1. Negligible T22‐GFP‐H6‐FdU biodistribution or toxicity on non‐tumor tissues
Negligible T22‐GFP‐H6‐FdU biodistribution or toxicity on non‐tumor tissues AUndetectable T22‐GFP‐H6‐FdU emitted fluorescence in normal tissues, except for a transient accumulation 5 h after a 100 μg dose in the liver, which disappears at 24 h. Liver emitted fluorescence is transient and significantly lower than the one registered in tumor tissue. Tumor/Liver ratio = 7.5 (see tumor intensity in Fig 2B, which was registered in the same experiment; N = 5 mice/group). Scale bar, 1 cm. Color key, radiant efficiency units.BRepresentative images depicting the level of DNA double‐strand break (DSB) induction in histologically normal bone marrow 5 h after treatment, as measured by anti‐γ‐H2AX, which is higher in free oligo‐FdU‐treated mice than in T22‐GFP‐H6‐FdU (P = 0.047). Low level of cells containing DSBs in histologically normal kidney after T22‐GFP‐H6‐FdU or free oligo‐FdU treatment, a finding occurring in all normal tissues analyzed (N = 50, 5 mice/group; 10 fields/mouse). Scale bar, 100 μm.CRepresentative images showing lack of histopathological alterations in H&E‐stained tissue or apoptotic induction in H&E‐stained samples of CXCR4+ (bone marrow) and CXCR4− (brain, kidney, liver, lung, and heart) normal tissues 24 h after the administration of a 100 μg dose of T22‐GFP‐H6‐FdU or an equimolecular dose of free oligo‐FdU (N = 5/group). Note that the transient nanoconjugate distribution to liver or the DNA damage induced in bone marrow does not lead to cytotoxicity on these non‐tumor tissues (N = 50, 5 mice/group; 10 fields/mouse). Scale bar, 100 μm.DLack of differences in body weight among groups registered along time in the SW1417‐derived CCR model and the regression of metastases protocol (mean ± s.e.m., N = 10 mice/group).ELack of differences in body mouse weight among groups registered along time in the SW1417 cell line‐derived model and the prevention of metastasis protocol [mean ± s.e.m., Buffer (N = 11; free oligo‐FdU (N = 12), T22‐GFP‐H6‐FdU (N = 12)].FLack of differences in body mouse weight among groups registered along time in the M5 patient‐derived model and the prevention of metastasis protocol [mean ± s.e.m., Buffer (N = 6); free oligo‐FdU (N = 17); T22‐GFP‐H6‐FdU (N = 8)].
María Virtudes Céspedes et al. EMBO Mol Med. 2018;emmm
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