2. Academic Validation
  3. Liposome-mediated delivery of a ruthenium-based metallodrug to overcome cisplatin resistance in osteosarcoma

Liposome-mediated delivery of a ruthenium-based metallodrug to overcome cisplatin resistance in osteosarcoma

  • Drug Deliv. 2026 Dec 31;33(1):2671485. doi: 10.1080/10717544.2026.2671485.
Dzohara Murillo 1 2,  Elena Domínguez-Jurado 3,  Carmen Huergo 1 2,  Borja Gallego 1 2,  Paula Díez 1 2 4,  Andrea Ferreras 1 2,  Enol Álvarez-González 1 2,  Verónica Rey 1 2,  Mar Rodríguez-Santamaría 1,  Ana S Indurain 1,  Fernando de Andrés Segura 5 6,  Iván Bravo 7,  Ángel Ríos 6 8,  Adela A Fernández-Velasco 1 2 9 10,  Iván Fernández-Vega 1 2 9 10,  Carlos Alonso-Moreno 3,  René Rodríguez 1 2 11 12
Affiliations

Affiliations

  • 1 Sarcomas and Experimental Therapeutics, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
  • 2 Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain.
  • 3 Departamento de Química Inorgánica, Orgánica y Bioquímica-Centro de Innovación en Química Avanzada (ORFEO-CINQA), Unidad nanoDrug, Facultad de Farmacia de Albacete, Universidad de Castilla-La Mancha, Albacete, Spain.
  • 4 Departamento de Biología Funcional, Área de Inmunología, Facultad de Medicina y Ciencias de la Salud, Universidad de Oviedo, Oviedo, Spain.
  • 5 Departamento de Química Analítica y Tecnología de Alimentos, Facultad de Farmacia de Albacete, Universidad de Castilla-La Mancha, Albacete, Spain.
  • 6 Universidad de Castilla-La Mancha, Instituto Regional de Investigación Científica Aplicada IRICA, Ciudad Real, Spain.
  • 7 Departamento de Química Física, Unidad nanoDrug, Facultad de Farmacia de Albacete, Universidad de Castilla-La Mancha, Albacete, Spain.
  • 8 Departamento de Química Analítica y Tecnología de Alimentos, Facultad de Ciencias y Tecnologías Químicas, Universidad de Castilla-La Mancha, Ciudad Real, Spain.
  • 9 Biobanco del Principado de Asturias, Oviedo, Spain.
  • 10 Servicio de Patología, Hospital Universitario Central de Asturias, Oviedo, Spain.
  • 11 Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC), CSIC-UC-SODERCAN, Santander, Spain.
  • 12 CIBER en oncología (CIBERONC), Madrid, Spain.
PMID: 42116576 DOI: 10.1080/10717544.2026.2671485
Abstract

The treatment of osteosarcoma has remained largely unchanged over the past decades. Its low incidence, predominantly affecting children and young adults, combined with marked biological heterogeneity, poses major challenges to the development of effective therapies, and currently approved regimens often yield variable responses. Additionally, the frequent emergence of drug-resistant phenotypes in these mesenchymal tumors further compromises treatment success. As a result, despite substantial research efforts, patients with osteosarcoma still face a poor prognosis, underscoring the urgent need for improved therapeutic strategies. Alongside doxorubicin and methotrexate, cisplatin is one of the primary first-line chemotherapeutic agents used for osteosarcoma. However, like Other cytotoxic drugs, cisplatin is limited by severe systemic toxicity and the development of resistance. In this study, we investigated the antitumor potential of a novel ruthenium organometallic compound, Ru3, and its liposomal encapsulation as a nanomedicine approach to provide a safer and more effective alternative to platinum-based therapy for both cisplatin-resistant and parental osteosarcoma models. In vitro, both free and liposomal Ru3 displayed stronger cytotoxicity than cisplatin in most models, effectively reversing drug resistance. Ru3 formulations also maintained potent activity in 3D osteosarcoma spheroids and selectively targeted Cancer stem cell-enriched tumorspheres. In vivo, treatment with liposomal Ru3 in mice bearing cisplatin-resistant xenografts produced superior therapeutic outcomes and was better tolerated than cisplatin, alleviating its systemic toxicity. Overall, these findings support ruthenium-based metallodrugs delivered via liposomes as promising alternatives to platinum-based chemotherapy for osteosarcoma management.

Keywords

Osteosarcoma; cisplatin; drug-resistance; liposomes; nanoencapsulation; ruthenium.

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