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Issue 17, 2020

“Watson–Crick G[triple bond, length as m-dash]C”-inspired supramolecular nanodrug of methotrexate and 5-fluorouracil for tumor microenvironment-activatable self-recognizing synergistic chemotherapy

Author affiliations

Abstract

Carrier-free nanodrugs, generated via the straightforward small-molecule self-assembly of anticancer drugs, provide a promising route for cancer chemotherapy. However, their low structural stability, lack of targeting specificity, and poor stimulus responsiveness are still limiting their therapeutic effect. Inspired by Watson–Crick G[triple bond, length as m-dash]C base pairing, the FDA-approved chemo-drug methotrexate (MTX, which can bind with folate receptors) and 5-fluorouracil (5-FU, a DNA/RNA synthetase inhibitor) were adopted for direct assembly 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 the nanoparticle 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 its self-recognition ability and significantly elevate tumor cell uptake; furthermore, the de-PEGylated MTX–5-FU nanoparticles could respond to the stronger acidity of lysosome, triggering core disassembly and thus the 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 with highly synergistic chemotherapeutic effects. The supramolecular recognition-inspired, cascade-triggered self-targeting and controlled release of nanodrugs could be a promising strategy to improve synergistic chemotherapy.

Graphical abstract: “Watson–Crick G [[triple bond, length as m-dash]] C”-inspired supramolecular nanodrug of methotrexate and 5-fluorouracil for tumor microenvironment-activatable self-recognizing synergistic chemotherapy

Supplementary files

Article information


Submitted
20 Feb 2020
Accepted
15 Mar 2020
First published
18 Mar 2020

J. Mater. Chem. B, 2020,8, 3829-3841
Article type
Paper

“Watson–Crick G[triple bond, length as m-dash]C”-inspired supramolecular nanodrug of methotrexate and 5-fluorouracil for tumor microenvironment-activatable self-recognizing synergistic chemotherapy

M. Chen, S. Chen, F. Zhu, F. Wang, H. Tian, Z. Fan, S. Ke, Z. Hou and Y. Li, J. Mater. Chem. B, 2020, 8, 3829 DOI: 10.1039/D0TB00468E

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