Double-Cross-Linked Hyaluronic Acid Nanoparticles with pH/Reduction Dual-Responsive Triggered Release and pH-Modulated Fluorescence for Folate-Receptor-Mediated Targeting Visualized Chemotherapy

A versatile folate-receptor-mediated targeting tumor theranostics has been designed for pH/reduction dual-responsive controlled anticancer drug release and pH-modulated fluorescent tumor imaging via facile ionic (pH sensitive) and covalent (reduction responsive) double-cross-linking (DCL) of the folic acid (FA) and Rhodamine 6G modified hyaluronic acid (HA) (FA-HA-Rh 6G). After optimizing the morphology and diameter of the resultant nanoparticles (DCL FA-HA-Rh 6G NPs) via modulating the concentration of the ionic and covalent cross-linking agents, the one with Ca and S contents of 1.70 and 2.84 wt % and an average hydrodynamic diameter of 154 nm was chosen as the desired drug delivery system (DDS) for DOX. They not only had high drug loading capacity and drug encapsulation efficiency (716 ± 34 mg/g and 71.6 ± 3.4%) but also possessed perfect triggered release and strong fluorescence intensity in the stimulated tumor microenvironment. The MTT assay and CLSM analysis revealed that the proposed double-cross-linked HA-based DDS had favorable cytocompatibility and folate-receptor-mediated targeting functionality to the HeLa cells and could obviously enhance the anticancer efficiency of DOX. The integration of the pH and reduction dual-responsiveness, folate-receptor-mediated targeting functionality, and pH-dependent fluorescence intensity into the biodegradable and biocompatible HA nanoparticles make the DCL FA-HA-Rh 6G NPs significant potential for future visualized chemotherapy of cancers.