N-acetyl-galactosamine modified metal-organic frameworks to inhibit the growth and pulmonary metastasis of liver cancer stem cells through targeted chemotherapy and starvation therapy

Hepatocellular carcinoma (HCC) is a common high-mortality malignancy which still needs efficient treat-ments. HCC patients undergoing extrahepatic metastases are mostly with unsatisfactory prognosis. There-fore, specific attention has been paid to extrahepatic HCC metastasis. We integrated Sorafenib (Sor) and glucose oxidase (GOx) into a N-acetyl-galactosamine (GalNAc) modified zeolitic imidazolate frame-work (ZIF-8), designated as SG@GR-ZIF-8, for targeted bimodal therapies of chemotherapy and starva-tion therapy against HCC. The hepatic delivery of SG@GR-ZIF was mediated by the specific recognition of GalNAc residues with asialoglycoprotein (ASGPR) on the liver cell surface. Sor is a clinically approved anti-proliferation and anti-angiogenesis drug for advanced HCC treatment. GOx can efficiently induce cell death and disturb malignant progression by suppressing glucose supply of cancer cells, which is highly associated with metabolic rewiring in metastasis. The nano-formulation exhibit significant anti-metastatic HCC activity against C5WN1 cells, a liver cancer stem cell-like cell line with tumorigenicity and pul-monary metastasis activity. In a subcutaneous C5WN1-tumor carrying mouse model, SG@GR-ZIF exhibits potent synergistic anti-tumor activity with a tumor inhibition rate of 89% and a prolonged survival sta-tus. The growth and pulmonary metastasis of HCC in an orthotopic mouse model of HCC was remarkably suppressed in SG@GR-ZIF treated group. The therapeutic strategy targeting energy supply combined with first-line treatment holds great promise for the future treatment of metastatic HCC.Statement of significanceSG@GR-ZIF, a N-acetyl-galactosamine modified metal-organic framework carrying Sorafenib and glucose oxidase, was fabricated for treating metastatic hepatocellular carcinoma (HCC). Sorafenib is an anti -proliferation and anti-angiogenesis drug for advanced HCC treatment. Glucose oxidase blocks energy de-mand in HCC metastasis by depleting glucose. C5WN1 was used for therapeutic evaluations as a liver cancer stem cell-like cell line with tumorigenicity and pulmonary metastasis activity. In subcutaneous C5WN1-tumor bearing mice, SG@GR-ZIF exhibited a tumor inhibition rate of 89% and prolonged survival period. In orthotopic C5WN1-tumor carrying mice, the growth and pulmonary metastasis of hepatocar-cinoma was remarkably suppressed by SG@GR-ZIF. Together, this study suggests the great potential of synergistic chemo/starvation therapy mediated by SG@GR-ZIF for treating metastatic HCC.(c) 2022 The Author(s). Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Automated summary

In this study, a N-acetyl-galactosamine modified metal-organic framework carrying Sorafenib and glucose oxidase, SG@GR-ZIF, was developed for targeted treatment of metastatic hepatocellular carcinoma (HCC). The nano-formulation exhibited significant anti-metastatic HCC activity and showed potent synergistic anti-tumor activity in mouse models. The results suggest the great potential of SG@GR-ZIF for treating metastatic HCC.