Methylene Blue‐Loaded Self‐Assembled Nanoparticles and Their Temperature, Reduction, and Near‐Infrared‐Responsive Release Property for Doxorubicin Delivery

ABSTRACT Poly(acrylic acid) (PAA) is a widely used polymer due to its biocompatibility, hydrophilicity, and customizable structure. Thus, it makes PAA a desirable candidate for developing advanced drug delivery systems. This study used PAA and aminophenyl disulfide (APD) to prepare ion pair self‐assembly (IPM), which is sensitive to temperature and reduction. The PAA/APD ion pair exhibited upper critical solution temperature (UCST) and surface‐active. The surface tension could be controlled by APD content and reducing agent concentration. The critical micelle concentration (CMC) was found at about 3.8 mg/mL and increased with increasing the reducing agent concentration. The APD reduction was verified by X‐ray photoelectron spectroscopy (XPS) microscopy. IPM containing methylene blue (IPM@MB) showed photothermal activity and high photostability under NIR irradiation. The ionic interaction between PAA and APD was confirmed by FT‐IR spectroscopy. IPM appeared as almost sphere‐like nanoparticles on the TEM and SEM images. MB can be loaded inside the IPM, evidenced by confocal images. Upon heating, doxorubicin (DOX) was appreciably released when the temperature was higher than the UCST of IPM. Under reducing conditions, the disulfide bond (S‐S) of APD was reduced to thiol (S‐H) groups. The IPM would lose its amphiphilicity, leading to IPM disintegration and accelerated release. Upon NIR irradiation, the IPM@MB showed burst release because of the heat generation from MB, leading to the IPM disassembly.