A tailored 4G <i>s</i>-triazine-based dendrimer vehicle for quercetin endowed with MMP-2/9 inhibition and VEGF downregulation for targeting breast cancer progression and liver metastasis

Motivated by our recent research progress on the exploitation of <i>s</i>-triazine dendritic platforms as bioactive carriers for well-known anticancer agents and/or targeting ligands, we set out to synthesize new rationally designed dendrimers endowed with MMP-2/9 inhibition potential for halting both breast and liver cancer progression with reduced off-target side effects. New three and four generation <i>s</i>-triazine based dendrimers were developed to incorporate potential ZBGs (Zinc Binding Groups) and carboxyl terminal groups to facilitate direct conjugation of anti-cancer drugs (quercetin) and/or targeting ligands (lactobionic acid) through a biodegradable ester bond. Compared to free quercetin (QUR), MTT assay revealed that all the quercetin-coupled dendrimers displayed better anticancer potential (IC₅₀ = 12.690-29.316, 4.137-29.090 μM) against MCF-7 and HepG-2 cancer cells, respectively within their safe doses (EC₁₀₀ = 134.35-78.44 μM). Conjugation of lactobionic acid and PEG boosted the anticancer potency against both treated cells, improved apoptosis and down regulated MMP-9 and VEGF gene expression levels in both treated cancer cells. Generally, the more branched G4 dendrimer conjugates exhibited a superior overall anticancer performance compared to their respective G3 analogues, except for their MMP-9 inhibition where G3 conjugate appeared to be more potent and more selective than its G4 analogue.