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Self-assembled multicomponent prodrugs with GSH/ROS site-responsiveness enable spatiotemporally controlled release

Chaozheng Zhang1, Yao Chen2, Xiaoke Shi3

  • 1State Key Laboratory of Southwestern Chinese Medicine Resources, Institute of Herbgenomics, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.

Journal of Controlled Release : Official Journal of the Controlled Release Society
|January 24, 2026
PubMed

Insights

This study developed PSOTNs, a novel nanoprodrug, to overcome Paclitaxel resistance in non-small cell lung cancer (NSCLC). PSOTNs combine three drugs for synergistic effects, enhancing treatment efficacy against resistant tumors.

Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Oncology

Background:

  • Non-small cell lung cancer (NSCLC) often develops resistance to Paclitaxel (PTX).
  • Mechanisms of resistance include enhanced drug efflux via ATP-binding cassette (ABC) transporters and upregulated PARP1-dependent DNA repair.
  • Novel strategies are needed to overcome PTX resistance in NSCLC.

Purpose of the Study:

  • To construct and evaluate a self-assembled nanoprodrug (PSOTNs) for overcoming PTX resistance in NSCLC.
  • To investigate the synergistic therapeutic effects of combining PTX, Olaparib (OLP), and tetramethylpyrazine (TMP) within a nanocarrier.
  • To explore the multi-pronged drug release mechanism triggered by intracellular stimuli (GSH, ROS, acidic pH).

Main Methods:

  • Covalent conjugation of PTX (disulfide bond), OLP (thioketal linker), and TMP (hydrophobic modification) into PSOTNs.
  • Characterization of PSOTNs for drug loading, colloidal stability, and tumor accumulation (EPR effect).
  • In vitro evaluation of drug release, cellular uptake, DNA damage, cell cycle arrest, apoptosis, and P-glycoprotein inhibition.
  • In vivo assessment of tumor growth inhibition in A549/Tax xenograft models and biocompatibility studies.

Main Results:

  • PSOTNs demonstrated high drug loading, stability, and tumor accumulation.
  • Stimuli-responsive release of PTX and OLP occurred intracellularly, leading to microtubule disruption and DNA repair inhibition.
  • TMP facilitated mitochondria-specific targeting, amplifying oxidative stress and suppressing drug efflux.
  • PSOTNs significantly enhanced drug accumulation, induced DNA damage, G2/M arrest, and apoptosis in vitro.
  • PSOTNs showed potent tumor growth inhibition, prolonged circulation, and good biocompatibility in vivo.

Conclusions:

  • PSOTNs represent a novel nanotherapeutic strategy overcoming PTX resistance in NSCLC.
  • The triple synergistic mechanism involves microtubule disruption, DNA repair inhibition, and mitochondrial function intervention.
  • PSOTNs offer a promising paradigm for treating drug-resistant malignancies.
Keywords:
Drug resistanceGSH/ROS site-responsivenessMulticomponent prodrugsNSCLCPARP inhibitorPaclitaxel

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