Contrast Agents

Photoacoustic contrast agents development

In spite of high intrinsic contrast in photoacoustic imaging, efforts have been put to develop contrast agents. Contrast agents not only help improving the contrast in the imaging, but it also help in molecular imaging. Recently, several groups are also working on developing theranostic contrast agent.

Contrast agent for second NIR window:

Most photoacoustic contrast agents developed are in the first near-infrared (NIR) window (650-900 nm), while few studies have been exploited in the second NIR window (1000-1700 nm), mainly due to the lack of NIR-II absorbing contrast agents. We reported a broadband absorbing PA contrast agent based on semiconducting polymer nanoparticles (SPN-II) for PA imaging in the NIR-II window. At 1064 nm SPN-II resulted better PA imaging compared with 750 nm when comparing at the imaging depth of 3 cm. More details can be found in Jiang et al., Nano Letters 17 (2017). We also reported the first series of SPN-based biodegradable NIR-II PA contrast agents with efficient in vivo clearance. By virtue of strong electron-withdrawing donor BBT, the obtained SPNs (SPN-PT, SPN-DT, and SPN-OT) had strong absorbance at ≈1079 nm and high η at 1064 nm. Taking advantage of oxidizable thiophene moiety in conjugated backbones and FDA-approved hydrolyzable polymer matrix (PLGA–PEG), three NIR-II SPNs could be effectively degraded in the presence of biologically abundant MPO and lipase, leading to the remarkable decomposition from 30 nm nanoparticles into NIR fluorescent ultrasmall nanoparticles (≈1 nm). Because of the ultrasmall hydrodynamic sizes of degradation products, these NIR-II SPNs could be effectively cleared from living mice via both renal and hepatobiliary excretions within 15 days post administration. As a representative agent, SPN-PT demonstrated excellent NIR-II PA imaging performance, achieving the high SBRs of 4.6 and 2.3, respectively, for tumor and brain vasculature in living mice at a systematic dosage lower than other reported agents. More details can be found in Jiang et al., Advanced Materials 31 (2019). In another study An ultra-narrow bandgap semiconducting polymers 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 to the brain vascular images without any contrast agent. Thus, PIGD NPs as a NIR-II contrast agent opens new opportunities for both preclinical and clinical imaging of deep tissues with enhanced contrast. More details can be found in Upputuri et al., Journal of Biomedical Optics 24 (2018). We also worked with hyperbranched Au plasmonic blackbody (AuPB) of compact sizes (< 50 nm) for NIR-II spectral window. 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). The compact plasmonic broadband nano-absorbers with tailored surface properties hold potentials for a wide spectrum of light-mediated applications. More details can be found in Zhou et al., ACS Nano 12 (2018). We also recently reported a new class of pH-sensitive charge-transfer nanocomplex (CTN) with strong absorption in the NIR-II window. The unique NIR-II-responsive CTN can specifically respond to pH change in the physiological range and allows noninvasive and sensitive visualization of the tumor acidic microenvironment (e.g., at pH 5) in mice with higher signal-to-noise ratio. The CTN is biodegradable under physiological conditions (e.g., pH 7.4), which alleviates the biosafety concern of nanoparticle accumulation in vivo. These results clearly show the potential of the CTN as a promising pH-activated and biodegradable molecular probe for specific tumor photoacoustic imaging in the NIR-II region. More details can be found in Wang et al., Nano Research 12 (2019).

Dual-functional theranostic agent:

Dual-functional theranostic materials integrating functionality of photoacoustic imaging and photothermal therapy using irnorganic materials have been reported. However, there inroganic materials still suffer from poor biocompatibility and biodegradibility. We reported a novel theranostic agent based on a narro-bandgap organic moecule, benzo[1,2-c;4,5-c']bis[1,2,5]thiadiazole-4,7-bis(9,9-dioctyl-9H-fluoren-2-yl)thiophene (denoted as BBT-2FT), with strong near infrared light absorption. It has shown 10 times stronger photoacoustic signal in comparison with blood and a very high photothermal conversion efficiency (40%). BBT-based nanoparticles are promising theranostic agent for cancer imaging and therapy. More details can be found in Huang et al., Journal of Materials Chemistry B 4 (2016).

Light-responsive liposomal contrast agent:

Near-infrared light-sensitive liposomes coated with gold nanostars (AuNSs) can be used for both imaging and drug release applications using photoacoustic imaging. Being amphiphilic, the liposomes lipid bilayer and the aqueous core enables encapsulation of both hydrophobic and hydrophilic drugs. The AuNSs on the surface of the liposomes act as photon absorbers due to their intrinsic surface plasmon resonance. Upon excitation by laser light at specific wavelength, AuNSs facilitates rapid release of the contents encapsulated in the liposomes due to local heating and pressure wave formation (photoacoustic wave). Due to its strong near-infrared light absorption they can also be used for photoacoustic contrast agent. More details can be found in Sivasubramanian et al., Journal of Biomedical Optics 22 (2017).

On-chip generation of microbubble for dual mode contrast agent:

Dual-modal photoacoustic (PA) and ultrasound (US) contrast agents are becoming increasingly popular in recent years. Here, a flow-focusing junction based microfluidic device is used for the generation of nitrogen microbubbles (<7 μm) in two photoacoustic contrast agents: methylene blue (MB) and black ink (BI). The microbubble diameter and production rate could be precisely controlled in both MB and BI solutions. Phantom and in vivo studies were done to characterise the performance of the dual mode contrast agent. More details can be found in Das et al., Scientific Reports 8 (2018).