Conjugating 4β-NH-(5-Aminoindazole)-Podophyllotoxin and Galectin-1-Targeted Aptamer for Synergistic Chemo-Immunotherapy of Hepatocellular Carcinoma.

By conjugating a chemotherapeutic candidate drug 4β-NH-(5-aminoindazole)-podophyllotoxin (βIZP) and an immunosuppressive protein galectin-1 targeted aptamer AP74, a chemo-immunotherapy molecule (AP74-βIZP) was developed to against liver cancer. AP74-βIZP could target galectin-1 and enrich in tumor microenvironment to improve the tumor inhibition ratio by 6.3% higher than that of βIZP in HepG2 xenograft model. In safety evaluation, βIZP could not be released from AP74-βIZP in normal tissues with low glutathione level. Therefore, the degrees of organs injury and myelosuppression after the treatment with AP74-βIZP were lower than those with βIZP. After 21 days treatment at the drug dose of 5 mg kg -1 , AP74-βIZP did not exhibit weight loss of mice, while the weight was significantly reduced by 24% and 14% in oxaliplatin and βIZP, respectively. In immune synergy, AP74-IZP enhanced CD4/CD8 cell infiltration to promote the expression of cell factor (i.e., IL-2, TNF-α, and IFN-γ), which further improved the antitumor activity. The tumor inhibition ratio of AP74-βIZP was 70.2%, which was higher than that of AP74 (35.2%) and βIZP (48.8%). Because of the dual effects of chemotherapy and immunotherapy, AP74-βIZP exhibited superior activity and lower toxicity. The approach developed in this work should be applicable to the other chemotherapy drugs. This article is protected by copyright. All rights reserved.