Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China.
School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, PR China; School of Science, Heihe University, Heihe 164300, PR China.
Acta Biomater. 2017 Oct 15;62:246-256. doi: 10.1016/j.actbio.2017.08.019. Epub 2017 Aug 16.
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 NaHCO. Methenamine mandelate/NaHCO-coloaded nanoparticle could enter cells via endosome/lysosome pathway. The pH in lysosomes and endo-lysosomes is approximately 5.0. In the acidic environment, NaHCO reacts with proton and produce CO 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/NaHCO-coloaded nanoparticles caused cell cycle arrest, cell growth inhibition and apoptosis of cancer cells. Moreover, methenamine mandelate/NaHCO-coloaded nanoparticles also show intensive inhibitory effect on the growth of MCF-7 xenograft tumor in vivo. Therefore, methenamine mandelate/NaHCO-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 NaHCO. Methenamine mandelate/NaHCO-coloaded nanoparticle could enter cells via endosome/lysosome pathway. The pH in lysosomes and endo-lysosomes is approximately 5.0. In the acidic environment, NaHCO reacts with proton and produce CO 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/NaHCO-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.
三聚氰胺马来酸盐是一种尿液抗菌剂，可在平均 pH 值为 5.5-6.8 的尿液中转化为甲醛。在这里，我们制备了一种基于 PLGA 的纳米粒子，其中同时包含三聚氰胺马来酸盐和 NaHCO。三聚氰胺马来酸盐/NaHCO 共载纳米粒子可通过内体/溶酶体途径进入细胞。溶酶体和内溶酶体中的 pH 值约为 5.0。在酸性环境中，NaHCO 与质子反应并产生 CO 气泡，这些气泡会使纳米粒子破裂并导致三聚氰胺马来酸盐迅速释放。同时，三聚氰胺马来酸盐随后在酸性环境中迅速转化为足够量的甲醛，从而诱导 DNA 损伤和 DNA 损伤反应 (DDR)。因此，三聚氰胺马来酸盐/NaHCO 共载纳米粒子会导致癌细胞周期停滞、细胞生长抑制和凋亡。此外，三聚氰胺马来酸盐/NaHCO 共载纳米粒子在体内对 MCF-7 异种移植肿瘤的生长也具有强烈的抑制作用。因此，三聚氰胺马来酸盐/NaHCO 共载纳米粒子是一种有前途的治疗癌症的制剂，可为临床中的“老药”三聚氰胺马来酸盐赋予新的抗癌功能。
