Journal
CHEMMEDCHEM
Volume 16, Issue 24, Pages 3701-3719Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202100465
Keywords
MMP-2; 9 inhibition; Targeted anticancer therapy; Hepatocellular carcinoma; s-Triazine dendrimers; lactobionic acid; Folic acid; Honokiol
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Funding
- Science, Technology & Innovation Funding Authority (STIFA), Cairo, Egypt [34857]
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Despite the challenges of off-target side effects and pharmacokinetics, recent targeting strategies have revitalized MMP research by introducing new s-triazine-based dendrimers with intrinsic MMP-2/9 inhibitory potential for targeted therapy against hepatocellular carcinoma. Preliminary screening showed promising potency against MMP-2/9 within safe doses, with hydrazide dendrimers being comparable to NNGH and superior to the carboxylic acid analogue, while conjugates of these dendrimers with anticancer agents exhibited enhanced potency in cancer cells, making them potential candidates for targeted cancer therapy.
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 mu M, MMP-2; IC50=0.39-0.77 mu M) within their safe doses (EC100=94.15-42.75 mu M). 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 (TPG(3)-NH2)-SuHK-FA-SuPEG (Huh-7; IC50=5.54 mu M, HepG-2; IC50=10.07 mu M) being 4 folds more active than HK, followed by the carboxylic acid conjugate (TPG(3)-OH)-HK-LA-PEG (Huh-7; IC50=14.97, HepG-2; IC50=21.29 mu M). This was consistent with apoptosis studies.
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