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 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.

Effect of galectin‐1 on prognosis and responsiveness of immune checkpoint plus tyrosine kinase inhibition in renal cell carcinoma

“… 33 Galectin‐1 has been investigated as a possible target for synergistic chemo‐immunotherapy in hepatocellular carcinoma. 34 However, the recent research has mainly focused on the expression and effect of galectin‐1 in pre‐treatment samples. The dynamic changes of galectin‐1 expression and its dynamic roles throughout immunotherapy are still unknown.…”

A Zero-Valent Sulfur Transporter Helps Podophyllotoxin Uptake into Bacterial Cells in the Presence of CTAB

“…Dysosma versipellis (Hance) M. Cheng ex Ying) [1]. Several of its derivatives, including etoposide (VP-16) and teniposide (VM-26) [2,3], are well-known antitumor drugs approved by the US Food and Drug Administration for the treatment of several types of cancer; hundreds of its derivatives, such as 4β-NH-(5-Aminoindazole)podophyllotoxin [4] and triazole/thiadiazole substituted 4 ′ -demethylepipodophyllotoxin [5], are potential drugs that may have different antitumor bioactivities. The derivatives are normally produced by chemical modifications of PTOX extracted from the plants [6], and overharvesting has put some Podophyllum plants at risk of extinction [7].…”