Abstract
Selective elimination of metastatic stem cells (MetSCs) promises to block metastatic dissemination. Colorectal cancer (CRC) cells overexpressing CXCR4 display trafficking functions and metastasis‐initiating capacity. We assessed the antimetastatic activity of a nanoconjugate (T22‐GFP‐H6‐FdU) that selectively delivers Floxuridine to CXCR4+ cells. In contrast to free oligo‐FdU, intravenous T22‐GFP‐H6‐FdU selectively accumulates and internalizes in CXCR4+ cancer cells, triggering DNA damage and apoptosis, which leads to their selective elimination and to reduced tumor re‐initiation capacity. Repeated T22‐GFP‐H6‐FdU administration in cell line and patient‐derived CRC models blocks intravasation and completely prevents metastases development in 38–83% of mice, while showing CXCR4 expression‐dependent and site‐dependent reduction in foci number and size in liver, peritoneal, or lung metastases in the rest of mice, compared to free oligo‐FdU. T22‐GFP‐H6‐FdU induces also higher regression of established metastases than free oligo‐FdU, 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.
Highlights
Selective elimination of metastatic stem cells (MetSCs) promises to block metastatic dissemination
The structure and physico-chemical characterization of this new T22-GFP-H6-FdU nanoconjugate are described in Fig 1A–C, and Appendix Figs S1 and S2, which contains T22, a green fluorescent protein and oligo-FdU, an oligonucleotide of a drug active against Colorectal cancer (CRC) (Shi et al, 2015), which allows to load a high number of drug molecules into the nanoconjugate
Based on the clear site-dependent antimetastatic potency achieved by T22-GFP-H6-FdU in the prevention of metastasis experiments (Fig 6A, Appendix Fig S8A, and Table 1), on its dependence on CXCR4 membrane expression for cell internalization (Fig 2E) and capacity to selectively kill CXCR4+ cancer cells (Fig 3A and B), we investigated if CXCR4 expression after therapy correlated with the observed antimetastatic effect at the different sites
Summary
Selective elimination of metastatic stem cells (MetSCs) promises to block metastatic dissemination. T22-GFP-H6-FdU induces higher regression of established metastases than free oligo-FdU, 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. There is an urgent need to develop less toxic and more effective antimetastatic agents To achieve this goal, preclinical and clinical drug development should shift its focus from primary tumor to metastasis control, using metastatic cancer models and evaluating promising drugs in patients with limited or non-metastatic disease (Steeg & Theodorescu, 2008; Steeg, 2016). After repeated T22-GFP-H6-FdU administration, and in contrast to free oligo-FdU, we achieved highly significant activity in the prevention and regression of metastases in the absence of toxicity, supporting the clinical relevance of developing drugs that selectively target MetSCs to achieve metastasis control
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