An intelligent and self-assembled nanoscale metal organic framework (99mTC-DOX loaded Fe3O4@FeIII-tannic acid) for tumor targeted chemo/chemodynamic theranostics

Abstract Background Recent advances in clinical transformation research have focused on chemodynamic theranostics as an emerging strategy for tackling cancer. Nevertheless, its effectiveness is hampered by the tumor's glutathione antioxidant effect, poor acidic tumor microenvironment (TME) and inadequate endogenous H 2 O 2 . Hence, we designed an activatable theranostics ( 99m Tc-DOX loaded AA-Fe 3 O 4 @Fe III -TA) that effectively boost the catalytic efficiency of the Fenton-reaction-induced ROS production and augment the chemotherapeutic efficacy combined with diagnostic action. Results A cross-linked matrix of tannic acid-ferric salt (Fe III -TA) as a pH-responsive shell onto ascorbic acid-decorated iron-oxide nanoparticles (AA-Fe 3 O 4 NPs) was prepared demonstrating a metal–organic- framework (MOF) nanostructure, followed by loading of 99m Tc-labelled DOX. The platform ( 99m Tc-DOX loaded AA-Fe 3 O 4 @Fe III -TA) displayed suitable physical–chemical properties, including 69.8 nm particle size, 94.8 nm hydrodynamic size, − 21 mV zeta potential, effective Fe III -TA shell crosslinking onto AA-Fe 3 O 4 NPs and 94% loading efficiency for 99m Tc-DOX. The results of the in-vitro release investigations showed that the platform exhibited a pH-dependent release manner with 98.3% of the 99m Tc-DOX being released at pH 5 (simulating the tumor’s pH) and only 10% being released at the physiological pH (pH 7.4). This indicates that there was negligible payload leakage into the systemic circulation during the platform's passive accumulation inside tumor. Due to the acidic TME nature, the MOF shell might be degraded releasing free Fe III , TA and a sustained release of 99m Tc-DOX. Besides its chemotherapeutic impact and capacity to raise intracellular H 2 O 2 content, the released 99m Tc-DOX might be used as SPECT imaging tracer for concurrent tumor diagnosis. Furthermore, the mild acidity of the tumor may be overcome by the released TA, which might raise the acidification level of cancer cells. The released Fe III , TA and the endogenous GSH could engage in a redox reaction that depletes GSH and reduces Fe III to Fe II ions which subsequently catalyze the elevated concentration of H 2 O 2 to reactive •OH via Fenton-like reaction, increasing the effectiveness of chemodynamic therapy. Moreover, the in-vivo evaluation in tumor-bearing mice showed significant radioactivity accumulation in the tumor lesion (16.8%ID/g at 1 h post-injection) with a potential target/non-target ratio of 8. Conclusions The 99m Tc-DOX loaded AA-Fe 3 O 4 @Fe III -TA could be introduced as an effective chemo/chemodynamic theranostics. Graphical Abstract