Effective encapsulation and biological activity of phosphorylated chemotherapeutics in calcium phosphosilicate nanoparticles for the treatment of pancreatic cancer

Abstract

Drug resistant cancers like pancreatic ductal adenocarcinoma (PDAC) are difficult to treat, and nanoparticle drug delivery systems can overcome some of the limitations of conventional systemic chemotherapy. In this study, we demonstrate that FdUMP and dFdCMP, the bioactive, phosphorylated metabolites of the chemotherapy drugs 5-FU and gemcitabine, can be encapsulated into calcium phosphosilicate nanoparticles (CPSNPs). The non-phosphorylated drug analogs were not well encapsulated by CPSNPs, suggesting the phosphate modification is essential for effective encapsulation. In vitro proliferation assays, cell cycle analyses and/or thymidylate synthase inhibition assays verified that CPSNP-encapsulated phospho-drugs retained biological activity. Analysis of orthotopic tumors from mice treated systemically with tumor-targeted FdUMP-CPSNPs confirmed the in vivo up take of these particles by PDAC tumor cells and release of active drug cargos intracellularly. These findings demonstrate a novel methodology to efficiently encapsulate chemotherapeutic agents into the CPSNPs and to effectively deliver them to pancreatic tumor cells.

Ten hub genes associated with progression and prognosis of pancreatic carcinoma identified by co-expression analysis

“…Chen et al reported that down-regulation of FAM83B in PDAC cells contributed to G0/G1 phase arrest and inhibition of cell proliferation 56 ; Liu et al discovered YY1 suppressed proliferation and migration of PDAC by regulating the CDKN3 / MdM2 / P53 / P21 signaling pathway 57 . Numerous biomarkers were reported to impact PDAC via cell cycle pathway, including the 10 hub real genes mentioned above 58 - 60 . Therefore, further exploration of cell cycle and associated genes was of enormous significance.…”

Characterization of Calcium Phosphosilicate (Hydrate) Nanoparticles: Novel Organic-Inorganic Composite Nanomaterial for Drug and Diagnostic Delivery

“…The TEM observations of the finer ultrastructure during synthesis of the CPSNPs lead us to hypothesize that encapsulation of the various active agents was mediated by adsorption on the precursor nanoparticle clusters that subsequently agglomerate into the final particle. This ultimately lead to the striking revelation that phosphorylated forms of the drugs would encourage robust encapsulation through phosphate on the drug molecule binding to excess calcium sites on the precursor nanoparticles ( Figure 2) [1,2]. This hypothesis was verified by an increase in encapsulation efficiency from < 1 mole% for prior formulations to 60 to 95 mole% for the phosphorylated drugs.…”

“…. Synthetic scheme for CPSNPs using reverse micelles with Os-stained CPSNPs revealing the 1-3 nm diameter ultra microstructure of the 50nm diameter CPSNPs through which the phosphorylated compounds obtain high encapsulation efficiency [1]. The aptamer 1153 targeting was more effective than gastrin 16 targeting with both active targeting more effective than passive mPEG-CPSNPs.…”

“…Synthetic scheme for CPSNPs using reverse micelles with Os-stained CPSNPs revealing the 1-3 nm diameter ultra microstructure of the 50nm diameter CPSNPs through which the phosphorylated compounds obtain high encapsulation efficiency[1].…”

“…CPSNPs for (Left) diagnostic determination of human pancreatic cancer in a murine model via near infra-red imaging[2] and (Right) delivery of novel chemo-therapeutic via encapsulation with high encapsulation efficiency in CPSNPs for treatment of human pancreatic cancer[1].…”