Self-assembled GSH-responsive polycyclophosphazene loaded honokiol nano-drug for enhanced cancer therapy

Honokiol (HK), a key bioactive compound extracted from the root and stem bark of Magnolia officinalis, has been a staple in traditional Chinese medicine for over a millennium. Despite its long history of use, HK exhibits low oral bioavailability, which hinders its potential for clinical applications. Herein, we report a GSH-responsive and biodegradable polyphosphazene based Nano-HK particles synthesized via covalent bonding of HK, a disulfide-containing linker, and hexachlorocyclotriphosphazene (HCCP). The Nano-HK particles are uniformly distributed, with an average size of approximately 160 nm. Thanks to the covalent bonding between HK molecules, Nano-HK remains stable in plasma, gradually releasing HK at the tumor site through the reduction of disulfide bonds by the high glutathione (GSH) concentration in cancer cells. This targeted release results in a significantly enhanced inhibitory effect on tumor growth in an A375 xenograft model, outperforming free HK. The results showed no toxic symptoms in mouse or any pathological alterations in major organs. These studies demonstrated that Nano-HK substantially enhanced cytotoxicity against tumor cells compared to free HK, inducing G2/M cell cycle arrest and apoptosis in A375 cells. The conjugated HCCP Nano-HK exhibited both efficacy and safety in mouse, showing promise for further development as a potential treatment for tumors.