Abstract
The inherent hypoxic environment in tumors severely resists the efficacy of photodynamic therapy. To address this problem, herein, the strategy of using oxygen self-sufficient liposomes (denoted as CaO2/B1/NH4HCO3 lipo), which contained aza-BODIPY dye (B1) and CaO2 nanoparticles in the hydrophobic layer and NH4HCO3 in the hydrophilic cavity, was presented to overcome hypoxia-associated photodynamic resistance. Under near-infrared (NIR) irradiation, NIR-absorbable B1 was activated to induce hyperthermia and further triggered the decomposition of NH4HCO3. Subsequently, with the aid of NH4HCO3 and CaO2 nanoparticles, oxygen was rapidly and self-sufficiently generated, during which clean by-products were produced. Furthermore, the increased amount of oxygen promoted the singlet oxygen production in the presence of B1, which served as a photosensitizer because of the heavy atom effect. The oxygen self-sufficient system improved the anticancer efficiency and alleviated the hypoxic environment in vivo, which demonstrated a valuable attempt to regulate intratumoral hypoxia and overcome the limitation of current photodynamic therapy systems. To our knowledge, this highlights the first example of using NIR light to activate CaO2 nanoparticle-containing liposomes for the modulation of the hypoxic environment in tumors.
Highlights
Keeping the aforementioned issues in mind, we proposed oxygen self-sufficient liposomes (CaO2/B1/NH4HCO3 lipo), which consisted of hydrophobic halogenated aza-BODIPY dye (B1), oxygen-generating CaO2 nanoparticles, and hydrophilic thermoresponsive ammonium bicarbonate (NH4HCO3) to regulate the hypoxic tumor microenvironment and overcome hypoxia-induced photodynamic resistance (Fig. 1a)
We selected the polyethylene glycol (PEG) shelled liposome system as the nanocarrier owing to its good biocompatibility, enhanced tumor permeation and retention, and efficient loading capacity
The thermoresponsive molecule NH4HCO3, which can produce CO2 when temperature reaches 40 C,44 was employed as the stimulus to trigger the rapid release of oxygen from CaO2 nanoparticles
Summary
Per uorocarbon, intracellular hydrogen peroxide (H2O2) catalytic catalase and manganese dioxide (MnO2).[23,24,25,26,27,28,29,30,31,32] the reported oxygen-generating materials have shown some promise, the amount of enriched oxygen is still difficult to improve because of the naturally limited effects and low endogenous H2O2 concentration.[33,34] In this regard, it is highly desirable to design a new generation of anti-hypoxia nanocarriers with enhanced and self-sufficient oxygen supplementation. CaO2 a potential biomaterial that can synergistically work with a photosensitizing reagent and improve PDT efficiency, but the oversized structure suffered from limited penetration in the tumor tissue and the difficulty of clearance from the body. Keeping the aforementioned issues in mind, we proposed oxygen self-sufficient liposomes (CaO2/B1/NH4HCO3 lipo), which consisted of hydrophobic halogenated aza-BODIPY dye (B1), oxygen-generating CaO2 nanoparticles, and hydrophilic thermoresponsive ammonium bicarbonate (NH4HCO3) to regulate the hypoxic tumor microenvironment and overcome hypoxia-induced photodynamic resistance (Fig. 1a). In the liposomes, halogenated B1 was regarded as a potential photosensitizer through the preferable singlet-to-triplet transition and a good organic photothermal agent because of strong near-infrared (NIR) absorption.[42,43] Under irradiation, B1 generated heat and triggered the decomposition of NH4HCO3, thereby resulting in the generation of CO2 bubbles. The relieved intratumoral hypoxia environment was demonstrated through immuno uorescence staining of hypoxia-associated proteins
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