Evaluation of antitumor effect of zoledronic acid entrapped in folate-linked liposome for targeting to tumor-associated macrophages. (June 2015)

• Record Type: Journal Article
• Authors: Hattori, Yoshiyuki; Yamashita, Jun; Sakaida, Chisato; Kawano, Kumi; Yonemochi, Etsuo
• Is Part Of: Journal of liposome research. Volume 25:Number 2(2015)
• Page Start: 131
• Page End: 140
• Publication Date: 2015-06
• Subjects: Liposomes -- Periodicals; Liposomes -- Periodicals; 575.57
• Languages: English
• ISSNs: 0898-2104

Abstract

<abstract> <title>Abstract</title> <p>In this study, we investigated the possibility of whether depletion of tumor-associated macrophages (TAMs) by zoledronic acid (ZOL) entrapped in folate-linked liposome could inhibit tumor angiogenesis and consequently tumor growth. Abundant expression of folate receptor β (FRβ) mRNA was detected in tumor tissues from subcutaneously implanted FR-negative tumor cells in mice, indicating that FRβ mRNA was expressed in TAMs, not in tumor cells. When fluorescent-labeled folic acid was intravenously injected into mice bearing FR-positive human nasopharyngeal tumor KB, and FR-negative human prostate tumor PC-3 and mouse colon adenocarcinoma Colon 26, fluorescence was strongly detected in KB and Colon 26 tumors, and moderately in PC-3 tumor, indicating that folic acid was taken up by TAMs <italic>via</italic> FRβ in PC-3 and Colon 26 tumors. For evaluation of ZOL delivery to TAMs, folate-linked liposomal ZOL (FL-ZOL) for TAM targeting and non-folate-linked liposomal ZOL (L-ZOL) as a control were prepared by incorporation with 0.5 mol% folate-PEG<sub>2000</sub>-DSPE and 0.5 mol% PEG<sub>2000</sub>-DSPE, respectively, into the liposomal formulation of egg phosphatidylcholine and cholesterol. FL-ZOL showed high cytotoxicity for KB and murine macrophage RAW264.7 cells, but not for Colon 26 cells, suggested that FL-ZOL was selectively taken up <italic>via</italic> FR-mediated endocytosis. However, injections of FL-ZOL and L-ZOL did not induce antitumor activities for KB and Colon 26 tumor-bearing mice, and had a lethal effect by high toxicity. From these findings, the severe <italic>in vivo</italic> toxicity of liposomal ZOL limited its utility for <italic>in vivo</italic> TAM targeting, although FL-ZOL could selectively induce <italic>in vitro</italic> cytotoxicity <italic>via</italic> FR.</p> </abstract>