Applications of the Photocatalytic and Photoacoustic Properties of Gold Nanorods in Contrast-Enhanced Ultrasound and Photoacoustic Imaging.

The applications of ultrasound imaging are often limited due to low contrast, which arises from the comparable acoustic impedance of normal tissues and disease sites. To improve the low contrast, we propose a contrast agent called gas-generating laser-activatable nanorods for contrast enhancement (GLANCE), which enhances ultrasound imaging contrast in two ways. First, GLANCE absorbs near-infrared lasers and generates nitrogen gas bubbles through the photocatalytic function of gold nanorods and photolysis of azide compounds. These gas bubbles decrease the acoustic impedance and highlight the injection site from the surrounding tissues. Second, GLANCE exhibits photoacoustic properties owing to the gold nanorods that emit photoacoustic signals upon laser irradiation. Additionally, GLANCE offers several benefits for biomedical applications such as nanometer-scale size, adjustable optical absorption, and biocompatibility. These distinctive features of GLANCE would overcome the limitations of conventional ultrasound imaging and facilitate the accurate diagnosis of various diseases.

Real-time monitoring of NIR-triggered drug release from phase-changeable nanodroplets by photoacoustic/ultrasound imaging.

Optical-responsive nanodroplets have recently been studied as a new mode of remotely controlled drug delivery. As a class of new emerging smart drug carriers, NIR-absorber-loaded perfluorocarbon nanodroplets can be converted into gas bubbles through laser stimulation, called optical droplet vaporization (ODV), which provides a potential strategy to deliver therapeutic agents to solid tumors on demand. However, there is a lack of suitable technologies to monitor these drug-loaded nanodroplet behaviors in vivo, and control the site and amount of drug released. In this study, ultrasound and photoacoustic imaging technology were applied to directly monitor optical-responsive, drug-loaded nanodroplets within the tissue. We explored the effects of laser energy, repetition rate, and number of pulses on the release profiles of the delivered drug as well as ultrasound and photoacoustic imaging signal-intensity curves. The conducted studies demonstrated that this noninvasive technology helped determine the optimum time point for laser activation on accumulated drug-loaded nanodroplets within tissues, allowing for the potential to effectively treat pathologies while minimizing drug-related toxicities.

Characterizing a photoacoustic and fluorescence imaging platform for preclinical murine longitudinal studies.

Significance: To effectively study preclinical animal models, medical imaging technology must be developed with a high enough resolution and sensitivity to perform anatomical, functional, and molecular assessments. Photoacoustic (PA) tomography provides high resolution and specificity, and fluorescence (FL) molecular tomography provides high sensitivity; the combination of these imaging modes will enable a wide range of research applications to be studied in small animals. Aim: We introduce and characterize a dual-modality PA and FL imaging platform using in vivo and phantom experiments. Approach: The imaging platform's detection limits were characterized through phantom studies that determined the PA spatial resolution, PA sensitivity, optical spatial resolution, and FL sensitivity. Results: The system characterization yielded a PA spatial resolution of 173 ± 17 µ m in the transverse plane and 640 ± 120 µ m in the longitudinal axis, a PA sensitivity detection limit not less than that of a sample with absorption coefficient µ a = 0.258 cm - 1 , an optical spatial resolution of 70 µ m in the vertical axis and 112 µ m in the horizontal axis, and a FL sensitivity detection limit not < 0.9 µ M concentration of IR-800. The scanned animals displayed in three-dimensional renders showed high-resolution anatomical detail of organs. Conclusions: The combined PA and FL imaging system has been characterized and has demonstrated its ability to image mice in vivo, proving its suitability for biomedical imaging research applications.

Correction: In vivo photoacoustic image-guided tumor photothermal therapy and real-time temperature monitoring using a core-shell polypyrrole@CuS nanohybrid.

Correction for 'In vivo photoacoustic image-guided tumor photothermal therapy and real-time temperature monitoring using a core-shell polypyrrole@CuS nanohybrid' by Yang Cao et al., Nanoscale, 2022, 14, 12069-12076, https://doi.org/10.1039/D2NR02848D.

Theragnostic Glycol Chitosan-Conjugated Gold Nanoparticles for Photoacoustic Imaging of Regional Lymph Nodes and Delivering Tumor Antigen to Lymph Nodes.

Lymph node mapping is important in cancer immunotherapy because the morphology of lymph nodes is one of the crucial evaluation criteria of immune responses. We developed new theragnostic glycol-chitosan-coated gold nanoparticles (GC-AuNPs), which highlighted lymph nodes in ultrasound-guided photoacoustic (US/PA) imaging. Moreover, the ovalbumin epitope was conjugated GC-AuNPs (OVA-GC-AuNPs) for delivering tumor antigen to lymph node resident macrophage. In vitro studies proved the vigorous endocytosis activity of J774A.1 macrophage and consequent strong photoacoustic signals from them. The macrophages also presented a tumor antigen when OVA-GC-AuNPs were used for cellular uptake. After the lingual injection of GC-AuNPs into healthy mice, cervical lymph nodes were visible in a US/PA imaging system with high contrast. Three-dimensional analysis of lymph nodes revealed that the accumulation of GC-AuNPs in the lymph node increased as the post-injection time passed. Histological analysis showed GC-AuNPs or OVA-GC-AuNPs located in subcapsular and medullar sinuses where macrophages are abundant. Our new theragnostic GC-AuNPs present a superior performance in US/PA imaging of lymph nodes without targeting moieties or complex surface modification. Simultaneously, GC-AuNPs were able to deliver tumor antigens to cause macrophages to present the OVA epitope at targeted lymph nodes, which would be valuable for cancer immunotherapy.

Photomagnetic Prussian blue nanocubes: Synthesis, characterization, and biomedical applications.

Nanoparticles play an important role in biomedicine. We have developed a method for size-controlled synthesis of photomagnetic Prussian blue nanocubes (PBNCs) using superparamagnetic iron oxide nanoparticles (SPIONs) as precursors. The developed PBNCs have magnetic and optical properties desired in many biomedical diagnostic and therapeutic applications. Specifically, the size-tunable photomagnetic PBNCs exhibit high magnetic saturation, strong optical absorption with a peak at approximately 700 nm, and superior photostability. Our studies demonstrate that PBNCs can be used as MRI and photoacoustic imaging contrast agents in vivo. We also showed the utility of PBNCs for labeling and magnetic manipulation of cells. Dual magnetic and optical properties, together with excellent biocompatibility, render PBNCs an attractive contrast agent for both diagnostic and therapeutic applications. The use SPIONs as precursors for PBNCs provides flexibility and allows researchers to design theranostic agents according to required particle size, optical, and magnetic properties.

Ultrasound-guided immunofunctional photoacoustic imaging for diagnosis of lymph node metastases.

Metastases, rather than primary tumors, determine mortality in the majority of cancer patients. A non-invasive immunofunctional imaging method was developed to detect sentinel lymph node (SLN) metastases using ultrasound-guided photoacoustic (USPA) imaging combined with glycol-chitosan-coated gold nanoparticles (GC-AuNPs) as an imaging contrast agent. GC-AuNPs, injected peritumorally into breast tumor-bearing mice, were taken up by immune cells, and subsequently transported to the SLN. Two-dimensional and three-dimensional USPA imaging was used to isolate the signal from GC-AuNP-tagged cells. Volumetric analysis was used to quantify GC-AuNP accumulation in the SLN after cellular uptake and transport by immune cells. The results show that the spatio-temporal distribution of GC-AuNPs in the SLN was affected by the presence of metastases. The parameter describing the spatial distribution of GC-AuNP-tagged cells within the SLN was more than 2-fold lower in metastatic lymph nodes compared with non-metastatic controls. Histological analysis confirmed that the distribution of GC-AuNP-tagged immune cells is changed by the presence of metastatic cells. The USPA immunofunctional imaging successfully distinguished metastatic from non-metastatic lymph nodes using biocompatible nanoparticles. This method could aid physicians in the detection of micrometastases, thus guiding SLN biopsy and avoiding unnecessary biopsy procedures.

Tunable aggregation of gold-silica janus nanoparticles to enable contrast-enhanced multiwavelength photoacoustic imaging in vivo.

Photoacoustic imaging using exogenous contrast agents has emerged as a hybrid technique that enables the deep imaging of optical properties of tissues with high spatial resolution. The power of this imaging technique can be greatly enhanced by the use of contrast agents that absorb at near-infrared wavelengths and whose optical properties can be modulated in response to the local environment. We have designed contrast agents consisting of gold nanoparticles coated with anisotropic silica nanoshells. The tunable aggregation of these janus particles in cell culture media resulted in a dramatic amplification of photoacoustic signals in the near-infrared region. We also demonstrated imaging using these contrast agents in mammalian cells, including macrophages and breast cancer cells as well as in vivo. The ability to modulate janus particle aggregation in response to a range of stimuli in combination with the high resolution and deep penetration of multiwavelength photoacoustic imaging are attractive for a broad range of applications in diagnostic imaging and theranostics.

Photoacoustic Image-Guided Delivery of Plasmonic-Nanoparticle-Labeled Mesenchymal Stem Cells to the Spinal Cord.

Regenerative therapies using stem cells have great potential for treating neurodegenerative diseases and traumatic injuries in the spinal cord. In spite of significant research efforts, many therapies fail at the clinical phase. As stem cell technologies advance toward clinical use, there is a need for a minimally invasive, safe, affordable, and real-time imaging technique that allows for the accurate and safe monitoring of stem cell delivery in the operating room. In this work, we present a combined ultrasound and photoacoustic imaging tool to provide image-guided needle placement and monitoring of nanoparticle-labeled stem cell delivery into the spinal cord. We successfully tagged stem cells using gold nanospheres and provided image-guided delivery of stem cells into the spinal cord in real-time, detecting as few as 1000 cells. Ultrasound and photoacoustic imaging was used to guide needle placement for direct stem cell injection to minimize the risk of needle shear and accidental injury and to improve therapeutic outcomes with accurate, localized stem cell delivery. Following injections of various volumes of cells, three-dimensional ultrasound and photoacoustic images allowed the visualization of stem cell distribution along the spinal cord, showing the potential to monitor the migration of the cells in the future. The feasibility of quantitative imaging was also shown by correlating the total photoacoustic signal over the imaging volume to the volume of cells injected. Overall, the presented method may allow clinicians to utilize imaged-guided delivery for more accurate and safer stem cell delivery to the spinal cord.

Copper Sulfide Perfluorocarbon Nanodroplets as Clinically Relevant Photoacoustic/Ultrasound Imaging Agents.

We have developed laser-activated perfluorocarbon nanodroplets containing copper sulfide nanoparticles (CuS NPs) for contrast-enhanced ultrasound and photoacoustic imaging. As potential clinical contrast agents, CuS NPs have favorable properties including biocompatibility, biodegradability, and enhance contrast in photoacoustic images at clinically relevant depths. However, CuS NPs are not efficient optical absorbers when compared to plasmonic nanoparticles and therefore, contrast enhancement with CuS NPs is limited, requiring high concentrations to generate images with sufficient signal-to-noise ratio. We have combined CuS NPs with laser-activated perfluorocarbon nanodroplets (PFCnDs) to achieve enhanced photoacoustic contrast and, more importantly, ultrasound contrast while retaining the favorable clinical characteristics of CuS NPs. The imaging characteristics of synthesized CuS-PFCnD constructs were first tested in tissue-mimicking phantoms and then in in vivo murine models. The results demonstrate that CuS-PFCnDs enhance contrast in photoacoustic (PA) and ultrasound (US) imaging. Upon systemic administration in vivo, CuS-PFCnDs remain stable and their unique vaporization provides sufficient PA/US contrast that can be further exploited for contrast-enhanced background-free imaging. The conducted studies provide a solid foundation for further development of CuS-PFCnDs as PA/US diagnostic and eventually therapeutic agents for clinical applications.

Monitoring/Imaging and Regenerative Agents for Enhancing Tissue Engineering Characterization and Therapies.

The past three decades have seen numerous advances in tissue engineering and regenerative medicine (TERM) therapies. However, despite the successes there is still much to be done before TERM therapies become commonplace in clinic. One of the main obstacles is the lack of knowledge regarding complex tissue engineering processes. Imaging strategies, in conjunction with exogenous contrast agents, can aid in this endeavor by assessing in vivo therapeutic progress. The ability to uncover real-time treatment progress will help shed light on the complex tissue engineering processes and lead to development of improved, adaptive treatments. More importantly, the utilized exogenous contrast agents can double as therapeutic agents. Proper use of these Monitoring/Imaging and Regenerative Agents (MIRAs) can help increase TERM therapy successes and allow for clinical translation. While other fields have exploited similar particles for combining diagnostics and therapy, MIRA research is still in its beginning stages with much of the current research being focused on imaging or therapeutic applications, separately. Advancing MIRA research will have numerous impacts on achieving clinical translations of TERM therapies. Therefore, it is our goal to highlight current MIRA progress and suggest future research that can lead to effective TERM treatments.