A self-activating nanovesicle with oxygen-depleting capability for efficient hypoxia-responsive chemo-thermo cancer therapy.

Hypoxia-activated prodrugs (HAPs) promise to mitigate side effects of conventional chemotherapy and to enable precise medication treatment. One challenge facing HAPs-based chemotherapy is prodrug failure in normoxic tumor region. However, current strategies to enhance tumor hypoxia rely on delivery of oxygen-consuming agents and external stimulation, which can impede the optimal application of HAPs. Herein, a novel self-activating nanovesicle, TH-302@BR-Chitosan NPs, is constructed by assembling bilirubin-chitosan conjugate (named as BR-Chitosan) with a HAP, TH-302. It is interesting to find that the BR-Chitosan shows the inherent oxygen-depleting performance, especially in the presence of over expressed H2O2 in tumor area, during which the BR-Chitosan can facily transform into biliverdin-chitosan (BV-Chitosan) and subsequently result in the disassembly of nanovesicles to release and activate the prodrug. Thus, this in situ strengthening hypoxia level of tumor can greatly promote the chemotherapy efficacy of HAPs. Moreover, as the oxidation derivatives of BR-Chitosan, BV-Chitosan exhibits intense absorbance at the range from long wavelength of visible region to near-infrared region, which can be acted as an effective photothermal agent for photothermal therapy (PTT). This biodegradable and self-activating nanovesicle with concise formulation demonstrates greatly enhanced synergistic therapeutic outcome in the activatable chemo-thermo combined therapy, showing much promising in future clinical transformation.

Hypoxia-Induced Photogenic Radicals by Eosin Y for Efficient Phototherapy of Hypoxic Tumors.

The current reported photosensitizers generally show a decreased reactive oxygen species (ROS) generation property under hypoxia conditions, which is the main reason for the clinical failure of photodynamic therapy (PDT) in treatment of solid tumors. Herein, for the first time, hypoxia-induced photogenic radicals by eosin Y (Eos) were reported for efficient phototherapy of hypoxic tumors. More importantly, Eos shows a higher ROS and radical production efficiency under hypoxia conditions than under normoxia conditions. The photogenic radicals were captured by electron paramagnetic resonance and further verified by ROS and radical probe. Introducing CoCl2 as a hypoxia inducer, the photoinduced therapy of the hypoxia cancer cell model and tumor-bearing mice indicated that bovine serum albumin-Eos in hypoxic tumor sites can produce even higher tumor toxicity, thereby crossing the clinical obstacles of hypoxic tumor therapy. This non-oxygen-dependent PDT may open up an avenue for fighting with hypoxia.