Transformable hybrid semiconducting polymer nanozyme for second near-infrared photothermal ferrotherapy.

Despite its growing promise in cancer treatment, ferrotherapy has low therapeutic efficacy due to compromised Fenton catalytic efficiency in tumor milieu. We herein report a hybrid semiconducting nanozyme (HSN) with high photothermal conversion efficiency for photoacoustic (PA) imaging-guided second near-infrared photothermal ferrotherapy. HSN comprises an amphiphilic semiconducting polymer as photothermal converter, PA emitter and iron-chelating Fenton catalyst. Upon photoirradiation, HSN generates heat not only to induce cytotoxicity but also to enhance Fenton reaction. The increased ·OH generation promotes both ferroptosis and apoptosis, oxidizes HSN (42 nm) and transforms it into tiny segments (1.7 nm) with elevated intratumoral permeability. The non-invasive seamless synergism leads to amplified therapeutic effects including a deep ablation depth (9 mm), reduced expression of metastasis-related proteins and inhibition of metastasis from primary tumor to distant organs. Thereby, our study provides a generalized nanozyme strategy to compensate both ferrotherapy and phototherapeutics for complete tumor regression.

Recent advances in photoacoustic contrast agents for in vivo imaging.

Photoacoustic imaging (PAI) is a noninvasive hybrid imaging modality offering rich optical contrast and high depth-to-resolution ratio deep-tissue imaging. Endogenous chromophores present in the body such as hemoglobin, lipid, melanin, and so on provide strong photoacoustic contrast due to their strong light absorption in certain optical window. To enhance the performance of PAI further, researchers have developed several exogenous contrast agents such as metallic nanoparticles, carbon-based nanomaterials, quantum dots, organic small molecules, semiconducting polymer nanoparticles, and so on. These exogenous contrast agents not only help improving the imaging contrast, but also make targeted molecular imaging possible. In this review article, we first discuss the state-of-the-art PAI techniques with endogenous contrast mechanism. Later, we provide an overview of recent progress in the development of exogenous photoacoustic contrast agents for in vivo imaging applications. Finally, we present the pros/cons of the existing PA contrast agents along with future challenges of contrast agent-based PAI for biomedical applications. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Real-time monitoring of temperature using a pulsed laser-diode-based photoacoustic system.

Tissue local temperature information is necessary for guiding energy-based medical treatments. In cancer treatments such as thermal therapy, heating is applied to local tissue to kill the tumor cells. These techniques require a temperature monitoring device with high sensitivity. In this Letter, we demonstrate a pulsed-laser-diode-(PLD)-based photoacoustic temperature sensing (PATS) system for monitoring tissue temperature in real time. The system takes advantage of a high repetition rate (7000 Hz), a near-infrared wavelength (803 nm), and a relatively high energy 1.42 mJ/pulse laser. The system is capable of providing local temperature information at high temporal resolution of 1 ms and high sensitivity of 0.31°C. The temperature data measured with a PLD-PATS system are compared with the data provided by the commercial fiber Bragg grating sensor. The proposed system will find applications in radio-frequency ablation, photothermal therapy, and focused ultrasound, etc., used for cancer treatments.

Pulsed Laser Diode-Based Desktop Photoacoustic Tomography for Monitoring Wash-In and Wash-Out of Dye in Rat Cortical Vasculature.

Photoacoustic (PA) tomography (PAT) imaging is an emerging biomedical imaging modality useful in various preclinical and clinical applications. Custom-made circular ring array-based transducers and conventional bulky Nd:YAG/OPO lasers inhibit translation of the PAT system to clinics. Ultra-compact pulsed laser diodes (PLDs) are currently being used as an alternative source of near-infrared excitation for PA imaging. High-speed dynamic in vivo imaging has been demonstrated using a compact PLD-based desktop PAT system (PLD-PAT). A visualized experimental protocol using the desktop PLD-PAT system is provided in this work for dynamic in vivo brain imaging. The protocol describes the desktop PLD-PAT system configuration, preparation of animal for brain vascular imaging, and procedure for dynamic visualization of indocyanine green (ICG) dye uptake and clearance process in rat cortical vasculature.

Photoacoustic imaging in the second near-infrared window: a review.

Photoacoustic (PA) imaging is an emerging medical imaging modality that combines optical excitation and ultrasound detection. Because ultrasound scatters much less than light in biological tissues, PA generates high-resolution images at centimeters depth. In recent years, wavelengths in the second near-infrared (NIR-II) window (1000 to 1700 nm) have been increasingly explored due to its potential for preclinical and clinical applications. In contrast to the conventional PA imaging in the visible (400 to 700 nm) and the first NIR-I (700 to 1000 nm) window, PA imaging in the NIR-II window offers numerous advantages, including high spatial resolution, deeper penetration depth, reduced optical absorption, and tissue scattering. Moreover, the second window allows a fivefold higher light excitation energy density compared to the visible window for enhancing the imaging depth significantly. We highlight the importance of the second window for PA imaging and discuss the various NIR-II PA imaging systems and contrast agents with strong absorption in the NIR-II spectral region. Numerous applications of NIR-II PA imaging, including whole-body animal imaging and human imaging, are also discussed.

Redox-Activatable and Acid-Enhanced Nanotheranostics for Second Near-Infrared Photoacoustic Tomography and Combined Photothermal Tumor Therapy.

Tumor phototheranostics in the second near-infrared window (NIR-II, 1000-1700 nm) holds great promise due to high spatiotemporal precision, enhanced penetration depth, and therapeutic efficacy. However, current "always-on" NIR-II phototheranostic agents remain restricted by the inherent nonspecificity from the pseudosignal readout and undesirable treatment-related side effects. To address these challenges, herein we explore an activatable and biocompatible nanotheranostics that generates diagnostic and therapeutic effects only after specific activation and enhancement by tumor microenvironmental redox and acid while keeping silent at normal tissues. Such an intelligent "turn-on" chromogenic nanotheranostics allows in vivo nearly zero-background photoacoustic tomography (PAT) and combined effective photothermal tumor therapy (PTT) both in the NIR-II range with minimal adverse effects. In light of the high sensitivity, superior penetration depth, and biocompatibility, this stimuli-activatable NIR-II photo-nanotheranostics provides broad prospects for the investigation and intervention of deep-tissue redox and acid-associated physiological and pathological events.

High-speed, low-cost, pulsed-laser-diode-based second-generation desktop photoacoustic tomography system.

Bulky, expensive Nd:YAG lasers are used in conventional photoacoustic tomography (PAT) systems, making them difficult to translate into clinics. Moreover, real-time imaging is not feasible when a single-element ultrasound transducer is used with these low-pulse-repetition-rate lasers (10-100 Hz). Low-cost pulsed laser diodes (PLDs) can be used instead for photoacoustic imaging due to their high-pulse-repetition rates and compact size. Together with acoustic-reflector-based multiple single-element ultrasound transducers, a portable desktop PAT system was developed. This second-generation PLD-based PAT achieved 0.5 s cross-sectional imaging time with high spatial resolution of ∼165 µm and an imaging depth of 3 cm. The performance of this system was characterized using phantom and in vivo studies. Dynamic in vivo imaging was also demonstrated by monitoring the fast uptake and clearance of indocyanine green in small animal (rat) brain vasculature.

Metabolizable Semiconducting Polymer Nanoparticles for Second Near-Infrared Photoacoustic Imaging.

Photoacoustic (PA) imaging in the second near-infrared (NIR-II) window (1000-1700 nm) holds great promise for deep-tissue diagnosis due to the reduced light scattering and minimized tissue absorption; however, exploration of such a noninvasive imaging technique is greatly constrained by the lack of biodegradable NIR-II absorbing agents. Herein, the first series of metabolizable NIR-II PA agents are reported based on semiconducting polymer nanoparticles (SPNs). Such completely organic nanoagents consist of π-conjugated yet oxidizable optical polymer as PA generator and hydrolyzable amphiphilic polymer as particle matrix to provide water solubility. The obtained SPNs are readily degraded by myeloperoxidase and lipase abundant in phagocytes, transforming from nonfluorescent nanoparticles (30 nm) into NIR fluorescent ultrasmall metabolites (≈1 nm). As such, these nanoagents can be effectively cleared out via both hepatobiliary and renal excretions after systematic administration, leaving no toxicity to living mice. Particularly these nanoagents possess high photothermal conversion efficiencies and emit bright PA signals at 1064 nm, enabling sensitive NIR-II PA imaging of both subcutaneous tumor and deep brain vasculature through intact skull in living animals at a low systematic dosage. This study thus provides a generalized molecular design toward organic metabolizable semiconducting materials for biophotonic applications in NIR-II window.

Contrast-enhanced photoacoustic imaging in the second near-infrared window using semiconducting polymer nanoparticles.

Photoacoustic imaging (PAI) is a fast growing deep-tissue imaging modality. However, light scattering and absorption in biological tissues limit imaging depth. Short near-infrared wavelengths (650 to 950 nm) are widely used for PAI. Using longer near-infrared wavelengths reduces scattering. We demonstrate deep-tissue contrast-enhanced in vivo photoacoustic imaging at a wavelength of 1064 nm. An ultranarrow bandgap semiconducting polymer poly (thienoisoindigo-alt-diketopyrrolopyrrole) (denoted as PIGD) is designed and demonstrated for imaging at 1064 nm. By embedding colloidal nanoparticles (NPs) of PIGD in chicken-breast tissue, an imaging depth of ∼5 cm is achieved. Intravenous injection of PIGD NPs in living rats showed brain vascular images with ∼2 times higher contrast compared with the brain vascular images without any contrast agent. Thus, PIGD NPs as an NIR-II contrast agent opens new opportunities for both preclinical and clinical imaging of deep tissues with enhanced contrast.

Compact Plasmonic Blackbody for Cancer Theranosis in the Near-Infrared II Window.

We have developed a class of blackbody materials, i. e., hyperbranched Au plasmonic blackbodies (AuPBs), of compact sizes (<50 nm). The AuPBs were prepared in a seedless and surfactant-free approach based on the use of mussel-inspired dopamine. Strong intraparticle plasmonic coupling among branches in close proximity leads to intense and uniform broadband absorption across 400-1350 nm. The blackbody absorption imparts the compact AuPB with a superior photothermal efficiency of >80% and closely matched photothermal activity in the first near-infrared (NIR-I) and the second near-infrared (NIR-II) spectral windows, making it a rare broadband theranostic probe for integrated photoacoustic imaging and photothermal therapy (PTT). Our comparative study, using the same probe, has demonstrated that the improved PTT outcome of NIR-II over NIR-I primarily results from its higher maximum permission exposure (MPE) rather than the deeper tissue penetration favored by longer wavelengths. The compact plasmonic broadband nanoabsorbers with tailored surface properties hold potential for a wide spectrum of light-mediated applications.

Fast photoacoustic imaging systems using pulsed laser diodes: a review.

Photoacoustic imaging (PAI) is a newly emerging imaging modality for preclinical and clinical applications. The conventional PAI systems use Q-switched Nd:YAG/OPO (Optical Parametric Oscillator) nanosecond lasers as excitation sources. Such lasers are expensive, bulky, and imaging speed is limited because of low pulse repetition rate. In recent years, the semiconductor laser technology has advanced to generate high-repetitions rate near-infrared pulsed lasers diodes (PLDs) which are reliable, less-expensive, hand-held, and light-weight, about 200 g. In this article, we review the development and demonstration of PLD based PAI systems for preclinical and clinical applications reported in recent years.

Amphiphilic semiconducting polymer as multifunctional nanocarrier for fluorescence/photoacoustic imaging guided chemo-photothermal therapy.

Chemo-photothermal nanotheranostics has the advantage of synergistic therapeutic effect, providing opportunities for optimized cancer therapy. However, current chemo-photothermal nanotheranostic systems generally comprise more than three components, encountering the potential issues of unstable nanostructures and unexpected conflicts in optical and biophysical properties among different components. We herein synthesize an amphiphilic semiconducting polymer (PEG-PCB) and utilize it as a multifunctional nanocarrier to simplify chemo-photothermal nanotheranostics. PEG-PCB has a semiconducting backbone that not only serves as the diagnostic component for near-infrared (NIR) fluorescence and photoacoustic (PA) imaging, but also acts as the therapeutic agent for photothermal therapy. In addition, the hydrophobic backbone of PEG-PCB provides strong hydrophobic and π-π interactions with the aromatic anticancer drug such as doxorubicin for drug encapsulation and delivery. Such a trifunctionality of PEG-PCB eventually results in a greatly simplified nanotheranostic system with only two components but multimodal imaging and therapeutic capacities, permitting effective NIR fluorescence/PA imaging guided chemo-photothermal therapy of cancer in living mice. Our study thus provides a molecular engineering approach to integrate essential properties into one polymer for multimodal nanotheranostics.

Dynamic in vivo imaging of small animal brain using pulsed laser diode-based photoacoustic tomography system.

We demonstrate dynamic in vivo imaging using a low-cost portable pulsed laser diode (PLD)-based photoacoustic tomography system. The system takes advantage of an 803-nm PLD having high-repetition rate ∼7000 Hz combined with a fast-scanning single-element ultrasound transducer leading to a 5 s cross-sectional imaging. Cortical vasculature is imaged in scan time of 5 s with high signal-to-noise ratio ∼48. To examine the ability for dynamic imaging, we monitored the fast uptake and clearance process of indocyanine green in the rat brain. The system will find applications to study neurofunctional activities, characterization of pharmacokinetic, and biodistribution profiles in the development process of drugs or imaging agents.

A High-performance Compact Photoacoustic Tomography System for In Vivo Small-animal Brain Imaging.

In vivo small-animal imaging has an important role to play in preclinical studies. Photoacoustic tomography (PAT) is an emerging hybrid imaging modality that shows great potential for both preclinical and clinical applications. Conventional optical parametric oscillator-based PAT (OPO-PAT) systems are bulky and expensive and cannot provide high-speed imaging. Recently, pulsed-laser diodes (PLDs) have been successfully demonstrated as an alternative excitation source for PAT. Pulsed-laser diode PAT (PLD-PAT) has been successfully demonstrated for high-speed imaging on photoacoustic phantoms and biological tissues. This work provides a visualized experimental protocol for in vivo brain imaging using PLD-PAT. The protocol includes the compact PLD-PAT system configuration and its description, animal preparation for brain imaging, and a typical experimental procedure for 2D cross-sectional rat brain imaging. The PLD-PAT system is compact and cost-effective and can provide high-speed, high-quality imaging. Brain images collected in vivo at various scan speeds are presented.

Broadband Absorbing Semiconducting Polymer Nanoparticles for Photoacoustic Imaging in Second Near-Infrared Window.

Photoacoustic (PA) imaging holds great promise for preclinical research and clinical practice. However, most studies rely on the laser wavelength in the first near-infrared (NIR) window (NIR-I, 650-950 nm), while few studies have been exploited in the second NIR window (NIR-II, 1000-1700 nm), mainly due to the lack of NIR-II absorbing contrast agents. We herein report the synthesis of a broadband absorbing PA contrast agent based on semiconducting polymer nanoparticles (SPN-II) and apply it for PA imaging in NIR-II window. SPN-II can absorb in both NIR-I and NIR-II regions, providing the feasibility to directly compare PA imaging at 750 nm with that at 1064 nm. Because of the weaker background PA signals from biological tissues in NIR-II window, the signal-to-noise ratio (SNR) of SPN-II resulted PA images at 1064 nm can be 1.4-times higher than that at 750 nm when comparing at the imaging depth of 3 cm. The proof-of-concept application of NIR-II PA imaging is demonstrated in in vivo imaging of brain vasculature in living rats, which showed 1.5-times higher SNR as compared with NIR-I PA imaging. Our study not only introduces the first broadband absorbing organic contrast agent that is applicable for PA imaging in both NIR-I and NIR-II windows but also reveals the advantages of NIR-II over NIR-I in PA imaging.

Self-quenched semiconducting polymer nanoparticles for amplified in vivo photoacoustic imaging.

Development of photoacoustic (PA) imaging agents provides opportunities for advancing PA imaging in fundamental biology and medicine. Despite the promise of semiconducting polymer nanoparticles (SPNs) for PA imaging, the molecular guidelines to enhance their imaging performance are limited. In this study, semiconducting polymers (SPs) with self-quenched fluorescence are synthesized and transformed into SPNs for amplified PA imaging in living mice. The self-quenched process is induced by the incorporation of an electron-deficient structure unit into the backbone of SPs, which in turn promotes the nonradiative decay and enhances the heat generation. Such a simple chemical alteration of SP eventually leads to 1.7-fold PA amplification for the corresponding SPN. By virtue of the targeting capability of cyclic-RGD, the amplified SPN can effectively delineate tumor in living mice and increase the PA intensity of tumor by 4.7-fold after systemic administration. Our study thus provides an effective molecular guideline to amplify the PA brightness of organic imaging agents for in vivo PA imaging.

Activatable Photoacoustic Nanoprobes for In Vivo Ratiometric Imaging of Peroxynitrite.

Organic semiconducting nanoprobes doped with bulky borane can undergo specific activation by ONOO- even at tumor-relevant acidic pH (6.8), permitting in vivo ratiometric photoacoustic imaging of ONOO- in the tumor environment of living mice.

Near-infrared light-responsive liposomal contrast agent for photoacoustic imaging and drug release applications.

Photoacoustic imaging has become an emerging tool for theranostic applications. Not only does it help in