Enhancing Therapeutic Effects of Photodynamic Therapy with 5-Aminolevulinic Acid Using Polymeric Iron Chelators

• Published in: Photodiagnosis and photodynamic therapy 2023-03, Vol.41, p.103430, Article 103430
• Main Authors: GUO, Haochen, NOMOTO, Takahiro, KOMOTO, Kana, NAGANO, Tomoya, ISHII, Takuya, HONDA, Yuto, OGURA, Shun-ichiro, ISHIZUKA, Masahiro, NISHIYAMA, Nobuhiro
• Format: Article
• Language: English
• Subjects: 5-aminolevulinic acid; deferoxamine; iron chelation; polymer
• ISSN: 1572-1000; 1873-1597
• DOI: 10.1016/j.pdpdt.2023.103430

5-Aminolevulinic acid (5-ALA) is commonly used in photodynamic therapy (PDT) and photodiagnosis. 5-ALA is converted into protoporphyrin IX (PpIX), which exerts phototoxicity upon photoirradiation in many kinds of cancer cells [1]. However, it has been suggested that tumoral iron sometimes compromises the PDT effect of 5-ALA by promoting the metabolization of PpIX to the non-phototoxic heme [2]. In this context, inactivating tumoral iron via an iron chelator is expected to improve the accumulation of 5-ALA-induced PpIX in tumors and enhance the therapeutic effect. Indeed, previous studies have successfully enhanced in vitro phototoxicity of 5-ALA using iron chelators including deferoxamine (DFO), which is the clinically approved chelator for iron overload. However, only a few studies reported the promise of such iron chelators in in vivo probably because of insufficient tumor accumulation of the iron chelators, as it is well known that intravenously injected DFO is quickly cleared from the body. In this regard, we recently developed a polymeric iron chelator by conjugating multiple DFO molecules on the side chain of a poly(ethylene glycol)-poly(aspartic acid). The polymeric iron chelator, termed PDFO, showed prolonged blood retention and higher tumor accumulation than conventional DFO through the enhanced permeability and retention effect [3]. Here, we investigated the effect of PDFO on the PDT efficiency with 5-ALA hydrochloride. In in vitro study, PDFO as well as DFO decreased the intercellular iron and enhanced the PpIX accumulation and phototoxicity to cancer cells. Importantly, in in vivo study, DFO did not enhance the PDT effect of 5-ALA hydrochloride; however, PDFO exhibited significantly enhanced therapeutic efficacy in subcutaneous tumor models. These results suggest that PDFO could be a promising polymer for enhancing therapeutic efficacy of 5-ALA hydrochloride.