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“Watson-Crick G≡C”-inspired supramolecular nanodrug of methotrexate and 5-fluorouracil for tumor microenvironment-activatable self-recognizing synergistic chemotherapy

Abstract

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.

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Supplementary files

Article information


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

J. Mater. Chem. B, 2020, Accepted Manuscript
Article type
Paper

“Watson-Crick G≡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. N. Tian, Z. Fan, S. Ke, Z. Hou and Y. Li, J. Mater. Chem. B, 2020, Accepted Manuscript , DOI: 10.1039/D0TB00468E

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