Dual-responsive polyphosphazene as a common platform for highly efficient drug self-delivery

For clinical applications, simplicity, high efficiency, and low toxicity are key issues in the design of anti-tumor drugs. In this work, a novel dual-responsive drug self-framed delivery system (DSFDS) with high drug delivery efficiency is proposed based on self-framing of an anticancer drug and a tumor-responsive molecule within phosphazene nanoparticles through a simple condensation polymerization method under mild conditions. Due to a unique structural feature of polyphosphazenes, the nanodrug-delivery system showed pH responsiveness. Furthermore, the DSFDS was endowed with glutathione (GSH)-responsiveness by incorporating a cysteine derivative into the polyphosphazene nanoparticles. The dual-responsive DSFDS has been demonstrated to retain high stability during blood circulation and high sensitivity to tumor micromilieu (lower pH in lysosomes and higher GSH concentration in cytoplasm). A super high drug-loading capacity of over 78 wt% made it possible to reduce the usage of the drug and relieve metabolic stress. The proposed DSFDS showed promising potential for highly efficient and controllable release of cancer therapeutics.