Abstract
Gliomas are rarely curable malignant brain tumors arising from normal glial cells. The scorpion-derived small peptide, chlorotoxin (CTX), can selectively bind malignant gliomas. In the present study, a CTX-conjugated onconase (Onc), a small cytotoxic ribonuclease, was prepared as a potential anti-glioma drug. In this conjugate, recombinant CTX was covalently linked with recombinant Onc by reversible disulfide linkage. The chemically conjugated CTX-Onc showed much higher cytotoxicity to the cultured glioma U251 and SHG-44 cells than the physical mixture of CTX and Onc (CTX + Onc). In the nude mouse models bearing subcutaneous U251 or SHG-44 tumors, the CTX-Onc conjugate also showed improved anti-tumor effects than the CTX + Onc control. These results suggested that the reversible chemical-conjugated CTX promoted the tumor targeting of Onc, and thus the present CTX-Onc conjugate could be further developed as a potential targeted anti-glioma drug.
Highlights
Gliomas are rarely curable malignant brain tumors arising from normal glial cells
To prepare the CTX‐conjugated Onc (CTX‐Onc) conjugate, an efficient conjugation procedure was established by which CTX and Onc were covalently crosslinked through reversible disulfide bond(s) (Fig. 1)
Owing to the presence of the reversible disulfide crosslinking in the present CTX‐Onc conjugate, free Onc is likely to be released from the conjugate and to enter the glioma cells to exert its cytotoxicity, since the disulfide crosslinking may be reduced by the reductive redox potential at the cell membrane
Summary
Gliomas are rarely curable malignant brain tumors arising from normal glial cells. The scorpion‐derived small peptide, chlorotoxin (CTX), can selectively bind malignant gliomas. A CTX‐conjugated onconase (Onc), a small cytotoxic ribonuclease, was prepared as a potential anti‐glioma drug In this conjugate, recombinant CTX was covalently linked with recombinant Onc by reversible disulfide linkage. In the nude mouse models bearing subcutaneous U251 or SHG‐44 tumors, the CTX‐Onc conjugate showed improved anti‐tumor effects than the CTX + Onc control These results suggested that the reversible chemical‐conjugated CTX promoted the tumor targeting of Onc, and the present CTX‐Onc conjugate could be further developed as a potential targeted anti‐glioma drug. As CTX exhibits glioma‐targeting properties and Onc exhibits cytotoxicity, in the present study a CTX‐conjugated Onc (CTX‐Onc) was prepared for the analysis of its anti‐glioma effects on cultured glioma cells and on a mouse model. The glioma‐binding properties of CTX have been extensively investigated and CTX conjugates have been developed for the treatment and diagnosis of gliomas and other
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