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<p>The diversity, complexity, heterogeneity, and drug resistance of tumors make it challenging to meet the clinical needs of a single apoptosis-inducing chemotherapy. The combination of apoptosis and ferroptosis is expected to address the side effects of chemotherapy and enhance therapeutic efficacy. Here, an amphiphilic pH-responsive doxorubicin (DOX) and ferrocene (Fc)-containing copolyprodrug (P(ADH-DOX-Fc)-PEG) was designed with high DOX and Fc content of 66.5% and 0.58 mmol/g by a facile polycondensation for combining chemotherapy with ferroptosis in cancer treatment. A drug self-delivery system (DSDS) with an average hydrodynamic diameter (<i>D</i><sub>h</sub>) of 135 nm can be easily obtained <i>via</i> self-assembly with the polyprodrug blocks as the hydrophobic core and PEG as the hydrophilic brush. The cumulative DOX release reached 72.7% in the simulated tumor intracellular acidic microenvironment within 56 h, whereas the premature drug leakage was only 6.2% in the simulated normal physiological medium. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay results indicated an IC<sub>50</sub> of 8.2 µg/mL, exhibiting enhanced anti-tumor efficacy and a successful combination of apoptosis and ferroptosis, with a combination index (CI) of 0.88.</p>

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Synthesis of Amphiphilic pH-Responsive Doxorubicin and Ferrocene-containing Copolyprodrug as Drug Self-delivery System and Its In Vitro Synergistic Apoptosis and Ferroptosis Tumor Therapy

  • 期刊论文

  • 发表日期：

    2025年3月13日

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  • Xiao-Mei Zhao,
  • Peng Liu

摘要

The diversity, complexity, heterogeneity, and drug resistance of tumors make it challenging to meet the clinical needs of a single apoptosis-inducing chemotherapy. The combination of apoptosis and ferroptosis is expected to address the side effects of chemotherapy and enhance therapeutic efficacy. Here, an amphiphilic pH-responsive doxorubicin (DOX) and ferrocene (Fc)-containing copolyprodrug (P(ADH-DOX-Fc)-PEG) was designed with high DOX and Fc content of 66.5% and 0.58 mmol/g by a facile polycondensation for combining chemotherapy with ferroptosis in cancer treatment. A drug self-delivery system (DSDS) with an average hydrodynamic diameter (Dh) of 135 nm can be easily obtained via self-assembly with the polyprodrug blocks as the hydrophobic core and PEG as the hydrophilic brush. The cumulative DOX release reached 72.7% in the simulated tumor intracellular acidic microenvironment within 56 h, whereas the premature drug leakage was only 6.2% in the simulated normal physiological medium. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay results indicated an IC50 of 8.2 µg/mL, exhibiting enhanced anti-tumor efficacy and a successful combination of apoptosis and ferroptosis, with a combination index (CI) of 0.88.