Abstract
A pH-sensitive, methoxy(polyethylene glycol)(hydrazone)block(hydroxypropyl methacrylamide), covalently linked to gemcitabine (mP(Hz)-bH(GEM)), was developed, which formed spherical nanoaggregates in the aqueous environment. The conjugate/nanoaggregates (NA) were physicochemically characterized using DLS, 1H NMR, FTIR, GPC, SAXS, MALDI-TOF, pH-dependent drug release, and hemolysis studies. Human HR+/- cells, MCF-7 and MDA-MB-231 were used to investigate the NA's therapeutic effectiveness in vitro via cytotoxicity, DNA fragmentation, cellular uptake, cell cycle assays, nuclear staining, and immunoblot analysis. mP(Hz)-bH(GEM) NAs exhibited decreased IC50 towards MCF-7 and MDA-MB-231 than free GEM. mP(Hz)-bH(GEM) NAs caused extensive DNA damage, cell-growth arrest (G1/S), increased intrinsic apoptotic markers, caspase 3, 7, p53, cytochrome-C, and suppressed the proliferative marker Bcl-2. Therefore, this new mP(Hz)-bH(GEM) nanoaggregate formulation could be an alternative, safe, biocompatible, and effective treatment option for breast cancer therapy.
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