A pH-sensitive methenamine mandelate-loaded nanoparticle induces DNA damage and apoptosis of cancer cells.

Abstract

Methenamine mandelate is a urinary antibacterial agent, which can be converted to formaldehyde in urine that has a relatively low pH of average 5.5-6.8. Here, we prepare a pH-sensitive PLGA-based nanoparticle containing both methenamine mandelate and NaHCO₃. Methenamine mandelate/NaHCO₃-coloaded nanoparticle could enter cells via endosome/lysosome pathway. The pH in lysosomes and endo-lysosomes is approximately 5.0. In the acidic environment, NaHCO₃ reacts with proton and produce CO₂ bubbles, which burst nanoparticles and lead to the rapidly release of methenamine mandelate. Meanwhile, methenamine mandelate was then quickly converted to a sufficient amount of formaldehyde in this acidic environment, which induced DNA damage and DNA damage response (DDR). Consequently, methenamine mandelate/NaHCO₃-coloaded nanoparticles caused cell cycle arrest, cell growth inhibition and apoptosis of cancer cells. Moreover, methenamine mandelate/NaHCO₃-coloaded nanoparticles also show intensive inhibitory effect on the growth of MCF-7 xenograft tumor in vivo. Therefore, methenamine mandelate/NaHCO₃-coloaded nanoparticle is a promising type of formulation for the treatment of cancer, which could give the "old drug" methenamine mandelate a new anti-cancer function in clinical. Methenamine mandelate is a urinary antibacterial agent, which can be converted to formaldehyde in urine that has a relatively low pH of average 5.5-6.8. Here, we prepare a pH-sensitive PLGA-based nanoparticle containing both methenamine mandelate and NaHCO₃. Methenamine mandelate/NaHCO₃-coloaded nanoparticle could enter cells via endosome/lysosome pathway. The pH in lysosomes and endo-lysosomes is approximately 5.0. In the acidic environment, NaHCO₃ reacts with proton and produce CO₂ bubbles, which burst nanoparticles and lead to the rapidly release of methenamine mandelate. Meanwhile, methenamine mandelate was then quickly converted to a sufficient amount of formaldehyde in this acidic environment, which induced DNA damage and DNA damage response (DDR). Methenamine mandelate/NaHCO₃-coloaded nanoparticle is a promising type formulation for the treatment of cancer, which could give the "old drug" methenamine mandelate a new anti-cancer function in clinical.