Self-immolative polyprodrug-based tumor-specific cascade amplificated drug release nanosystem for orchestrated synergistic cancer therapy

Reactive oxygen species (ROS)-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the inability to release sufficient drugs at tumor sites due to the paucity of ROS, which is required for prodrug activation usually limits the antitumor potency. Herein, a delivery nanosystem with self-amplifiable drug release pattern is constructed by encapsulating a tumor specificity ROS inducer NAD(P)H: quinone oxidoreductase-1 (NQO1)-responsive hemicyanine fluorescent dye (NCyNH2) in a ROS-responsive self-immolative polyprodrug nanoparticle for orchestrated oxidation-chemotherapy. In response to ROS stimulation, the self-immolative polyprodrug can degrade and release doxorubicin (DOX) through a domino-like fragmentation, which can impart advanced attributes of this nanosystem such as minimum cleavage events required and maximum cleavage speed for disintegration. Thus, the NCyNH2-loaded self-immolative polyprodrug nanoparticle (SIPN) could be dissociated in response to endogenous ROS, triggering the release of DOX and NCyNH2. Subsequently, the NCyNH2 could be activated by intratumoral overexpressed NQO1 to generate additional ROS, which further induces the amplifiable degradation of self-immolative polyprodrug to release sufficient drugs. The in vitro and in vivo studies consistently demonstrate that SIPN amplifies the drug release efficiency of ROS-responsive polyprodrug by specifically upregulating intratumoral ROS levels, resulting in significant antitumor efficacy with minimal side effects.