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


STATEMENT OF SIGNIFICANCE
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.
['Zhang|Linhua|L|', 'Hao|Wenbo|W|', 'Xu|Lv|L|', 'Gao|Yongfeng|Y|', 'Wang|Xusheng|X|', 'Zhu|Dunwan|D|', 'Chen|Zhuo|Z|', 'Zhang|Xudong|X|', 'Chen|Hongbo|H|', 'Mei|Lin|L|']
D017209:Apoptosis D004249:DNA Damage D004337:Drug Carriers D004354:Drug Screening Assays, Antitumor D006367:HeLa Cells D006801:Humans D006863:Hydrogen-Ion Concentration D061986:MCF-7 Cells D008333:Mandelic Acids D008709:Methenamine D053758:Nanoparticles D009369:Neoplasms
pH-sensitive DNA damage Cancer therapy Methenamin emandelate Nanomedicine