H-Aggregates of Prodrug-Hemicyanine Conjugate for Enhanced Photothermal Therapy and Sequential Hypoxia-Activated Chemotherapy

Photothermal therapy (PTT) as a single treatment still faces a challenge in completely eradicating deep tumors due to the limited tissue penetration of light. The combination of PTT and chemotherapy could effectively improve the therapeutic effect. Herein, we report a prodrug-hemicyanine conjugate (Cy-azo) to achieve H-aggregation improved photothermal therapy and sequential hypoxia-activated chemotherapy. Due to the introduction of the chemotherapeutic drug, nitrogen mustard, Cy-azo demonstrates high photothermal conversion efficiency (PCE, 39.3%) caused by the enhanced H-aggregation of the prodrug through π–π stacking. Moreover, the activated drug is released in the tumor hypoxic microenvironment, which can kill cancer cells and greatly reduce the toxic side effects of chemotherapy. In addition, Cy-azo is further encapsulated into polymer nanoparticles to stabilize the Cy-azo H-aggregates and increase the tumor accumulation of Cy-azo through the enhanced permeability and retention effect (EPR). Interestingly, Cy-azo NPs show an enhanced PCE as 56.1% and demonstrate an excellent anticancer therapeutic effect under 808 nm light irradiation. The combination of PTT with hypoxia-activated chemotherapy is promising for anticancer treatment and would guide future development of prodrugs for combined PTT and chemotherapy.