A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models
Aïda Falgàs,
Victor Pallarès,
Ugutz Unzueta,
María Virtudes Céspedes,
Irene Arroyo-Solera,
María José Moreno,
Jorge Sierra,
Alberto Gallardo,
María Antonia Mangues,
Esther Vázquez,
Antonio Villaverde,
Ramon Mangues,
Isolda Casanova
Affiliations
Aïda Falgàs
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau;CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN)
Victor Pallarès
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau;Department of Hematology, Hospital de la Santa Creu i Sant Pau
Ugutz Unzueta
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau;CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN)
María Virtudes Céspedes
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau;CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN)
Irene Arroyo-Solera
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau;CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN)
María José Moreno
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau
Jorge Sierra
Department of Hematology, Hospital de la Santa Creu i Sant Pau;Josep Carreras Research Institute
Alberto Gallardo
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau;Department of Pathology, Hospital de la Santa Creu i Sant Pau
María Antonia Mangues
Department of Pharmacy, Hospital de la Santa Creu i Sant Pau
Esther Vázquez
CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN);Institut de Biotecnologia i de Biomedicina, Universitat Autonoma de Barcelona;Departament de Genètica i de Microbiologia, Universitat Autonoma de Barcelona, Barcelona, Spain
Antonio Villaverde
CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN);Institut de Biotecnologia i de Biomedicina, Universitat Autonoma de Barcelona;Departament de Genètica i de Microbiologia, Universitat Autonoma de Barcelona, Barcelona, Spain
Ramon Mangues
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau;CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN);Josep Carreras Research Institute
Isolda Casanova
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau;CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN);Josep Carreras Research Institute
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 selectively deliver antitumor agents to cancer cells; a novel approach that promises to revolutionize therapy by dramatically increasing drug concentration in target tumor cells. In this study, we intravenously administered a liganded protein nanocarrier (T22-GFP-H6) targeting CXCR4+ lymphoma cells in mouse models to assess its selectivity as a nanocarrier by measuring its tissue 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+ lymphoma subcutaneous model, as detected by fluorescent emission. We demonstrated that tumor uptake was CXCR4-dependent because pretreatment 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 intravenous 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 structure 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.