Fan Zhang

In vivo assessment of vascular permeability and therapeutic response provides novel insights into photothermal therapy (PTT) that is currently under clinical investigation. We have developed noninvasive imaging strategies to improve the monitoring of nanoparticle-mediated PTT responses for personalized nanomedicine. Briefly, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and photoacoustic imaging (PAI) were applied to study the enhanced permeability and retention (EPR) effect in tumor models of different microvascular permeabilities (i.e., 4T1 mouse breast tumor model and HUH-7 human hepatoma model in nude mice). Magnetic resonance temperature imaging (MRTI) and diffusion-weighted MRI (DWI) showed that the 4T1 tumor model exhibits a higher PTT temperature response than that of the HUH-7 tumor model. Our findings demonstrate that the combined use of MRI and PAI techniques is useful in monitoring the vascular permeability and temperature status following PTT, promising to help guide PTT in future translational investigation.

Photothermal therapy (PTT) and photodynamic therapy (PDT) are promising cancer treatment modalities. Because each modality has its own set of advantages and limitations, there has been interest in developing methods that can co-deliver the two regimens for enhanced tumor treatment. Among the efforts, nano-graphene oxide-mediated phototherapies have recently attracted much attention. Nano-graphene oxide has a broad absorbance spectrum and can be loaded with photosensitizers, such as chlorin e6, with high efficiency. Chlorin e6-loaded and PEGylated nano-graphene (GO-PEG-Ce6) can be excited at 660 nm, 808 nm, or both, to induce PDT, PTT, or PDT/PTT combination. Despite the potential of the treatments, there is a lack of a diagnostic tool which can monitor their therapeutic response in a non-invasive and prognostic manner; such an ability is urgently needed for the transformation and translation of the technologies. In this study, we performed diffusion-weighted and blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) after GO-PEG-Ce6-mediated PTT, PDT, or PTT/PDT. We found that after efficient PTT, there is a significant increase of the tumor apparent diffusion coefficient (ADC) value in diffusion-weighted imaging (DWI) maps; meanwhile, an efficient PDT led to an increase of in BOLD images. In both the cases, the amplitude of the increase was correlated with the treatment outcomes. More interestingly, a synergistic treatment efficacy was observed when the PTT/PDT combination was applied, and the combination was associated with a greater ADC and increase than when either modality was used alone. In particular, the PTT/PDT condition that induced the most dramatic short-term increase of the ADC value (>70%) caused the most effective tumor control in the long-run, with 60% of the treated animals being tumor-free after 60 days. These results suggest the great promise of the combination of DWI and BOLD MRI as a tool for accurate monitoring and prognosis of phototherapies, which is of great value to the future developments of the methodologies.

Photothermal therapy (PTT) as a relatively new cancer treatment method has attracted worldwide attention. Previous research on PTT has focused on its therapy efficiency and selectivity. The early prognosis of PTT, which is pivotal for the assessment of the treatment and the therapy stratification, however, has been rarely studied. In the present study, we investigated diffusion-weighted magnetic resonance imaging (DW-MRI) as a tool for therapy monitoring and early prognosis of PTT. To this end, we injected PEGylated graphene oxide (GO-PEG) or iron oxide deposited graphene oxide (GO-IONP-PEG) to 4T1 tumor models and irradiated the tumors at different drug-light intervals to induce PTT. For GO-IONP-PEG injected animals, we also included therapy arms where an external magnetic field was applied to the tumors to improve the delivery of the nanoparticle transducers. DW-MRI was performed at different time points after PTT and the tumor apparent diffusion coefficients (ADCs) were analyzed and compared. Our studies show that photothermal agents, magnetic guidance, and drug-light intervals can all affect PTT treatment efficacy. Impressively, ADC value changes at early time points after PTT (less than 48 h) were found to be well-correlated with tumor growth suppression that was apparent days or weeks later. The changes were most sensitive to conditions that can extend the survival for more than 4 weeks, in which cases the 48 h ADC values were increased by more than 80%. These studies demonstrate for the first time that DW-MRI can be an accurate prognosis tool for PTT, suggesting an important role it can play in the future PTT evaluation and clinical translation of the modality.

In spite of rapidly increasing interest in the use of nanoparticle-mediated photothermal therapy (PTT) for treatment of different types of tumors, very little is known on early treatment-related changes in tumor response. Using graphene oxide (GO) as a model nanoparticle (NP), in this study, we tracked the changes in tumors after GO NP-mediated PTT by magnetic resonance imaging (MRI) and quantitatively identified MRI multiple parameters to assess the dynamic changes of MRI signal in tumor at different heating levels and duration. We found a time- and temperature-dependent dynamic change of the MRI signal intensity in intratumor microenvironment prior to any morphological change of tumor, mainly due to quick and effective eradication of tumor blood vessels. Based on the distribution of GO particles, we also demonstrated that NP-medited PTT caused heterogeneous thermal injury of tumor. Overall, these new findings provide not only a clinical-related method for non-invasive early tracking, identifying, and monitoring treatment response of NP-mediated PTT but also show a new vision for better understanding mechanisms of NP-mediated PTT.