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Abstracto
Hyaluronic Acid-zinc Protoporphyrin IX Conjugates for Photodynamic Antitumor Therapy
Eguchi K, Hideaki Nakamura, Zhou JR, Jun F, Yokomizo K and Haratake M
Zinc (II) protoporphyrin (ZnPP) strongly inhibits antioxidative enzyme heme oxygenase-1 (HO-1), and ZnPP generates reactive oxygen species (ROS) upon light irradiation. ZnPP can induce lethal oxidative stress in the tumor, when ZnPP is selectively delivered to the tumor followed by light irradiation. In this study, ZnPP was conjugated to hyaluronic acid (HA-ZnPP) for improving its solubility in aqueous media and tumor selective delivery of ZnPP by the enhanced permeability and retention (EPR) effect. Though photosensitizing activity of the HA-ZnPP was quenched in phosphate buffered saline, it was partially recovered by addition of lecithin. Similar to other polymer-conjugated ZnPP, cellular uptake of the HA-ZnPP was lower than that of the free ZnPP in HeLa cells. In tumor-bearing mice, plasma halflife of HA-ZnPP became longer than that of free ZnPP, and thus selective accumulation of the HA-ZnPP in the tumor by the EPR effect was observed. Combination of the HA-ZnPP and light irradiation potentially suppressed the tumor growth, approximately 60% tumor volume reduction was observed without apparent adverse effects at day 31 after the drug treatment. These data demonstrate that HA is a preferable carrier for ZnPP, and the HA-conjugated ZnPP is a promising antitumor agent for photodynamic therapy.