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<p>Doxorubicin (DOX) efficacy in breast cancer is limited by dose-dependent cardiotoxicity and the development of multidrug resistance, while celastrol (Cel) suffers from poor solubility, low bioavailability and systemic toxicity. Their combination offers synergistic potential, but effective co-delivery remains challenging. We designed a protein-based nanoplatform via ferric ion-mediated biomimetic mineralization co-assembly of DOX, Cel, and human serum albumin (HSA) for enhanced antitumor therapy. HSA-Fe(III)-Cel-DOX nanoparticles were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Drug loading and encapsulation efficiencies were determined by high-performance liquid chromatography (HPLC). In vitro drug release was evaluated with or without glutathione (GSH). Cytotoxicity against 4T1 murine breast cancer cells was assessed by CCK-8 assay. The optimized HSA-Fe(III)-Cel-DOX NPs (8&#xa0;mM Fe<sup>3</sup>⁺) exhibited uniform spherical morphology with an average diameter of approximately 64.6&#xa0;nm and narrow size distribution (PDI = 0.103). The nanoparticles demonstrated exceptionally high drug encapsulation efficiencies (96.7 ± 1.9% for DOX and 94.5 ± 1.4% for Cel) and drug loading capacities (19.7 ± 0.5% for DOX and 17.3 ± 0.4% for Cel). The formulation exhibited excellent colloidal stability over 28&#xa0;days of storage. In vitro release studies revealed remarkable GSH-responsive behavior, with cumulative release reaching 77.0 ± 3.3% for DOX and 64.0 ± 2.9% for Cel at 12&#xa0;h under reducing conditions, while negligible release (&lt; 5%) under non-reducing conditions was observed in the absence of GSH. Cytotoxicity assays demonstrated that HSA-Fe(III)-Cel-DOX NPs exerted significantly enhanced antitumor effect against 4T1 cells compared to free DOX or free Cel alone. At an equivalent DOX concentration of 0.5&#xa0;μg/mL, the nanoparticles reduced cell viability to 29.2 ± 1.2%, substantially lower than free DOX (89.7 ± 2.0%) or free Cel (100.4 ± 2.2%). We successfully constructed a ferric ion-mediated biomimetic nanoplatform via co-assembly of DOX, Cel, and HSA. This nanoplatform offers facile preparation, excellent stability, GSH-responsive drug release, and significantly enhanced in vitro cytotoxicity, representing a promising strategy for synergistic breast cancer therapy.</p>

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Ferric ion-mediated biomimetic mineralization of human serum albumin with doxorubicin and celastrol for enhanced antitumor therapy

  • 期刊论文

  • 发表日期：

    2026年6月28日

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  • Jie Liu,
  • Jun Chen,
  • Lei Zhang,
  • Chunyong Xia

摘要

Doxorubicin (DOX) efficacy in breast cancer is limited by dose-dependent cardiotoxicity and the development of multidrug resistance, while celastrol (Cel) suffers from poor solubility, low bioavailability and systemic toxicity. Their combination offers synergistic potential, but effective co-delivery remains challenging. We designed a protein-based nanoplatform via ferric ion-mediated biomimetic mineralization co-assembly of DOX, Cel, and human serum albumin (HSA) for enhanced antitumor therapy. HSA-Fe(III)-Cel-DOX nanoparticles were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Drug loading and encapsulation efficiencies were determined by high-performance liquid chromatography (HPLC). In vitro drug release was evaluated with or without glutathione (GSH). Cytotoxicity against 4T1 murine breast cancer cells was assessed by CCK-8 assay. The optimized HSA-Fe(III)-Cel-DOX NPs (8 mM Fe3⁺) exhibited uniform spherical morphology with an average diameter of approximately 64.6 nm and narrow size distribution (PDI = 0.103). The nanoparticles demonstrated exceptionally high drug encapsulation efficiencies (96.7 ± 1.9% for DOX and 94.5 ± 1.4% for Cel) and drug loading capacities (19.7 ± 0.5% for DOX and 17.3 ± 0.4% for Cel). The formulation exhibited excellent colloidal stability over 28 days of storage. In vitro release studies revealed remarkable GSH-responsive behavior, with cumulative release reaching 77.0 ± 3.3% for DOX and 64.0 ± 2.9% for Cel at 12 h under reducing conditions, while negligible release (< 5%) under non-reducing conditions was observed in the absence of GSH. Cytotoxicity assays demonstrated that HSA-Fe(III)-Cel-DOX NPs exerted significantly enhanced antitumor effect against 4T1 cells compared to free DOX or free Cel alone. At an equivalent DOX concentration of 0.5 μg/mL, the nanoparticles reduced cell viability to 29.2 ± 1.2%, substantially lower than free DOX (89.7 ± 2.0%) or free Cel (100.4 ± 2.2%). We successfully constructed a ferric ion-mediated biomimetic nanoplatform via co-assembly of DOX, Cel, and HSA. This nanoplatform offers facile preparation, excellent stability, GSH-responsive drug release, and significantly enhanced in vitro cytotoxicity, representing a promising strategy for synergistic breast cancer therapy.