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<p>Multidrug resistance (MDR) remains one of the principal challenges in cancer chemotherapy, necessitating new strategies to restore drug efficacy. In this study we developed and characterize a redox-responsive nanoplatform based on trithiocyanuric acid and polyethylene glycol (TTCA-PEG NPs) as a potential tool to overcome MDR and provide a biocompatible delivery system for conventional antitumor drugs. The platform was evaluated using doxorubicin (DOX), bleomycin (Bleo), or cisplatin (Cis) each pre-loaded into TTCA-PEG NPs and tested across three pairs of drug-sensitive and resistant cancer cell lines. TTCA-PEG NPs reduced drug resistance from 2- to 5&#xa0;fold compared with free drug, consistent with the recovery of intracellular drug accumulation and cytotoxic activity. The nanoplatform was synthesized through a one-step process completed within one hour, offering substantial simplification compared with conventional redox-responsive systems. Mechanistic studies revealed that treatment induced G<sub>2</sub>/M cell cycle arrest and apoptosis, confirming the restoration of the drugs' cytotoxic pathways in resistant cells. In vivo evaluation demonstrated a biocompatible profile, with no detectable hematopoietic, hepatic, renal, neurological, or cardiac toxicity at therapeutic doses. Pharmacokinetic studies showed that TTCA–PEG NPs modulated the rapid burst release of free Cis into a controlled, sustained-release profile, resulting in prolonged circulation and reduced systemic exposure. These findings present TTCA–PEG NPs as a biocompatible and adaptable redox-responsive platform. While in vivo efficacy studies are required to fully establish therapeutic utility, the current data regarding safety, pharmacokinetics, and in vitro MDR reversal suggest the platform is a promising candidate for further development.</p> Graphical abstract <p></p>

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Rapid synthesis of redox-responsive trithiocyanuric acid-based nanocarriers: in vitro multidrug resistance reversal and in vivo safety assessment

  • 期刊论文

  • 发表日期：

    2026年4月19日

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  • Elena Kopoleva,
  • Sergey A. Tsymbal,
  • Oleg A. Kuchur,
  • Daria S. Kulchanovskaya,
  • Anna Yu. Grishina,
  • Alevtina A. Pinova,
  • Ilia V. Doroshenko,
  • Roman I. Romanov,
  • Albert R. Muslimov,
  • Alexander V. Syuy,
  • Dmitry Yu. Ivkin,
  • Valeriy M. Kondratev,
  • Svetlana Rodimova,
  • Kirill V. Lepik,
  • Alexey D. Bolshakov,
  • Oleksii O. Peltek,
  • Mikhail V. Zyuzin

摘要

Multidrug resistance (MDR) remains one of the principal challenges in cancer chemotherapy, necessitating new strategies to restore drug efficacy. In this study we developed and characterize a redox-responsive nanoplatform based on trithiocyanuric acid and polyethylene glycol (TTCA-PEG NPs) as a potential tool to overcome MDR and provide a biocompatible delivery system for conventional antitumor drugs. The platform was evaluated using doxorubicin (DOX), bleomycin (Bleo), or cisplatin (Cis) each pre-loaded into TTCA-PEG NPs and tested across three pairs of drug-sensitive and resistant cancer cell lines. TTCA-PEG NPs reduced drug resistance from 2- to 5 fold compared with free drug, consistent with the recovery of intracellular drug accumulation and cytotoxic activity. The nanoplatform was synthesized through a one-step process completed within one hour, offering substantial simplification compared with conventional redox-responsive systems. Mechanistic studies revealed that treatment induced G2/M cell cycle arrest and apoptosis, confirming the restoration of the drugs' cytotoxic pathways in resistant cells. In vivo evaluation demonstrated a biocompatible profile, with no detectable hematopoietic, hepatic, renal, neurological, or cardiac toxicity at therapeutic doses. Pharmacokinetic studies showed that TTCA–PEG NPs modulated the rapid burst release of free Cis into a controlled, sustained-release profile, resulting in prolonged circulation and reduced systemic exposure. These findings present TTCA–PEG NPs as a biocompatible and adaptable redox-responsive platform. While in vivo efficacy studies are required to fully establish therapeutic utility, the current data regarding safety, pharmacokinetics, and in vitro MDR reversal suggest the platform is a promising candidate for further development.

Graphical abstract