Gema Vivo-Llorca1,2,3, Ángela Morellá-Aucejo1,2,3, Alba García-Fernández1,2,3, Paula Díez1,2,3,4, Antoni Llopis-Lorente1,5, Mar Orzáez3,6, Ramón Martínez-Máñez1,2,3,4,7. 1. Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, València, Spain. 2. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain. 3. Unidad Mixta UPV-CIPF de Investigación de Mecanismos de Enfermedades y Nanomedicina, Valencia, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, València, Spain. 4. Unidad Mixta de Investigación en Nanomedicina y sensores, Universitat Politènica de València, Instituto de Investigación Sanitaria la Fe, Valènica, Spain. 5. Department of Chemical Engineering and Chemistry, Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands. 6. Centro de Investigación Príncipe Felipe, Laboratorio de Péptidos y Proteínas, València, Spain. 7. Departamento de Química, Universitat Politècnica de València, València, Spain.
Abstract
INTRODUCTION: Breast cancer has the highest mortality rate among cancers in women. Patients suffering from certain breast cancers, such as triple-negative breast cancer (TNBC), lack effective treatments. This represents a clinical concern due to the associated poor prognosis and high mortality. As an approach to succeed over conventional therapy limitations, we present herein the design and evaluation of a novel nanodevice based on enzyme-functionalized gold nanoparticles to efficiently perform enzyme prodrug therapy (EPT) in breast cancer cells. RESULTS: In particular, the enzyme horseradish peroxidase (HRP) - which oxidizes the prodrug indole-3-acetic acid (IAA) to release toxic oxidative species - is incorporated on gold nanoconjugates (HRP-AuNCs), obtaining an efficient nanoplatform for EPT. The nanodevice is biocompatible and effectively internalized by breast cancer cell lines. Remarkably, co-treatment with HRP-AuNCs and IAA (HRP-AuNCs/IAA) reduces the viability of breast cancer cells below 5%. Interestingly, 3D tumor models (multicellular tumor spheroid-like cultures) co-treated with HRP-AuNCs/IAA exhibit a 74% reduction of cell viability, whereas the free formulated components (HRP, IAA) have no effect. CONCLUSION: Altogether, our results demonstrate that the designed HRP-AuNCs nanoformulation shows a remarkable therapeutic performance. These findings might help to bypass the clinical limitations of current tumor enzyme therapies and advance towards the use of nanoformulations for EPT in breast cancer.
INTRODUCTION: Breast cancer has the highest mortality rate among cancers in women. Patients suffering from certain breast cancers, such as triple-negative breast cancer (TNBC), lack effective treatments. This represents a clinical concern due to the associated poor prognosis and high mortality. As an approach to succeed over conventional therapy limitations, we present herein the design and evaluation of a novel nanodevice based on enzyme-functionalized gold nanoparticles to efficiently perform enzyme prodrug therapy (EPT) in breast cancer cells. RESULTS: In particular, the enzyme horseradish peroxidase (HRP) - which oxidizes the prodrug indole-3-acetic acid (IAA) to release toxic oxidative species - is incorporated on gold nanoconjugates (HRP-AuNCs), obtaining an efficient nanoplatform for EPT. The nanodevice is biocompatible and effectively internalized by breast cancer cell lines. Remarkably, co-treatment with HRP-AuNCs and IAA (HRP-AuNCs/IAA) reduces the viability of breast cancer cells below 5%. Interestingly, 3D tumor models (multicellular tumor spheroid-like cultures) co-treated with HRP-AuNCs/IAA exhibit a 74% reduction of cell viability, whereas the free formulated components (HRP, IAA) have no effect. CONCLUSION: Altogether, our results demonstrate that the designed HRP-AuNCs nanoformulation shows a remarkable therapeutic performance. These findings might help to bypass the clinical limitations of current tumor enzyme therapies and advance towards the use of nanoformulations for EPT in breast cancer.
Authors: F Cardoso; S Kyriakides; S Ohno; F Penault-Llorca; P Poortmans; I T Rubio; S Zackrisson; E Senkus Journal: Ann Oncol Date: 2019-08-01 Impact factor: 32.976