Hydrogen-Bond-Driven Core-Crosslinked Supramolecular Micelles with pH/Thermal/Glutathione-Responsive Drug Release toward Enhanced Cancer Therapy

The field of anticancer nanomedicine seeks to boost the arsenal's exploitation with intelligent performance. One opportunistic choice comes from the fabrication of amphiphilic polymer micelles that are reversibly crosslinked. Here, hydrogen-bond (H-bond)-driven core-crosslinked supramolecular polymer micelles (FUS/ICG@PEDD) are constructed, co-loading α,ω-functionalized symmetrical H-bonding prodrug 5-fluorouracil-acetic acid–SS–5-fluorouracil-acetic acid (FUS) and a dual photothermal/photodynamic agent (indocyanine green, ICG). Such core-crosslinked nanomedicine is characterized by enhanced drug loading content, crosslinking-prompted stability, pH-responsive charge reversal, and smart drug release, which can facilitate the engineering of synergistic chemo/photothermal/photodynamic therapies (CT/PTT/PDT). To do so, an amphiphilic diblock copolymer, PEG-b-P(DAPA-co-DEAEMA) (denoted as PEDD), is developed to serve as a drug delivery vehicle, with hydrophilic PEG [poly(ethylene glycol)] and hydrophobic P(DAPA-co-DEAEMA) [poly(diaminopyridine acrylamide-co-2-(diethylamino)ethyl methacrylate], bearing randomly dispersed dual functionalities: pH-responsive charge-reversal DEAEMA and H-bonding DAP motifs. Thanks to the specific DAP/FUS H-bonding interactions and two-terminal FU structure of the prodrug, core-crosslinked nanomedicine FUS/ICG@PEDD is thus enabled. In vitro and in vivo investigations indeed reveal remarkable antitumor efficacy. We believe that such H-bonded nanomedicines can fuel the development of intelligent nanomedicines with value in cancer therapy.