Tumor microenvironment sensitization via dual-catalysis of carbon-based nanoenzyme for enhanced photodynamic therapy.

Photodynamic therapy (PDT) is limited in tumor therapy due to the mature antioxidant barrier of tumor microenvironment (TME) and phototoxicity/easy-degradation characteristics of photosensitizers. Therefore, we prepared Cu2+-doped hollow carbon nanoparticles (CHC) to protect the loaded photosensitizers and sensitize TME by glutathione-depletion and peroxidase (POD)-like activity for enhanced PDT. CHC significantly increased the maximum speed of POD-like reaction (Vm) of 8.4 times. By coating with hyaluronic acid (HA), the active sites on CHC were temporarily masked with low catalytic property, and restored in response to the overexpressed hyaluronidase in TME. Meanwhile, due to the excellent photothermal conversion efficiency (32.5 %) and hollow structure of CHC, the loaded photosensitizers were well protected from sunlight activation-induced unwanted phototoxicity and rapid degradation under the near-infrared light irradiation. In-vivo anti-tumor experiments demonstrated that the combination of photothermal-photodynamic effect achieved the best anti-tumor effect (tumor inhibition rate at 87.8 %) compared with any monotherapy. In addition, the combination of photothermal and photodynamic effect could efficiently suppress the cell migration, manifesting the reduced number of lung metastasized nodules by 74 %. This work provides an integrated platform for photosensitizers protection and TME sensitization for enhanced PDT.

Mesoporous carbon nanoenzyme as nano-booster for photothermal-enhanced photodynamic therapy compared with graphene oxide.

The over-expressed GSH in tumor microenvironment significantly weakens the lethal reactive oxygen species (ROS) generated by photodynamic therapy (PDT) and catalysis of nanoenzyme. Hence, it is necessary to excavate a versatile and effective vehicle with oxidative stress-enhancement and GSH-depletion capacity to break the redox homeostasis in tumor microenvironment. GO has been reported to possess GSH-depletion and peroxidase (POD)-like capacity. Based on this, PEGylated mesoporous carbon (MC-PEG) was prepared as ICG vehicle to compare with PEGylated graphene oxide (GO-PEG). Excitingly, MC-PEG was found to exhibit three times higher oxidative capacity by POD-like process than GO-PEG, and owned more effective and continuous GSH-depletion capacity to further amplify the oxidative stress. Meanwhile, MC-PEG exhibited better protective effect on the loaded ICG against unwanted light excitation than GO-PEG. Together with the higher photothermal conversion effect, under the NIR light irradiation, MC-PEG could markedly improve the temperature of tumor cells and produce more hydroxyl radical, continuously consume GSH and provide more better protection for ICG compared with GO-PEG, thus further boosting the combination of photothermal and photodynamic effects. The anti-tumor experiment in cell and in-vivo level both validated that ICG/MC-PEG showed better synergistic effect with lower IC50 value and higher tumor suppression rate than ICG/GO-PEG.

Biomimetic smart mesoporous carbon nanozyme as a dual-GSH depletion agent and O2 generator for enhanced photodynamic therapy.

Photodynamic therapy (PDT) has been thriving in the theranostics of cancer in recent years. However, due to a series of problems such as high concentration of GSH and insufficient O2 partial pressure in the tumor micro-environment, it is difficult to achieve the desired therapeutic effects with single PDT. Mesoporous carbon (MC-COOH) has been widely used in photothermal therapy (PTT) due to its high photothermal conversion efficiency and drug loading. In addition, we have discovered that MC-COOH owned high-efficiency glutathione oxidase-like activity for intracellular lasting GSH consumption. Hence, a smart mesoporous carbon nanozyme (CCM) was designed as a dual-GSH depletion agent and O2 generator combined with PTT to overcome the dilemma of PDT. MnO2-doped carbon nanozyme (MC-Mn) was developed as the photothermal vehicles for the efficient loading of photosensitizer (Ce6). Subsequently, 4T1 membrane-coated nanozyme (Ce6/CCM) was constructed to achieve homologous targeting capability. The carbon nanozyme owned the sustained dual-GSH depletion function through MC-COOH and MnO2, which greatly destroyed the antioxidant system of the tumor. Meanwhile, MnO2 could produce affluent O2 in the presence of H2O2, thereby alleviating the hypoxic state of tumor tissues and further promoting the generation of ROS. In addition, the novel carbon nanozyme was designed as photoacoustic imaging (PAI) agent and magnetic resonance imaging (MRI) contrast for real-time imaging during tumor therapy. In summary, this work showed that the biomimetic carbon nanozyme could be used as dual-GSH depletion agent and O2 generator for dual-mode imaging-guided PTT-PDT. STATEMENT OF SIGNIFICANCE: - MC-COOH with highly efficient GSH-OXD activity was first discovered and applied in PDT. - MnO2 acted as an O2 generator and GSH depletion agent to enhance PDT. - The tumor-targeting ability of the nanozyme was improved by cell membrane camouflage. - CCM nanozyme possesses both PAI and MRI dual-mode imaging modalities to guide PDT/PTT.