Multi-stimuli-responsive porous organic polymers for syn-ergistic drug-gas anticancer therapy

Combination therapies can significantly aid in the treatment of biologically complex diseases, including cancer. These powerful therapies, such as synergistic nitric oxide (NO) gas and chemotherapy, are able to simultaneously target different biological targets, thereby overcoming or reducing drug resistance and decreasing dose-related toxicity. However, in nearly all existing carriers, gases and drugs compete for loading in the same physical space of the carrier and can thus interfere with each other. Herein, we use a porous organic polymer (POP) as a design strategy to pre-pare a combination therapy vehicle with spatially segregated gas and drug loading sites. SH-POP, synthesized by a facile, room-temperature method, is rich in both thiol (-SH) and secondary amine (R-NH-R’) functional groups, which can be post-synthetically nitrosated, yielding light-stimulated NO-releasing SNO-POP. Upon white light irradiation, SNO-POP releases up to ~56 µmol of NO per gram and exhibits reversible on-off NO release behavior triggered by simple light irradiation for at least 20 cycles. Unlike many conventional systems, where a known small-molecule NO donor is incorporated into the pores, here, the porous polymer scaffold serves as a NO reservoir, so the pores remain available for the encapsulation of another therapeutic, Doxorubicin (Dox). The release of Dox from the Dox@SNO-POP system is pH-sensitive and occurs preferentially in a slightly acidic environment (pH = 5.4). HeLa and HepG2 cancer cell viability studies confirm an enhancement in toxicity that can be ascribed to the synergistic effects of light-triggered NO release and pH-triggered Dox release. Confocal fluorescence microscopy imaging reveals the presence of both therapeutic species inside cancer cells. This study is expected to stimulate interest in the development of other combination therapy vehicles that minimize the interference between different cargos in cancer treatment.