“Watson-Crick G≡C”-inspired supramolecular nanodrug of methotrexate and 5-fluorouracil for tumor microenvironment-activatable self-recognizing synergistic chemotherapy
Carrier-free nanodrugs via straightforward small-molecule self-assembly of anticancer drugs provide a promising route for cancer chemotherapy. However, the low structural stability, lack of targeting specificity, and poor stimulus responsiveness still limited therapeutic effect. Inspired by Watson-Crick G≡C base pairing, the FDA-approved chemo-drug methotrexate (MTX, could bind with folate receptors) and 5-fluorouracil (5-FU, DNA/RNA synthetase inhibitor) were adopted to be directly assembled into self-recognizing MTX-5-FU nanoparticles via “Watson-Crick-like base pairing”-driven precise supramolecular assembly. Sequentially, our synthesized weak acidity-responsive polyethylene glycol (PEG) was inserted onto nanoparticles’ surface to temporarily shield the self-targeting function of MTX and prolong the blood circulation time. Once PEG-MTX-5-FU nanoparticles reached the weakly acidic tumor microenvironment, the PEG corona could be cleaved from their surface and then MTX could be re-exposed to recover self-recognition ability to significantly elevate tumor cell uptake; furthermore, the de-PEGylated MTX-5-FU nanoparticles could be in response to stronger acidity of lysosome, triggering core disassembly and thus burst release of both MTX and 5-FU. Further in vitro and in vivo studies consistently confirmed that the nanodrugs exhibited preferable accumulation at the tumor sites and highly synergistic chemotherapeutic effects. The supramolecular recognition-inspired, cascade-triggered self-targeting and controlled release nanodrugs could be a promising strategy to improve synergistic chemotherapy.
- This article is part of the themed collection: Journal of Materials Chemistry B HOT Papers