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

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