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 microe...

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Published in:Advanced healthcare materials 2023-09, Vol.12 (22), p.e2203144-n/a
Main Authors: Cong, Ying, Zhang, Shu‐Yue, Tang, Paula Yun‐Zhi, Li, Hong‐Mei, Liu, Xue, Zhao, Wei, Tang, Ya‐Jie
Format: Article
Language:English
Subjects:
4β‐NH‐(5‐aminoindazole)‐podophyllotoxin
Anticancer properties
Antitumor activity
Aptamers
CD4 antigen
CD8 antigen
Chemotherapy
chemo‐immunotherapy
galectin‐1
Glutathione
Hepatocellular carcinoma
immune infiltration
Immunosuppressive agents
Immunotherapy
Liver cancer
Metastases
Myelosuppression
Oxaliplatin
Podophyllotoxin
Toxicity
Tumor microenvironment
Tumors
Weight loss
Weight reduction
Xenotransplantation
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Summary: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. A novel chemo‐immunotherapy molecule (AP74‐βIZP) is developed by conjugating aptamer (AP74) and chemotherapy molecule (βIZP). Compared with βIZP, AP74‐βIZP can target galectin‐1, enrich in tumor microenvironment, enhance CD4/CD8 cell infiltration, and promote cell factors to significantly improve the antitumor activity. This strategy is also applicable to the other chemotherapy drugs.
ISSN:2192-2640
2192-2659
DOI:10.1002/adhm.202203144