Iron chelation cancer therapy using hydrophilic block copolymers conjugated with deferoxamine. Issue 1 (29th November 2020)

• Record Type: Journal Article
• Authors: Komoto, Kana; Nomoto, Takahiro; El Muttaqien, Sjaikhurrizal; Takemoto, Hiroyasu; Matsui, Makoto; Miura, Yutaka; Nishiyama, Nobuhiro
• Is Part Of: Cancer science. Volume 112:Issue 1(2021)
• Page Start: 410
• Page End: 421
• Publication Date: 2020-11-29
• Subjects: chelation -- deferoxamine -- drug delivery systems -- iron -- polymers; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14607
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Cancer cells have high iron requirements due to their rapid growth and proliferation. Iron depletion using iron chelators has a potential in cancer treatment. Previous studies have demonstrated that deferoxamine (DFO) specifically chelates Fe(III) and exhibited antitumor activity in clinical studies. However, its poor pharmacokinetics has limited the therapeutic potential and practical application. Although polymeric iron chelators have been developed to increase the blood retention, none of previous studies has demonstrated their potential in iron chelation cancer therapy. Here, we developed polymeric DFO by the covalent conjugation of DFO to poly(ethylene glycol)‐poly(aspartic acid) (PEG‐PAsp) block copolymers. The polymeric DFO exhibited iron‐chelating ability comparable with free DFO, thereby arresting cell cycle and inducing apoptosis and antiproliferative activity. After intravenous administration, the polymeric DFO showed marked increase in blood retention and tumor accumulation in subcutaneous tumor models. Consequently, polymeric DFO showed significant suppression of the tumor growth compared with free DFO. This study reveals the first success of the design of polymeric DFO for enhancing iron chelation cancer therapy. Abstract : Deferoxamine (DFO) is a unique iron chelator that exhibits antiproliferative activity on cancer cells by regulating the amount of iron in cells; however, its poor pharmacokinetics has limited the therapeutic potential and practical application. To realize effective iron chelation cancer therapy, we synthesized a simple biocompatible polymeric DFO (a polymer‐DFO conjugate) offering prolonged retention in blood and augmented tumor accumulation through the enhanced permeability and retention effect. Our polymeric DFO exhibited significant suppression of the tumor growth compared with free DFO, and was consistent with the pharmacokinetics and pharmacodynamics.