Biodegradable Porous Polymeric Drug with pH-Stimuli-Responsive Delivery Capacity for Combined Cancer Therapy

Polymeric drugs are a class of drug in which the polymer itself acts as the active ingredient of the drug. Here, we constructed a biodegradable covalent organic porous polymer (COP), denoted as Fc-Ma, composed of clinical drug molecules, i.e., ferrocene (Fc) and d-mannitol (Ma) and pH-responsive acetal bonds. The coexistence of Fc and Ma brought special properties to Fc-Ma, which can be used directly as a polymeric drug integrating the performance of both components. Thus, this special COP features enzyme activity, which can catalyze the conversion of cellular H2O2 to ·OH through a Fenton-like reaction. As an artificial enzyme, Fc-Ma may overcome many of the limitations of natural enzymes with more pronounced catalytic activity in weakly acidic environments. Therefore, it enables the sufficient generation of reactive oxygen species (ROS) in tumors and effectively kills tumor cells. Meanwhile, the intrinsic open porous skeleton coupled with the large specific surface areas (393 m2 g–1) makes Fc-Ma an ideal carrier for other drugs. For example, it presents a doxorubicin hydrochloride (DOX) drug loading capacity of 64.4 ± 0.27%, compared with individual drugs; the acetal linkage endowed Fc-Ma with passive targeting, resulting in highly controlled drug delivery with selective and sustained release in acidic media, almost twice as much as that under neutral conditions. Hence, the tumor microenvironment can not only stimulate the generation of multiple ROS but also induce the passive targeted release of DOX, thereby ensuring the accumulation of drugs in the cancer sites, preventing the nonspecific distribution of drugs in the whole body and protecting renal tissues against DOX-induced nephrotoxicity. In summary, Fc-Ma-DOX exhibits significant synergistic actions of enzymatic therapy and chemotherapy, thus significantly improving the overall therapeutic effect.