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Haematologica. 2019 Jun 27. pii: haematol.2018.211490. doi: 10.3324/haematol.2018.211490. [Epub ahead of print]

A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models.

Author information

1
Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
2
CIBER en Bioingenieria, Biomateriales y Nanomedicina, Barcelona, Spain.
3
Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
4
Department of Pharmacy, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
5
Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
6
Institut de Biotecnologia i de Biomedicina, Universitat Autonoma de Barcelona, Barcelona, Spain.
7
Departament de Genetica i de Microbiologia, Universitat Autonoma de Barcelona, Barcelona, Spain.
8
Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; rmangues@santpau.cat.

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 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 to specifically target 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 T22-DITOX-H6 administration, a nanoparticle incorporating a toxin with the same structure as the nanocarrier. Hence, the use of 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.

KEYWORDS:

Aggressive Non-Hodgkin's Lymphoma; CXCR4 receptor; DLBCL; nanomedicine; targeted-therapy

PMID:
31248974
DOI:
10.3324/haematol.2018.211490
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