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

Abstract

The “Watson–Crick G≡C”-inspired carrier-free nanodrug have excellent tumor microenvironment-triggered active self-targeting ability and enhanced synergistic chemotherapeutic effects.

Hydrogen‐Bonds‐Mediated Nanomedicine: Design, Synthesis, and Applications

“…Furthermore, de‐PEGylated MTX/5‐FU nanoparticles react to the stronger acidity of lysosome, triggering H‐bonds dissociation and core disassembly and finally leading to the burst release of both MTX and 5‐FU for chemotherapy. [ 82 ] In vitro and in vivo studies confirmed that the H‐bonded nanomedicine indeed exhibited preferable accumulation at tumor sites along with extraordinarily synergistic chemotherapeutic effects (Figure 6b).…”

“…[107] Importantly, the DOX-loaded micelles indeed exert effective cytotoxic effect against HepG2cells, a model cancer cell line, highlighting the importance of the control of H-bonding interactions Reproduced with permission. [82] Copyright 2020, Royal Society of Chemistry.…”

“…Inspired by Watson‐Crick G.C base pairing, the FDA‐approved the chemotherapeutic molecule methotrexate (MTX, a folate analogue and an inhibitor of dihydrofolate reductase) and 5‐fluorouracil (5‐FU, a pyrimidine analogue and an inhibitor of DNA/RNA synthetase), sequentially aggregated into MTX/5‐FU nanoparticles via a H‐bonding directed assembly ( Figure a). [ 82 ] Within such MTX/5‐FU nanoparticles, both MTX and 5‐FU demonstrate different but complementary action sites and antitumor mechanisms, therefore the combination of MTX with 5‐FU into carrier‐free nanomedicine can significantly enhance the antitumor synergetic efficiency with reduced side effects if compared to conventional strategy involving free drugs. Sequentially, a weak acidity‐responsive polyethylene glycol (PEG) is localized onto the MTX/5‐FU nanoparticles surface, to temporarily shield the self‐targeting function of MTX and thus to increase the time during which it circulates into blood.…”

“…C-like H-bonds-driven supramolecular self-assembly followed by dynamic PEGylation. b) Illustration of tumor acidity-triggered self-targeting activation and lysosomal acidity triggered drug release of PEG-MTX/5-FU nanoparticles.Reproduced with permission [82]. Copyright 2020, Royal Society of Chemistry.…”

Multicomponent carrier-free nanodrugs for cancer treatment

“…Similarly, Huang and coworkers synthesized an ADDC from the hydrophilic irinotecan (Ir) and the hydrophobic chlorambucil (Cb) via an ester linkage for enhanced cancer synergistic chemotherapy. 50 In another novel idea, inspired by the “Watson–Crick GC” base pairing, Chen and coworkers developed a dual-drug, 51 methotrexate (MTX) and 5-fluorouracil (5-FU), which was assembled into amphiphilic MTX-5-FU NPs based on “Watson–Crick GC” bonds. The synthesized PEG was modified on the surface of nanodrugs to temporarily shield the targeting function of MTX.…”