Redox and CD44 Dual‐Responsive Nanophotosensitizer Composed of Chlorin e6‐Conjugated Hyaluronic Acid via Disulfide Linkage for Targeted Photodynamic Treatment of Cancer Cells

For redox- and CD44 receptor-sensitive photodynamic treatment of cancer cells, chlorin e6 (Ce6) was conjugated to the end of hyaluronic acid (HA) via disulfide linkages. Ce6-conjuated HA (HAssCe6) nanophosensitizers showed small particle size less than 100 nm and spherical morphology. Ce6 was liberated from HAssCe6 nanophotosensitizer with redox-sensitive manner and Ce6 release rate was faster in the presence of GSH than normal condition. HAssCe6 nanophotosensitizers showed extremely higher Ce6 uptake ratio than Ce6 itself. Pretreatment of HA properly inhibited intracellular uptake of HAssCe6 nanophotosensitizers, indicating that nanophotosensitizers can be entered into cells by CD44 receptor-mediated pathway. HAssCe6 nanophotosensitizer treatment increased reactive oxygen species production and PDT efficacy with negligible dark toxicity against HCT116 cells. Furthoremore, HAssCe6 nanophotosensitizers was efficiently delivered to tumor tissues of HCT116-bearing mice while pretreatment of free HA properly inhibited delivery of nanophotosensitizers against tumor tissues. These results indicated that HAssCe6 nanophotosensitizers have redox- and CD44-senstivity for cancer targeting. We suggested HAssCe6 nanophotosensitizers as a promising candidate for PDT of cancer cells.