Nanomedicine targeting cuproplasia in cancer: labile copper sequestration using polydopamine particles blocks tumor growth in vivo through altering metabolism and redox homeostasis

Bonet-Aleta, Javier (Universidad de Zaragoza) ; Encinas-Giménez, Miguel (Universidad de Zaragoza) ; Oi, Miku ; Pezacki, Aidan T. ; Sebastián, Víctor (Universidad de Zaragoza) ; de Martino, Alba ; Martín Pardillos, Ana (Universidad de Zaragoza) ; Martín-Duque, Pilar (Universidad de Zaragoza) ; Hueso, José L. (Universidad de Zaragoza) ; Chang, Christopher J. ; Santamaría, Jesús (Universidad de Zaragoza)

Resumen: Copper plays critical roles as a metal active site cofactor and metallo-allosteric signal for enzymes involved in cell proliferation and metabolism, making it an attractive target for cancer therapy. In this study, we investigated the efficacy of polydopamine nanoparticles (PDA NPs), classically applied for metal removal from water, as a therapeutic strategy for depleting intracellular labile copper pools in triple negative breast cancer models through the metal-chelating groups present on PDA surface. By using the activity-based sensing probe FCP-1, we could track the PDA-induced labile copper depletion while leaving total copper levels unchanged, and link it to the selective MDA-MB-231 cell death. Further mechanistic investigations revealed that PDA NPs increased reactive oxygen species (ROS) levels, potentially through the inactivation of superoxide dismutase 1 (SOD1), a copper-dependent antioxidant enzyme. Additionally, PDA NPs were found to interact with the mitochondrial membrane, resulting in an increase in mitochondrial membrane potential, which may contribute to enhanced ROS production. We employed an in vivo tumor model to validate the therapeutic efficacy of PDA NPs. Remarkably, in the absence of any additional treatment, the presence of PDA NPs alone led to a significant reduction in tumor volume by a factor of 1.66 after 22 days of tumor growth. Our findings highlight the potential of PDA NPs as a promising therapeutic approach for selectively targeting cancer by modulating copper levels and inducing oxidative stress, leading to tumor growth inhibition as shown in these triple negative breast cancer models.

Idioma: Inglés

DOI: 10.1021/acsami.4c04336

Año: 2024

Publicado en: ACS applied materials & interfaces 16, 23 (2024), 29844-29855
ISSN: 1944-8244

Financiación: info:eu-repo/grantAgreement/EC/H2020/742684/EU/Catalytic Dual-Function Devices Against Cancer/CADENCE
Financiación: info:eu-repo/grantAgreement/ES/ISCIII DTS21-00130
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI19-01007
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PDC2022-133866-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2021-127847OB-I00
Financiación: info:eu-repo/grantAgreement/ES/UZ/ICTS NANBIOSIS-CIBER-BBN

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Estomatología (Dpto. Cirugía)
Área (Departamento): Área Ingeniería Química (Dpto. Ing.Quím.Tecnol.Med.Amb.)
Área (Departamento): Área Tecnologi. Medio Ambiente (Dpto. Ing.Quím.Tecnol.Med.Amb.)