Block HPMA-based pH-sensitive gemcitabine pro-drug nanoaggregates for cancer treatment

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.

Automated summary

A pH-sensitive nanoaggregate was developed by covalently linking a methoxy(polyethylene glycol)(hydrazone)block(hydroxypropyl methacrylamide) to gemcitabine. The nanoaggregate formed spherical structures in an aqueous environment. The nanoaggregate exhibited a lower IC50 and induced DNA damage, cell-growth arrest, and apoptosis in breast cancer cells, suggesting its potential as a safe and effective treatment option.