Home > Articles > Published articles > A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models |
Date: | 2020 |
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 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. |
Grants: | Ministerio de Economía y Competitividad BIO2016-76063-R Instituto de Salud Carlos III PI18/00650 Instituto de Salud Carlos III PI15/00378 Instituto de Salud Carlos III PIE15/00028 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/FI_B 00680 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-865 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1395 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-229 |
Note: | Altres ajuts: U COST Action CA 17140 to RM; FIS PI17/01246, RD12/0036/0071 and FIS PI14/00450 to JS; CP15/00163 to MVC; FIS PI15/00272 to EV ; CIBER-BBN [CB06/01/1031 and 4NanoMets to RM ; and VENOM4CANCER to AV. Grant from La Generalitat de Catalunya (PERIS) [SLT002/16/00433 to JS |
Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Published in: | Haematologica, Vol. 105, issue 3 (Jan. 2020) , p. 741-753, ISSN 1592-8721 |
13 p, 4.5 MB |