Engineered s‐Triazine‐Based Dendrimer‐Honokiol Conjugates as Targeted MMP‐2/9 Inhibitors for Halting Hepatocellular Carcinoma

Despite the advances in developing MMP-2/9 inhibitors, off-target side effects and pharmacokinetics problems remain major challenges hindering their clinical success in cancer therapy. However, recent targeting strategies have clearly revitalized MMP research. Herein, we introduce new s-triazine-based dendrimers endowed with intrinsic MMP-2/9 inhibitory potential and tetherable to hepatocellular carcinoma-specific targeting ligands and anticancer agents via biodegradable linkages for targeted therapy. The designed dendrimeric platform was built with potential zinc-binding branching linkers (hydrazides) and termini (carboxylic acids and hydrazides) to confer potency against MMP-2/9. Preliminary cytotoxicity screening and MMP-2/9 inhibition assay of the free dendrimers revealed promising potency (MMP-9; IC50 =0.35-0.57 μM, MMP-2; IC50 =0.39-0.77 μM) within their safe doses (EC100 =94.15-42.75 μM). The hydrazide dendrimer was comparable to NNGH and superior to the carboxylic acid analogue. MTT assay showed that the free dendrimers were superior to the reference anticancer agent honokiol. Their anticancer potency was enhanced by HK conjugation, targeting ligands installation and PEGylation as exemplified by the hydrazide dendrimer conjugate (TPG3 -NH2 )-SuHK-FA-SuPEG (Huh-7; IC50 =5.54 μM, HepG-2; IC50 =10.07 μM) being 4 folds more active than HK, followed by the carboxylic acid conjugate (TPG3 -OH)-HK-LA-PEG (Huh-7; IC50 =14.97, HepG-2; IC50 =21.29 μM). This was consistent with apoptosis studies.