A free-radical initiator-based carrier-free smart nanobomb for targeted synergistic therapy of hypoxic breast cancer.

Thermodynamic therapy (TDT) is a promising alternative to photodynamic therapy (PDT) by absorbing heat through thermosensitive agents (TSAs) to generate oxygen-irrelevant highly toxic free radicals. Therefore, TDT can be a perfect partner for photothermal therapy (PTT) to achieve efficient synergistic treatment of anoxic tumors using a single laser, greatly simplifying the treatment process and overcoming hypoxia limitations. However, the issues of how to improve the stability and delivery efficiency of TSAs still need to be addressed urgently. Herein, polyethylene glycol-folic acid (PEG-FA)-modified and indocyanine green (ICG)-encapsulated nanoscale Zn and 2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) coordinated nanomaterials (IANM-PEG-FA) were developed as a nanobomb for targeted photothermal/thermodynamic/ion-interference cancer therapy. Co-triggered by a single 808 nm laser and mildly acidic tumor microenvironment, the photothermal agent of ICG would induce rapid decomposition of AIPH to generate alkyl radicals and release ICG and Zn, resulting in effectively cascaded oxygen-independent photothermal/thermodynamic therapy and co-enhanced synergistic intracellular overload of Zn interference. Additionally, PEG-FA enabled favorable stability and active targeting ability to achieve low side effects and efficient tumor enrichment for good photothermal/near-infrared fluorescence imaging-guided precise tumor therapy. Significantly, the IANM-PEG-FA nanosystem exhibited remarkable anticancer effects even at low doses in hypoxic breast cancer, achieving 80% tumor elimination. Our study might provide a highly effective strategy for developing a multifunctional carrier-free nanosystem with high performance in hypoxic cancer to meet the requirements in the clinic.