Chengbo Liu

Ultrasmall Cu2‐xS Nanodots for Highly Efficient Photoacoustic Imaging‐Guided Photothermal Therapy

Monodisperse, ultrasmall (<5 nm) Cu(2-x)S nanodots (u-Cu(2-x)S NDs) with significantly strong near-infrared absorption and conversion are successfully demonstrated for effective deep-tissue photoacoustic imaging-guided photothermal therapy both in vitro and in vivo. Owing to ultrasmall nanoparticle size and high water dispersibility as well as long stability, such nanodots possess a prolonged circulation in blood and good passive accumulation within tumors through the enhanced permeability and retention effect. These u-Cu(2-x)S NDs have negligible side effects to both blood and normal tissues according to in vivo toxicity evaluations for up to 3 months, showing excellent hemo/histocompatibility. Furthermore, these u-Cu(2-x)S NDs can be thoroughly cleared through feces and urine within 5 days, showing high biosafety for further potential clinical translation. This novel photoacoustic imaging-guided photothermal therapy based on u-Cu(2-x)S NDs composed of a single component shows great prospects as a multifunctional nanoplatform with integration and multifunction for cancer diagnosis and therapy.

Intravascular optical-resolution photoacoustic tomography with a 1.1 mm diameter catheter.

Photoacoustic imaging is an emerging technology that can provide anatomic, functional, and molecular information about biological tissue. Intravascular spectroscopic and molecular photoacoustic imaging can potentially improve the identification of atherosclerotic plaque composition, the detection of inflammation, and ultimately the risk stratification of atherosclerosis. In this study, a first-of-its-kind intravascular optical-resolution photoacoustic tomography (OR-PAT) system with a 1.1 mm diameter catheter is developed, offering optical-diffraction limited transverse resolution as fine as 19.6 μm, ∼10-fold finer than that of conventional intravascular photoacoustic and ultrasonic imaging. To offer complementary imaging information and depth, the system also acquires co-registered intravascular ultrasound images in parallel. Imaging of an iliac stent and a lipid phantom shows that the high resolution and contrast of OR-PAT can enable improved stent implantation guidance and lipid identification. In the future, these capabilities may ultimately improve the diagnosis and interventional treatment of vulnerable atherosclerotic plaques, which are prone to cause thrombotic complications such as myocardial infarction and stroke.

A facile synthesis of versatile Cu2-xS nanoprobe for enhanced MRI and infrared thermal/photoacoustic multimodal imaging.

A novel type of intelligent nanoprobe by using single component of Cu2-xS for multimodal imaging has been facilely and rapidly synthesized in scale via thermal decomposition followed by biomimetic phospholipid modification, which endows them with uniform and small nanoparticle size (ca.15 nm), well phosphate buffer saline (PBS) dispersity, high stability, and excellent biocompatibility. The as-synthesized Cu2-xS nanoprobes (Cu2-xS NPs) are capable of providing contrast enhancement for T1-weighted magnetic resonance imaging (MRI), as demonstrated by the both in vitro and in vivo imaging investigations for the first time. In addition, due to their strong near infrared (NIR) optical absorption, they can also serve as a candidate contrast agent for enhanced infrared thermal/photoacoustic imaging, to meet the shortfalls of MRI. Hence, complementary and potentially more comprehensive information can be acquired for the early detection and accurate diagnosis of cancer. Furthermore, negligible systematic side effects to the blood and tissue were observed in a relatively long period of 3 months. The distinctive multimodal imaging capability with excellent hemo/histocompatibility of the Cu2-xS NPs could open up a new molecular imaging possibility for detecting and diagnosing cancer or other diseases in the future.

High-speed intravascular spectroscopic photoacoustic imaging at 1000 A-lines per second with a 0.9-mm diameter catheter

Abstract. Intravascular spectroscopic photoacoustic technology can image atherosclerotic plaque composition with high sensitivity and specificity, which is critical for identifying vulnerable plaques. Here, we designed and engineered a catheter of 0.9 mm in diameter for intravascular photoacoustic (IVPA) imaging, smaller than the critical size of 1 mm required for clinical translation. Further, a quasifocusing photoacoustic excitation scheme was developed for the catheter, producing well-detectable IVPA signals from stents and lipids with a laser energy as low as ∼30  μJ/pulse. As a result, this design enabled the use of a low-energy, high-repetition rate, ns-pulsed optical parametric oscillator laser for high-speed spectroscopic IVPA imaging at both the 1.2-μm and 1.7-μm spectral bands for lipid detection. Specifically, for each wavelength, a 1-kHz IVPA A-line rate was achieved, ∼100-fold faster than previously reported IVPA systems offering a similar wavelength tuning range. Using the system, spectroscopic IVPA imaging of peri-adventitial adipose tissue from a porcine aorta segment was demonstrated. The significantly improved imaging speed, together with the reduced catheter size and multiwavelength spectroscopic imaging ability, suggests that the developed high-speed IVPA technology is of great potential to be further translated for in vivo applications.

Indocyanine green–loaded polydopamine–iron ions coordination nanoparticles for photoacoustic/magnetic resonance dual-modal imaging-guided cancer photothermal therapy

Multi-modal imaging-guided cancer photothermal therapy (PTT) with advanced theranostic nanoagents can efficiently improve therapeutic efficacy and reduce treatment side effects. Herein, we have developed a theranostic nanoagent based on indocyanine green (ICG)-loaded polydopamine (PDA)-iron ions coordination nanoparticles (PDA-Fe3+-ICG NPs), which are used for photoacoustic (PA) and magnetic resonance (MR) dual-modal imaging-guided cancer PTT treatments. In this nanoplatform, ICG molecules, the U.S. Food and Drug Administration approved near-infrared (NIR) dye, absorbing on PDA NPs (a melanin-like biopolymer) to significantly increase the NIR optical absorption of PDA NPs nearly 6 times and decreases their fluorescence emission, which can improve the PA contrast ability and promote the photothermal conversion efficiency of PDA NPs. Meanwhile, Fe3+ ions chelated on the PDA NPs act as a T1-weighted MRI contrast agent (r1 = 14 mM-1 s-1). In a mouse 4T1 breast tumor model, PA/MRI dual-modal imaging and highly efficient PTT treatments with low laser density were achieved with remarkable therapeutic efficiency and minimal side effects. This study illustrates that the highly integrated and biocompatible PDA-based NPs can serve as a versatile nanoplatform by loading different imaging molecules and drugs for multi-modal imaging and cancer combination therapy.

Multi-parametric quantitative microvascular imaging with optical-resolution photoacoustic microscopy in vivo.

Many diseases involve either the formation of new blood vessels (e.g., tumor angiogenesis) or the damage of existing ones (e.g., diabetic retinopathy) at the microcirculation level. Optical-resolution photoacoustic microscopy (OR-PAM), capable of imaging microvessels in 3D in vivo down to individual capillaries using endogenous contrast, has the potential to reveal microvascular information critical to the diagnosis and staging of microcirculation-related diseases. In this study, we have developed a dedicated microvascular quantification (MQ) algorithm for OR-PAM to automatically quantify multiple microvascular morphological parameters in parallel, including the vessel diameter distribution, the microvessel density, the vascular tortuosity, and the fractal dimension. The algorithm has been tested on in vivo OR-PAM images of a healthy mouse, demonstrating high accuracy for microvascular segmentation and quantification. The developed MQ algorithm for OR-PAM may greatly facilitate quantitative imaging of tumor angiogenesis and many other microcirculation related diseases in vivo.

Biocompatible conjugated polymer nanoparticles for highly efficient photoacoustic imaging of orthotopic brain tumors in the second near-infrared window

A new second near-infrared (NIR II) conjugated polymer (CP) was designed and synthesized. The CP nanoparticles have good biocompatibility, excellent photostability and high imaging contrast, and have been successfully used to demonstrate the first example of NIR II photoacoustic imaging of orthotopic brain tumors. In comparison with existing contrast agents for photoacoustic imaging, the NIR II CP nanoparticles showed more efficient skull penetration and a much higher signal/background ratio using a 1064 nm laser.

Advances in Imaging Techniques and Genetically Encoded Probes for Photoacoustic Imaging.

Photoacoustic (PA) imaging is a rapidly emerging biomedical imaging modality that is capable of visualizing cellular and molecular functions with high detection sensitivity and spatial resolution in deep tissue. Great efforts and progress have been made on the development of various PA imaging technologies with improved resolution and sensitivity over the past two decades. Various PA probes with high contrast have also been extensively developed, with many important biomedical applications. In comparison with chemical dyes and nanoparticles, genetically encoded probes offer easier labeling of defined cells within tissues or proteins of interest within a cell, have higher stability in vivo, and eliminate the need for delivery of exogenous substances. Genetically encoded probes have thus attracted increasing attention from researchers in engineering and biomedicine. In this review, we aim to provide an overview of the existing PA imaging technologies and genetically encoded PA probes, and describe further improvements in PA imaging techniques and the near-infrared photochromic protein BphP1, the most sensitive genetically encoded probe thus far, as well as the potential biomedical applications of BphP1-based PA imaging in vivo.

Hybrid MoSe2–indocyanine green nanosheets as a highly efficient phototheranostic agent for photoacoustic imaging guided photothermal cancer therapy

Phototheranostic technology based on photoacoustic imaging (PAI) and photothermal therapy (PTT) is emerging as a powerful tool for tumor theranostic applications. For effective tumor eradication, a novel PAI/PTT theranostic nanoagent with an excellent optical absorption and photothermal capability is highly desired. Herein, we present a new PAI/PTT nanohybrid named sMoSe2-ICG NSs by covalently conjugating aminated indocyanine green (ICG) onto a single layer of molybdenum selenide nanosheets (sMoSe2 NSs). We first validate the sMoSe2-ICG NS agent for the PAI and PTT effect in vitro and then use it for highly-sensitive PAI guided highly efficient tumor PTT in vivo. The sMoSe2-ICG NS hybrid possesses several advantages for PAI/PTT applications: (1) the sMoSe2-ICG NSs have strong absorbance in the broad near-infrared (NIR) region, enabling a highly efficient PAI/PTT theranostic effect and the selection of the most widely used excitation wavelength of 808 nm for PTT; (2) the photothermal ability of ICG in sMoSe2-ICG NSs is augmented due to ICG aggregation induced fluorescence quenching and the re-absorbance of ICG fluorescence by sMoSe2 NSs, which further enhances the PAI/PTT theranostic effect. (3) The characteristic absorption peak of sMoSe2-ICG NSs is red-shifted compared to free ICG, resulting in a higher PAI signal-to-noise ratio (SNR) in vivo. Thus, combined with the good stability, high biocompatibility and minimal toxicity properties, the obtained sMoSe2-ICG NSs hybrid has bright prospects for use in future PAI/PTT clinical applications.

Indocyanine Green-holo-Transferrin Nanoassemblies for Tumor-Targeted Dual-Modal Imaging and Photothermal Therapy of Glioma

Active-targeted cancer imaging and therapy of glioma has attracted much attention in theranostic nanomedicine. As a promising tumor-targeting ligand, holo-transferrin (holo-Tf) has been applied for enhancing delivery of nanotheranostics. However, holo-Tf-based nanoassemblies for active targeting mediated multimodal imaging and therapeutics have not been previously reported. Here, we develop a one-step method for the preparation of holo-Tf-indocyanine green (holo-Tf-ICG) nanoassemblies for fluorescence (FL) and photoacoustic (PA) dual-modal imaging and photothermal therapy (PTT) of glioma. The nanoassemblies are formed by hydrophobic interaction and hydrogen bonds between holo-Tf and ICG, which exhibit excellent active tumor-targeting and high biocompability. The brain tumor with highly expressed Tf receptor can be clearly observed with holo-Tf-ICG nanoassemblies base on FL and PA dual-modal imaging in subcutaneous and orthotopic glioma models. Under the near-infrared laser irradiation, the holo-Tf-ICG nanoassemblies accumulated in tumor regions can efficiently convert laser energy into hyperthermia for tumor ablation. The novel theranostic nanoplatform holds great promise for precision diagnosis and treatment of glioma.