Synthesis of Glutathione-Responsive Cyclomatrix Polyphosphazene for Multimodal Theranostic Nanodrug Delivery

In this work, a multimodal (chemotherapeutic/photodynamic/photothermal)theranostic nanodrug delivery platform was developed based on thesynergetic action of self-framed polyphosphazene prodrug and heptamethinecyanine dye IR-780. First, an electronegative glutathione (GSH)-responsivepolyphosphazene prodrug abbreviated as HGEH was prepared via multicomponentcondensation reaction of genistein (GEN), bis-(4-hydroxyphenyl)-disulfide,and hexachlorocyclotriphosphazene. The particle size of drug (GEN)-containingHGEH nanoparticles is adjustable. Subsequently, cationic near-infraredphotosensitizer IR-780 was adsorbed onto the electron-rich HGEH toobtain the multimodal theranostic nanodrug delivery platform HGEH-IR780.The platform was demonstrated to retain high stability in avoidingdrug leakage and enable controlled drug release in response to thetumor microenvironment, in which a higher GSH concentration exists.The in vitro experiments show that HGEH-IR780 undergoes photothermaland photodynamic processes to concurrently generate heat and reactiveoxygen species for efficiently killing mouse breast cancer cells (4T1)upon exposure to a single-bandwidth near-infrared laser (808 nm).Specifically, HGEH-IR780 inhibits 4T1 cells by up to 80% at a concentrationof 100 mu g/mL. The as-developed HGEH-IR780 exhibits promisingresults in GSH-responsive anticancer activity and photodynamic/photothermaltherapy, which provides a reference for the construction of the polyphenolflavonoid multimodal therapeutic nanoplatform.

Automated summary

In this study, a multimodal theranostic nanodrug delivery platform was developed for simultaneous chemotherapy, photodynamic therapy, and photothermal therapy. This platform utilizes the synergistic action of self-framed polyphosphazene prodrug and heptamethine cyanine dye IR-780, allowing controlled drug release in response to the tumor microenvironment and showing high stability and anticancer activity.