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

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