E-selectin-targeted polymer-doxorubicin conjugate induces regression of established colorectal liver metastases and improves mice survival

Liver metastases arising from colorectal cancer (CRC) are a major challenge for cancer treatment, as they often emerge as unresectable and resistant to therapy. Novel treatments targeting the specific metastatic tumor microenvironment (TME) may improve the therapeutic outcome. One relevant receptor at the TME in the liver is the endothelial-expressed cell adhesion molecule E-selectin. In this study, we showed in a mouse model of aggressive CT26-derived liver metastasis, that the delivery of otherwise non-effective Doxorubicin via an E-selectin-targeted polymer-peptide-drug conjugate reduced tumor burden of liver metastases and significantly prolonged survival, with ∼50% of mice being tumor-free. In contrast to B16-derived lung metastases, which can successfully be prevented by a "drug-free" E-selectin-blocking copolymer, neither E-selectin-blocking pre-treatment nor the combination with targeted Doxorubicin-delivery proved beneficial against CT26 liver metastasis. In-depth inquiry revealed that E-selectin-blockade by the "drug-free" copolymer reduced E-selectin expression in metastatic livers, but did not prevent CT26 liver colonization, and increased the prevalence of B-cells, possibly indicating an ambiguous role of these cells. However, it did not significantly alter leukocyte migration into the malignant tissue. Overall, targeting E-selectin with nanomedicines is a highly efficient strategy to treat established liver metastases, while the benefit of E-selectin blockade by itself may depend on tumor type and TME-specific factors.