Hybrid nanoparticles based on chlorin e6-conjugated hyaluronic Acid/poly(L-histidine) copolymer for theranostic application of tumor

Sang-Joon Lee, Young-Il Jeong

Index: 10.1039/C7TB03068A

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Abstract

The aim of this study is to synthesize multifunctional hybrid nanoparticles composed of hyaluronic acid (HA) and poly(L-histidine) (PHS) having disulfide linkage and chlorin e6 (HAPHSce6ss) for diagnostic and therapeutic application against breast tumor cells. Reductive end of HA was conjugated with cystamine to make disulfide linkage (HA-cystamine). PHS was conjugated with ce6 by aid of carbodiimide chemistry (PHS-ce6). Then, HA-cystamine was conjugated with carboxyl group of ce6 to make HAPHSce6ss copolymer. Nanoparticles of HAPHSce6ss copolymer have small particle sizes less than 100 nm and their diameter were increased at acidic pH, indicating that HAPHSce6ss nanoparticles have pH-sensitivity. Furthermore, ce6 were activated in the acidic environment and redox-status in the fluorescence study. At cell culture study, nanoparticles were specifically targeted CD44 receptor of MDA MB231 cells while CD44-negative MCF7 cells have no CD44-specificity. Nanoparticles exhibited enhanced association with cells and were more fluorescent at acidic pH or in the presence of GSH. They inhibited growth of tumor cells according to CD44 receptor specific or pH-sensitive manner. At in vivo animal tumor xenograft study using mice, HAPHSce6ss nanoparticles dominantly targeted MDA MB231 tumor rather than MCF7 tumor and effectively inhibit tumor growth. HAPHSce6ss nanoparticles have CD44 specificity, pH/redox dual sensitivity and fluorescence diagnostic function against tumor cells. We suggest HAPHSce6ss nanoparticles as a promising candidate for theranostic application of tumor.