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. 2018 Jan 31;9:450. doi: 10.1038/s41467-017-02707-6

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/.

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Fig. 9 — Shielding with retargeting reduces off-targeting and increases tumor–liver ratio. a 1.5 × 10⁶ HAdV5^HVR7 particles were injected into subcutaneous HER2⁺ SKOV3.ip tumors in Rag1^-/- mice. Gene delivery was analyzed 48 hpi by luciferase activity, normalized to total protein amount. Fiber knob blocking of a shielded virus reduces viral gene delivery to the tumor only slightly compared to virus with free knob. In contrast, HER2 retargeting significantly increases gene delivery within the tumor by a factor of around 40 compared to the fiber knob-blocked virus. Shielding in combination with a blocked fiber knob significantly reduces gene delivery to the liver and all other organs, compared to non-modified virus. Presented data are representative for two independent experiments. b Shielding and retargeting significantly increases the tumor-to-liver ratio of gene delivery from ca. 1300 to ca. 1.1-million-fold, an improvement by a factor of ca. 900. Tumor-to-liver ratios of individual mice from two independent experiments are presented. c Retargeting of a shielded virus increased viral gene delivery to the tumor after intratumoral injection in A431 xenografts. In addition, off-targeting to liver and spleen was reduced. d The ratio of transgene activity between tumor and liver was increased from 300 for the unmodified virus to 9200 for the retargeted and shielded virus. Tumor-to-liver ratios of individual mice from two independent experiments are presented. e Intravenous delivery: in comparison to unmodified virus, shielding of an EGFR-targeted virus decreased the gene delivery to the tumor slightly upon intravenous virus injection, but drastically reduced off-targeting to all organs analyzed. f Systemic biodistribution was changed by the shield. The tumor–liver ratio in the A431 xenograft was increased by more than 2500-fold (each symbol represents (a, c, e) one organ analyzed with two-way ANOVA of log-transformed data or (b, d, f) the ratio of an individual with two-sided, unpaired Welch’s t-test of log-transformed data, *P < 0.05, **P < 0.01, ****P < 0.0001). Background signals from control injections with PBS are indicated by dashed lines