophages in the tumor. Key Words: tumor-associated macrophages (TAMs); zoledronic acid; liposome; hepatocellular carcinoma The incidence of cancer in the world is steadily increasing, while the treatment outcome in major malignancies remains unsatisfactory and cancer-related deaths constitute a great part of overall deaths [11]. In particular, liver cancer is one of leading causes of cancer death among males in less developed countries [11]. Cancer cells are embedded in the tumor microenvironment, a complex ecosystem of stromal cells. The treatment of cancer is predominantly focused on cancer cell, while stromal cells of the tumor are almost never considered. Recent studies have demonstrated that tumor stromal cells play an important role in the development and metastasis of cancer, so treatment aimed at stromal cells can be a useful and complementary to the cancer treatment [10]. Tumor-associated macrophages originating from circulating monocytes are among the most abundant normal cells in the tumor microenvironment. Their role consists in stimulation of the innate and adaptive Department of Ultrasound, 2Department of Emergency Medicine, the First Affiliated Hospital of Hainan Medical University, Haikou 570102, PR China. Address for correspondence: [email protected]. S. Wu
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immunity and phagocytosis of dead or dying cells and cell debris (M1-like). Tumors can considerably affect macrophage phenotype and re-educate them to a phenotype that promotes tumor growth and spread (M2-like) [1-7,9]. Several studies have shown that tumor-associated macrophages can activate and protect tumor stem cells, stimulate their proliferation, and promote angiogenesis and metastasis, while elimination of tumor-associated macrophages can inhibit tumor progression and metastasis [1-7,9]. Bisphosphonates (e.g., zoledronic acid, ZOL) are calcium antiresorptive agents that selectively block the function of osteoclasts. These drugs are used to treat bone diseases such as h
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