Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis

• Published in: Journal of colloid and interface science Vol. 660; pp. 257 - 276
• Main Authors: Zhao, Rui-Rui, Wu, Ju-Hong, Tong, Ling-Wu, Li, Jin-Yu, Lu, Yu-sheng, Shao, Jing-Wei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.04.2024
• Subjects: antiporters; biocompatibility; Chemodynamical therapy; cystine; cytotoxicity; drugs; epithelial cell adhesion molecule; Ferroptosis; glutamic acid; glutathione; hepatoma; hydrogen peroxide; hydroxyl radicals; immune response; Immunotherapy; Metal-coordinated nanoplatform; metastasis; oligonucleotides; phospholipid-hydroperoxide glutathione peroxidase; Synergistic chemotherapy; T-lymphocytes; ursolic acid; VEGFR2; System Xc; CPP; EpCAM; CRT; SRF; Ferroptosis; LPO; ICAM-1; HMGB1; Metal-coordinated nanoplatform; UA; DAMPs; MTX; CDT; Immunotherapy; PD-L1; GSH; GPX4; HCC; ICD; ICG; TME; TA; Chemodynamical therapy; Synergistic chemotherapy; LMWP; ATP
• ISSN: 0021-9797; 1095-7103; 1095-7103
• DOI: 10.1016/j.jcis.2024.01.066

Herein, we designed a metal-coordinated carrier-free nanodrug (USFe3+LA NPs) with near sphere shape by co-assembling of UA, SRF, Fe3+, low molecular weight protamine (LMWP), and epithelial cell adhesion molecule (EpCAM) aptamer via a facile self-assembly method to improve the efficacy of chemotherapy monotherapy and achieve synergistic therapy. USFe3+LA NPs could inhibit tumor metastasis by inhibiting the intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF) expression. In addition, USFe3+LA NPs could enhance immune response and sensitize tumors to immune checkpoint inhibitors PD-L1 antibody. It was demonstrated that USFe3+LA NPs significantly inhibited tumor growth and metastasis, showing that this nano-delivery system synergistically enhanced its anti-tumor effect. These nanodrugs will provide a new strategy for combined chemotherapy, CDT, ferroptosis, and immunotherapy. [Display omitted] The heterogeneity of hepatocellular carcinoma (HCC) and the complexity of the tumor microenvironment (TME) pose challenges to efficient drug delivery and the antitumor efficacy of combined or synergistic therapies. Herein, a metal-coordinated carrier-free nanodrug (named as USFe3+ LA NPs) was developed for ferroptosis-mediated multimodal synergistic anti-HCC. Natural product ursolic acid (UA) was incorporated to enhance the sensitivity of tumor cells to sorafenib (SRF). Surface decoration of cell penetration peptide and epithelial cell adhesion molecule aptamer facilitated the uptake of USFe3+ LA NPs by HepG2 cells. Meanwhile, Fe3+ ions could react with intracellular hydrogen peroxide, generating toxic hydroxyl radical (·OH) for chemodynamical therapy (CDT) and amplified ferroptosis by cystine/glutamate antiporter system (System Xc−), which promoted the consumption of glutathione (GSH) and inhibited the expression of glutathione peroxidase 4 (GPX4). Notably, these all-in-one nanodrugs could inhibit tumor metastasis and induced immunogenic cell death (ICD). Last but not least, the nanodrugs demonstrated favorable biocompatibility, augmenting the immune response against the programmed death-ligand 1 (PD-L1) by increasing cytotoxic T cell infiltration. In vivo studies revealed significant suppression of tumor growth and distant metastasis. Overall, our work introduced a novel strategy for applications of metal-coordinated co-assembled carrier-free nano-delivery system in HCC combination therapy, especially in the realms of cancer metastasis prevention and immunotherapy.