RESUMEN
O-linked-N-acetylglucosaminylation (O-GlcNAcylation) plays a key role in hepatocellular carcinoma (HCC) development, and the inhibition of O-GlcNAcylation has therapeutic potential. To decrease the systemic adverse events and increase targeting, we used sialic acid (SA)-decorated liposomes loaded with OSMI-1, an inhibitor of the O-GlcNAcylation, to further improve the anti-HCC effect. Fifty pairs of HCC tissue samples and the cancer genome atlas database were used to analyze the expression of O-GlcNAc transferase (OGT) and its effects on prognosis and immune cell infiltration. OSMI-1 cells were treated with SA and liposomes. Western blotting, immunofluorescence, cell proliferation assay, flow cytometry, enzyme-linked immunosorbent assay, immunohistochemistry, and tumorigenicity assays were used to investigate the antitumor effect of SA-modified OSMI-1 liposomes in vitro and in vivo. OGT was highly expressed in HCC tissues, negatively correlated with the degree of tumor infiltration of CD8+ and CD4+T cells and prognosis, and positively correlated with the degree of Treg cell infiltration. SA-modified OSMI-1 liposome (OSMI-1-SAL) was synthesized with stable hydrodynamic size distribution. Both in vitro and in vivo, OSMI-1-SAL exhibited satisfactory biosafety and rapid uptake by HCC cells. Compared to free OSMI-1, OSMI-1-SAL had a stronger capacity for suppressing the proliferation and promoting the apoptosis of HCC cells. Moreover, OSMI-1-SAL effectively inhibited tumor initiation and development in mice. OSMI-1-SAL also promoted the release of damage-associated molecular patterns, including anticalreticulin, high-mobility-group protein B1, and adenosine triphosphate, from HCC cells and further promoted the activation and proliferation of the CD8+ and CD4+T cells. In conclusion, the OSMI-1-SAL synthesized in this study can target HCC cells, inhibit tumor proliferation, induce tumor immunogenic cell death, enhance tumor immunogenicity, and promote antitumor immune responses, which has the potential for clinical application in the future.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Carcinoma Hepatocelular/genética , Liposomas/farmacología , Neoplasias Hepáticas/metabolismo , Ácido N-Acetilneuramínico , Proliferación CelularRESUMEN
It is well known that stealth coating effectively extends the circulation lifetime of nanomaterials in blood, which favors systemic delivery but also limits their cellular internalization and in turn prevents efficient tumor-targeting and accumulation. In this study, we address this dilemma by developing an enzyme-responsive zwitterionic stealth peptide coating capable of responding to matrix metalloproteinase-9 (MMP-9) which is overexpressed in tumor microenvironment. The peptide consists of a cell-penetrating Tat sequence, an MMP-9 cleavable sequence, and a zwitterionic antifouling sequence. Using this coating to protect photothermal gold nanorods (AuNRs), we found that responsive AuNRs showed both satisfactory systemic circulation lifetime and significantly enhanced cellular uptake in tumors, resulting in clearly improved photothermal therapeutic efficacy in mouse models. These results suggest that multifunctional peptide coated AuNRs sensitive to MMP-9 are promising nanomaterials, conferring both extended systemic circulation and enhanced tumor tissue accumulation, for more specific and efficient tumor therapy. STATEMENT OF SIGNIFICANCE: It is well known that stealth coating effectively extends the circulation lifetime of nanomaterials in blood, which favors systemic delivery but also limits their cellular internalization and in turn prevents efficient tumor-targeting and accumulation. In this study, we address this dilemma by developing an enzyme-responsive zwitterionic stealth peptide coating capable of responding to matrix metalloproteinase-9 (MMP-9) which is overexpressed in tumor microenvironment. The peptide consists of a cell-penetrating Tat sequence, an MMP-9 cleavable sequence, and a zwitterionic antifouling sequence. Using this coating to protect photothermal gold nanorods (AuNRs), we found that responsive AuNRs showed both satisfactory systemic circulation lifetime and significantly enhanced cellular uptake in tumors, resulting in clearly improved photothermal therapeutic efficacy in mouse models.