title: Transferrin-mediated fullerenes nanoparticles as Fe(2+)-dependent drug vehicles for synergistic anti-tumor efficacy.
abstract: Artesunate (AS) is an iron-dependent drug, which has been used extensively as anti-malarial drugs worldwide with no obvious side effects. Recently, studies have shown that AS also possess profound cytotoxicity against tumor cells. However, simultaneous delivery of hydrophobic AS and Fe(2+) into tumor cells remains a major challenge. Herein, we report a new kind of active-targeting preparations which could not only specially target to tumor cells but also synchronously transfer AS and irons into tumor tissue. In this study, hyaluronic acid (HA) was grafted onto fullerene to get a water-soluble biomaterial (HA-C60) with excellent biocompatibility, and then combined with transferrin (Tf) to obtain a multi-functional drug delivery system (HA-C60-Tf) with significant tumor-targeting efficacy and powerful photodynamic therapy capacity. Finally, AS was adsorbed on HA-C60-Tf with a high loading efficacy of 162.4% (weight ratio of AS: HA-C60-Tf). Compared with free AS, remarkably enhanced antitumor efficacy of AS-loaded HA-C60-Tf nanoparticles was realized both in a cultured MCF-7 cells in vitro and in a tumor-bearing murine model in vivo, due to increased intracellular accumulation of AS in tumor and activated mechanism by co-delivery of Tf and AS analogs. Furthermore, with laser irradiation in vivo, the relative tumor volume (V/V0) of HA-C60-Tf/AS declined by half, from 1.72 ± 0.12 to 0.84 ± 0.07, suggesting a new way with multi-mechanism for tumor treatment was developed.
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Road, Zhengzhou 450001, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Road, Zhengzhou 450001, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Hou
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Road, Zhengzhou 450001, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Jiao
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Road, Zhengzhou 450001, China.
authors.forename: Yandan
authors.initials: Y
authors.lastname: Ji
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Road, Zhengzhou 450001, China; School of Pharmaceutical Sciences, Henan University of Trational Chinese Medicine, Zhengzhou, China.
authors.forename: Xiali
authors.initials: X
authors.lastname: Zhu
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Road, Zhengzhou 450001, China. Electronic address: zhangzz08@126.com.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000493:pharmacokinetics / Q000494:pharmacology; D000077332:Artesunate; D016503:Drug Delivery Systems; D004357:Drug Synergism; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D037741:Fullerenes / Q000737:chemistry*; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D042541:Intracellular Space / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D014168:Transferrin / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; D037741:Fullerenes; D017382:Reactive Oxygen Species; D014168:Transferrin; D000077332:Artesunate; D006820:Hyaluronic Acid; D007501:Iron
keywords: Hyaluronic acid-derivatized fullerenes vehicles; Iron-dependent artesunate; Photodynamic therapy; Transferrin