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Non-Hodgkin Lymphoma
A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models
Aïda Falgàs,1,2,* Victor Pallarès,1,3,* Ugutz Unzueta,1,2
María Virtudes Céspedes,1,2 Irene Arroyo-Solera,1,2 María José Moreno,1 Alberto Gallardo,1,4 María Antonia Mangues,5 Jorge Sierra,3,6
Antonio Villaverde,2,7,8 Esther Vázquez,2,7,8* Ramon Mangues1,2,6,*
and Isolda Casanova1,2,6
*AF and VP contributed equally to this work.
ABSTRACT
One-third of diffuse large B-cell lymphoma patients are refractory to initial treatment or relapse after rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy. In these patients, CXCR4 overexpression (CXCR4+) associates with lower overall and disease-free survival. Nanomedicine pursues active targeting to selec- tively deliver antitumor agents to cancer cells; a novel approach that prom- ises to revolutionize therapy by dramatically increasing drug concentration in target tumor cells. In this study, we intravenously administered a ligand- ed protein nanocarrier (T22-GFP-H6) targeting CXCR4+ lymphoma cells in mouse models to assess its selectivity as a nanocarrier by measuring its tis- sue biodistribution in cancer and normal cells. No previous protein-based nanocarrier has been described as specifically targeting lymphoma cells. T22-GFP-H6 achieved a highly selective tumor uptake in a CXCR4+ lym- phoma subcutaneous model, as detected by fluorescent emission. We demonstrated that tumor uptake was CXCR4-dependent because pretreat- ment with AMD3100, a CXCR4 antagonist, significantly reduced tumor uptake. Moreover, in contrast to CXCR4+ subcutaneous models, CXCR4– tumors did not accumulate the nanocarrier. Most importantly, after intra- venous injection in a disseminated model, the nanocarrier accumulated and internalized in all clinically relevant organs affected by lymphoma cells with negligible distribution to unaffected tissues. Finally, we obtained antitumor effect without toxicity in a CXCR4+ lymphoma model by administration of T22-DITOX-H6, a nanoparticle incorporating a toxin with the same struc- ture as the nanocarrier. Hence, the use of the T22-GFP-H6 nanocarrier could be a good strategy to load and deliver drugs or toxins to treat specifically CXCR4-mediated refractory or relapsed diffuse large B-cell lymphoma without systemic toxicity.
Introduction
Diffuse large B-cell lymphoma (DLBCL) represents 30-33% of all non-Hodgkin lymphomas (NHL).1 Management of DLBCL has been improved by the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. However, despite this advancement, R-CHOP treatment is still associated with high toxicity, relapse and an unacceptably high treatment failure
Ferrata Storti Foundation
Haematologica 2018 Volume 105(3):741-753
1Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau; 2CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); 3Department of Hematology, Hospital de la Santa Creu i Sant Pau; 4Department of Pathology, Hospital de la Santa Creu i Sant Pau; 5Department of Pharmacy, Hospital de la Santa Creu i Sant Pau; 6Josep Carreras Research Institute; 7Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona and 8Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Barcelona, Spain
Correspondence:
RAMON MANGUES
mangues@santpau.cat
ESTHER VÁZQUEZ
esther.vazquez@uab.cat
Received: November 19, 2018. Accepted: June 26, 2019. Pre-published: June 27 2019.
doi:10.3324/haematol.2018.211490
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/741
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