Currently, the
polysaccharide-based nano-
prodrug crosslinked by stimuli-responsive synergetic
prodrug is of great demand, owing to its excellent stability, synergetic effect and
tumor selectivity, and circumventing the dilemma of dose-limiting toxicity and immunogenicity induced by that crosslinked or grafted via a single drug. Herein, the dynamic
carboxymethyl chitosan (CMCS)-based nano-
prodrugs with precise structure were facilely fabricated, via crosslinking reaction between CMCS and water-soluble synergistic small molecule
prodrug (
cisplatin-
demethylcantharidin conjugate) and further stabilization by
glutaraldehyde. The pH/
glutathione (GSH)-responsive double-crosslinked structure endowed the nano-
prodrugs with long-term storge and circulation stability at physiological pH, and dynamic transitions at
tumor sites including extracellular surface amino protonation and intracellular efficient drug release, which promoted selective
tumor accumulation and synergistic cytotoxicity, therefore achieving robust
tumor suppression while decreasing side effects. Thus, the dynamic precise CMCS-based nano-
prodrugs crosslinked by water-soluble synergistic
prodrug have great potential for highly selective robust
chemotherapy attractive for clinical translation.