A calcium phosphate drug carrier loading with 5-fluorouracil achieving a synergistic effect for pancreatic cancer therapy

The mechanism of synergetic cytotoxicity of 5Fu and Ca2+ based on 5Fu/CaPO-NH2 drug delivery system. ROS: reactive oxygen species, ERS: endoplasmic reticulum stress, DDR: DNA damage repair. [Display omitted] •Calcium phosphate hollow sphere was synthesized using G5-PAMAM dendrimer as a macromolecular template for 5-fluorouracil loading.•Released Ca2+ and 5-fluorouracil achieved synergistic treatment for pancreatic cancer.•Obvious calcification was observed in tumor tissue after treatment of 5Fu/CaPO-NH2. Calcium based biomaterials were widely used for drug delivery application due to their biodegradability, biocompatibility, and high drug loading capacity. Herein, amino-capped polyamidoamine (PAMAM) dendrimer was applied as a macromolecular template to form amino-modified calcium phosphate hollow sphere (CaPO-NH2). After loading with 5-fluorouracil (5Fu), this system performed synergistic cancer chemotherapy. In this study, the 5Fu/CaPO-NH2 particles could be efficiently uptaken by cancer cells, and then decompose into Ca2+ and release 5Fu drug in the cytoplasm; therefore calcium overload and reactive oxygen species (ROS) accumulation were found in PSN1 cells that could induce cell membrane damage and elicit cell apoptosis through a series of biochemical reactions including endoplasmic reticulum stress, lipid peroxidation and mitochondrial apoptosis. In the PSN1 pancreatic cancer xenograft model, the 5Fu/CaPO-NH2 system performed high tumor inhibition via chemotherapy and calcium overload induced apoptosis. Comparingly, the normal cells and organs were insensitive to this synergistic therapy, which indicated the well biocompatibility of delivery system. Thus, this study provided a promising CaPO-NH2 drug delivery platform for enhanced 5Fu chemotherapeutic effect.