Hypoxia-responsive core-cross-linked supramolecular nanoprodrug based on dendritic drug-drug conjugates for synergetic anticancer therapy

A hypoxia-responsive dendritic drug-drug conjugates IR806-(Azo-CB)₄ was prepared and combined with β-cyclodextrin-pendant poly(ethylene glycol)-block-poly(glutamic acid) block copolymer (PEG-PGlu-CD) to construct the core-cross-linked supramolecular nanoprodrug (CSN-IR806/CB, synthesized by appending chlorambucil (CB) to the terminals of IR806-containing dendritic structure via azobenzene linkages) with enhanced physiological stability through the synergy of π-π stacking interaction, host-guest complexation, hydrogen bonds, and hydrophobic interaction.

The near-infrared (NIR) light irradiation of the CSN-IR806/CB treated tumor cells induced IR806-mediated PDT and PTT, and aggravated hypoxia, which triggered the disassembly of CSN-IR806/CB and the subsequent release of activated CB for synergetic cancer cell killing.

The CSN-IR806/CB can realize a synergistic triple therapeutic effect of photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy (CT; i.e., PTT-PDT-CT).

Ding, Y., Xie, Y., Zheng, L. et al. Hypoxia-responsive core-cross-linked supramolecular nanoprodrug based on dendritic drug-drug conjugates for synergetic anticancer therapy. J Nanobiotechnol 23, 316 (2025). https://doi.org/10.1186/s12951-025-03394-y