Highly Penetrable and On-Demand Oxygen Release with Tumor Activity Composite Nanosystem for Photothermal/Photodynamic Synergetic Therapy

A deep penetrating and pH-responsive composite nanosystem was strategically developed to improve the efficacy of synergetic photothermal/photodynamic therapy (PTT/PDT) against hypoxic tumor. The designed nanosystem ([PHC]PP@HA NPs) was constructed by coloading hemoglobin (Hb) and chlorin e6 on polydopamine to build small-sized PHC NPs, which were encapsulated inside the polymer micelles (poly(ethylene glycol)-poly(ethylenimine)) and then capped with functionalized hyaluronic acid. The pH-responsive feature made [PHC]PP@HA NPs retain an initial size of ∼140 nm in blood circulation but rapidly release small PHC NPs (∼10 nm) with a high tumor-penetrating ability in the tumor microenvironment. The in vitro penetration experiment showed that the penetration depth of PHC NPs in the multicellular tumor spheroids exceeded 110 μm. The [PHC]PP@HA NPs exhibited excellent biocompatibility, deep tumor permeability, high photothermal conversion efficiency (47.09%), and low combination index (0.59) under hypoxic conditions. Notably, the nanosystem can freely adjust the release of oxygen and damaging PHC NPs in an on-demand manner on the basis of the feedback of tumor activity. This feedback tumor therapy significantly improved the synergistic effect of PTT/PDT and reduced its toxic side effects. The in vivo antitumor results showed that the tumor inhibition rate of [PHC]PP@HA NPs with an on-demand oxygen supply of Hb was ∼100%, which was much better than those of PTT alone and Hb-free nanoparticles ([PC]PP@HA NPs). Consequently, the [PHC]PP@HA NP-mediated PTT/PDT guided by feedback tumor therapy achieved an efficient tumor ablation with an extremely low tumor recurrence rate (8.3%) 60 d later, indicating the versatile potential of PTT/PDT.