Biodegradable cross-linked flavone networks featuring either ester or carbamate linkages for controlled delivery of anti-cancer agents

Abstract

Flavonoids show broad preclinical anticancer activity, but their translation to the clinic is limited by poor aqueous solubility, rapid metabolism and limited systemic exposure after conventional administration. Here, the flavonoids quercetin, luteolin and apigenin were exploited as multifunctional building blocks to generate insoluble cross-linked flavonoid networks containing either ester (1–3) or carbamate (4–6) linkages, intended as degradable local depot matrices. Network formation was confirmed by FTIR and thermal analysis, and flavonoid loading was quantified by exhaustive degradation (pH 2.0, 60 °C), giving loadings of 28–36 wt/wt% (esters) and 32–44 wt/wt% (carbamates). Release of parent flavonoids was quantified by HPLC under aqueous conditions (PBS, 37 °C) at pH 7.4, 6.5 and 5.0. Ester networks showed comparatively higher baseline release at pH 7.4, whereas carbamate networks exhibited stronger pH-responsiveness (e.g., cross-linked 4 : 6 wt/wt% at pH 7.4 vs. 24 wt/wt% at pH 5.0; 288 h). Extract-based MTT assays using MCF-7 cells showed that medium pre-exposed to ester networks for 24 h retained antiproliferative activity (e.g., cross-linked 1 : 19% viability), whereas 5 min extracts were not cytotoxic, consistent with time-dependent release rather than rapid leaching. Cytocompatibility was also confirmed in the non-malignant fibroblast cell line 161BR, where all matched extract conditions were non-significantly different from the untreated control. Overall, incorporating flavonoids into degradable network architectures enables tunable release governed by linker chemistry, pH and flavonoid scaffold.