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) is developed against liver cancer. AP74-βIZP can target galectin-1 and enrich the tumor microenvironment to improve the tumor inhibition ratio by 6.3%, higher than that of βIZP in a HepG2 xenograft model. In safety evaluation, βIZP cannot 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 are lower than those with βIZP. After 21 d treatment at a drug dose of 5 mg kg-1 , AP74-βIZP does not cause weight loss in mice, while the weight is significantly reduced by 24% and 14% from oxaliplatin and βIZP, 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-βIZP is 70.2%, which is higher than that of AP74 (35.2%) and βIZP (48.8%). Because of the dual effects of chemotherapy and immunotherapy, AP74-βIZP exhibits superior activity and lower toxicity. The approach developed in this work could be applicable to other chemotherapy drugs.