title: Evaluation of antitumor effect of zoledronic acid entrapped in folate-linked liposome for targeting to tumor-associated macrophages.
abstract: 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 via 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-PEG2000-DSPE and 0.5 mol% PEG2000-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 via 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 in vivo toxicity of liposomal ZOL limited its utility for in vivo TAM targeting, although FL-ZOL could selectively induce in vitro cytotoxicity via FR.
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University , Ebara, Shinagawa-ku, Tokyo , Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hattori
authors.forename: Jun
authors.initials: J
authors.lastname: Yamashita
authors.forename: Chisato
authors.initials: C
authors.lastname: Sakaida
authors.forename: Kumi
authors.initials: K
authors.lastname: Kawano
authors.forename: Etsuo
authors.initials: E
authors.lastname: Yonemochi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007624:KB Cells; D008081:Liposomes / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D008081:Liposomes; D000077211:Zoledronic Acid; D005492:Folic Acid
keywords: Folate receptor; folic acid; liposomes; tumor-associated macrophages; zoledronic acid