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

By encapsulating chemotherapeutic agents into nanocarriers, such as calcium phosphosilicate nanoparticles (CPSNPs), metabolic inactivation of pro-drugs, for instance the inactivation of 5-FU by the liver enzyme dihydropyrimidine dehydrogenase (DPD), often can be avoided. Herein we demonstrate that the bioactive metabolite of 5-FU, FdUMP, can be effectively encapsulated into CPSNPs. Once taken up by tumor cells, the mPEG-FdUMP-CPSNPs dissolve in the late endosome to release the FdUMP cargo. In the presence of folate (CH2THF), FdUMP irreversibly binds to and inhibits thymidylate synthase (TS), resulting in a cellular depletion of dTMP, increased DNA damage, and ultimately cell death.146