Redox-Activated Photoacoustic Imaging-Guided Photothermal Therapy with Bioresponsive Polyoxometalate Cluster
JOURNAL OF NUCLEAR MEDICINE(2018)
Abstract
188 Objectives: Although various types of imaging agents have been developed for photoacoustic (PA) imaging, relatively few imaging agents exhibit high selectivity/sensitivity to the tumor microenvironment for on-demand PA imaging and therapy. Meantime, a common concern about nanoparticles for PA imaging is the nonspecific uptake by mononuclear phagocyte systems (e.g., liver/spleen) and low accumulation in tumors due to the poor enhanced permeability and retention (EPR) effect. Our goal is to develop an intelligent theranostic agent, which can remain as small molecules during circulation in the bloodstream, self-assemble into larger nanostructures in the tumor, and then be activated by the tumor microenvironment for PA imaging-guided tumor therapy. Methods: Herein, we reported molybdenum-based polyoxometalate (POM) clusters with the highest oxidation state of Mo(VI) (denoted as Ox-POM) as novel agents for redox-activated PA imaging-guided photothermal therapy (PTT). Capable of escaping from recognition and capture by the liver and spleen, these renal clearable clusters with ultra-small size can accumulate in the tumor, self-assemble into larger nanoclusters at low pH, and are reduced to near-infrared (NIR) absorptive agents in the tumor microenvironment. Systematic in vitro and in vivo experiments were performed to evaluate their bioresponsive and theranostic capability. Results: These Ox-POMs were highly uniform with their hydrated size increasing from 1.9 nm (pH = 7.4) to 29.3 nm (pH = 6.5) and to ∼0.43 μm at pH 5.0. The clusters showed no NIR absorption in their original chemical form but exhibited strong NIR absorption because Mo(VI) is reduced to Mo(V) when incubated with glutathione (GSH), exhibiting high-performance PA imaging and photothermal conversion in vitro. The PET imaging of 89Zr-Ox-POM results showed these clusters could escape from recognition by the liver and spleen and were mainly excreted through the kidneys, which is highly desirable for reducing the potential toxic effects. Studies in 4T1 tumor-bearing mice indicated that these clusters could be employed for bioresponsive PA imaging-guided tumor ablation in vivo. The PA signal was detected in the tumors as early as 1 h p.i., demonstrating the strong redox-activated effect of Ox-POM by the tumor redox status. The temperature of the tumor rapidly increased to above 40 °C in 30 s and reached 52 °C in 5 min under laser irradiation, and the tumor growth was eliminated without subsequent recurrence for a prolonged period of up to 2 months, whereas the control groups demonstrated rapid tumor growth. CONCLUSION: In summary, we present here the redox-activated Ox-POM clusters for tumor microenvironment-responsive PA imaging-guided tumor ablation. Importantly, these bioresponsive clusters with long in vivo circulation half-life can be passively accumulated in the tumor, self-assemble into larger nanosizes under the tumor’s acidic environment, and be reduced to NIR absorptive agents for efficient PA imaging-guided PTT of cancer. As a proof-of-concept, this finding is expected to establish a new class of redox-activated probes based on clusters, bridging the conventional concepts of “molecule” and “nano” in the bioimaging field.
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Key words
photothermal therapy,redox-activated,imaging-guided
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