posted on 2021-04-19, 04:44authored byZi-Yue Xu, Hong-Kun Liu, Yan Wu, Yun-Chang Zhang, Wei Zhou, Hui Wang, Dan-Wei Zhang, Da Ma, Zhan-Ting Li
A water-soluble
flexible organic framework FOF-hz of
low cytotoxicity has been synthesized from a pyridinium-derived tetracationic
tetraaldehyde and a citric acid-derived tritopic acylhydrazine (1:2)
through the formation of a hydrazone bond. Dynamic light-scattering
experiments reveal that FOF-hz has a hydrodynamic diameter
of 79 nm at 0.1 mM concentration of the tetrahedral precursor. Dialysis
experiments show that the free acylhydrazine units of FOF-hz can react with the C-13 ketone units of anthracycle drugs, including
doxorubicin (DOX), daunorubicin, epirubicin, and pirarubicin,
at pH = 3.0 to conjugate the drugs in 78–85% yields. The resulting
FOF-prodrugs exhibit remarkable acid-responsive deconjugation of the
conjugated active agents. Laser confocal scanning microscopy and flow
cytometric analysis support that FOF-hz displays enhanced
permeability and retention effect, which helps to overcome the multidrug
resistance of MCF-7/ADR tumor cells and leads to enhanced cytotoxicity
for MCF-7/ADR cells. In vivo studies reveal a considerable improvement
of the efficacy of the prodrug FOF-DOX for the inhibition
of the growth of the MCF-7/ADR tumor.