1 research outputs found
Selective depletion of metastatic stem cells as therapy for human colorectal cancer
Selective elimination of metastatic stem cells (MetSCs) promises to block metastatic dissemination. Colorectal cancer (CRC) cells overexpressing CXCR4 display trafficking functions and metastasisâinitiating capacity. We assessed the antimetastatic activity of a nanoconjugate (T22âGFPâH6âFdU) that selectively delivers Floxuridine to CXCR4+ cells. In contrast to free oligoâFdU, intravenous T22âGFPâH6âFdU selectively accumulates and internalizes in CXCR4+ cancer cells, triggering DNA damage and apoptosis, which leads to their selective elimination and to reduced tumor reâinitiation capacity. Repeated T22âGFPâH6âFdU administration in cell line and patientâderived CRC models blocks intravasation and completely prevents metastases development in 38â83% of mice, while showing CXCR4 expressionâdependent and siteâdependent reduction in foci number and size in liver, peritoneal, or lung metastases in the rest of mice, compared to free oligoâFdU. T22âGFPâH6âFdU induces also higher regression of established metastases than free oligoâFdU, with negligible distribution or toxicity in normal tissues. This targeted drug delivery approach yields potent antimetastatic effect, through selective depletion of metastatic CXCR4+ cancer cells, and validates metastatic stem cells (MetSCs) as targets for clinical therapy.This work was supported by Plan Estatal de I+D+I 2013-2016, Instituto de
Salud Carlos III and MINECO (co-funding from FEDER, Integrated Project of
Excellence PIE15/00028, PI18/00650, PI15/00378, PI15/00272, PI12/00327, PI17/00150, BIO2013-41019-P CTQ2014-52588-R, and BFU2010-17450), AGAUR
(2017 SGR 865, 2017 SGR 229, 2014PROD-00055), MaratĂłTV3 (416/C/2013), La
Caixa Foundation, and CIBER-BBN Nanomets and Nanoprother Intramural
Projects, and used CIBER-BBN Nanotoxicology and Protein Production Platforms
for its development. GOA and NBT groups are part of the Spanish ICTS-
141007 NANBIOSIS Network for Nanomedicine. M.V.C and U.U. are supported
by Miguel Servet and Sara Borrell contracts from ISCIII, respectively. P.A.
obtained a Fellowship from the Josep Carreras Research Institute. A.V. received
an ICREA ACADEMIA Award.Peer reviewe