Xiao Yang†
b,
Zeyu Jiang†b,
Jiayong Dai*c,
Qinrui Fu
*b and
Shuhan Pan*a
aDepartment of Emergency Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266003, China. E-mail: panshe88@126.com
bInstitute of Chronic Disease, College of Medicine, Qingdao University, Qingdao 266021, China. E-mail: fuqinrui2022@qdu.edu.cn
cDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou 310016, China. E-mail: daijy@zju.edu.cn
First published on 23rd April 2025
Photoacoustic (PA) imaging is a burgeoning imaging modality that has a broad range of applications in the early diagnosis of cancer, detection of various diseases, and relevant scientific research. It is a non-invasive imaging modality that relies on the absorption coefficient of the imaging tissue and the injected PA-imaging contrast agent. Nevertheless, PA imaging exhibits weak imaging depth due to its exponentially decaying signal intensity with increasing tissue depth. To improve the depth and heighten the contrast of imaging, a series of PA contrast agents has been developed based on nanomaterials. In this review, we present a comprehensive overview of recent advancements in contrast agents for photoacoustic (PA) imaging, encompassing the emergence of first near-infrared region (NIR-I, 700–950 nm) PA contrast agents, second near-infrared region (NIR-II, 1000–1700 nm) PA contrast agents, and ratiometric PA contrast agents. Subsequently, the latest advances in PA image-guided cancer therapy were introduced, such as photothermal therapy (PTT), photodynamic therapy (PDT), sonodynamic therapy (SDT), and PTT-based synergistic therapy. Finally, the prospects of PA contrast agents and their biomedical applications were also discussed. This review provides a systematic summary of the development and utilization of the cutting-edge photoacoustic agents, which may inspire fresh thinking in the fabrication and application aspects of imaging agents.
PA-imaging technology provides a unique advantage as the US wave signals obtained possess negligible scattering and dissipation in biological tissue, allowing for deeper tissue imaging compared to other optical imaging techniques.9–11 Nonetheless, the exponential decay of light intensity and the PA signal-to-noise ratio (SNR) with increasing tissue depth due to strong light absorption/scattering by the skin, blood, and tissue necessitates the development of suitable PA imaging contrast agents, which has become an immediate and significant challenge.12–14
Various nanomaterials can play a significant part in the early diagnosis, treatment, and monitoring of illnesses due to their particular physical and chemical features.15–17 With the acceleration of nanotechnology development, numerous nanomaterial-based contrast agents for PA imaging have been developed with high molar extinction coefficients, excellent photostability, and high biocompatibility.18,19 Diverse contrast agents for PA imaging, including the first near-infrared (NIR) region (NIR-I, 700–950 nm) PA contrast agents, the second NIR region (NIR-II, 1000–1700 nm) PA contrast agents, and ratiometric PA contrast agents, have been presented.20–22
Additionally, the integration of diagnosis and treatment into one nanocarrier is a hot topic of current research. Since theranostics integrates diagnostic and therapeutic functions, it has obvious advantages over a single diagnostic or therapeutic tool.23 Nanomaterials with integrated diagnosis and treatment functions can accurately diagnose the disease in real-time and treat it simultaneously, providing direct evidence for the early diagnosis, development, and progress of the disease and exhibiting broad clinical prospects.24,25
Despite the existence of numerous studies in the field of PA imaging, there is a dearth of comprehensive reviews that specifically focus on its application in guiding cancer treatment, as far as knowledge extends. Herein, this review systematically summarizes the PA contrast agents and their biomedical applications (Fig. 1). The usable PA contrast agents are comprehensively overviewed and classified into three different categories, NIR-I PA contrast agents, NIR-II PA contrast agents, and ratiometric PA contrast agents, based on their wavelengths and imaging capabilities for PA imaging. Additionally, attention has also been paid to their synthesis methods. Next, the latest advances in PA-imaging-guided cancer therapy are presented as well, which include photothermal therapy (PTT), photodynamic therapy (PDT), sonodynamic therapy (SDT), and PTT-based synergistic therapy. Lastly, the challenges and perspectives related to PA imaging and PA contrast agents’ development are discussed.
Although PA imaging is a promising biomedical imaging method, the lack of highly effective contrast agents drastically limited its further clinical application. For instance, some endogenous contrast agents, such as hemoglobin, chromophores, and lipids, have the ability to convert light energy into PA signals that carry characteristic information when exposed to laser irradiation. However, the endogenous contrast agents show considerable tissue background noise, limited tissue penetration ability, and restricted imaging site selection based on them.47–49 Exhilaratingly, the development of scientific instruments and imaging techniques in recent years enabled numerous exogenous contrast agents to generate enough PA signals in vivo or in specific pathological tissues, providing pathological information about diseases.50,51
It has been proved that NIR-II PA imaging (1000–1700 nm) is more suitable for improving the spatial resolution and penetration depth of in vivo imaging compared to NIR-I PA imaging (700–950 nm), as its longer wavelength reduces light scattering and minimizes thermal tissue damage.52–54 However, NIR-II PA imaging still faces significant challenges due to the absence of imaging contrast agents with NIR-II absorption and PA conversion capabilities. To address this challenge, this review article presents an overview of three categories of PA contrast agents that have been reported previously: (1) NIR-I PA contrast agents, (2) NIR-II PA contrast agents, and (3) ratiometric PA contrast agents (Table 1).
Classification | Advantages | Disadvantages | Ref. |
---|---|---|---|
NIR-I PA contrast agents | Improving PA-imaging contrast and resolution by locally enhancing tissue absorption performance compared with endogenous PA contrast agents | Limited tissue-penetration depth; the signal-to-noise ratio is relatively low | 55 and 56 |
NIR-II PA contrast agents | Higher tissue-penetration depth; the scattering effect of biological tissue on photons is significantly inhibited | Potential toxicity; low quantum yields and lack of optimization of imaging systems | 57–60 |
Ratiometric PA contrast agents | Built-in self-calibration, enabling more sensitive and reliable detection | Complex synthesis and fine molecular design | 61–63 |
Gold nanomaterials are famous for their various nanostructures such as gold nanorods (AuNRs),66,67 gold nanospheres (AuNSp),68 gold nanostars (AuNSts),69 and gold nanocages (AuNCs),70 having been broadly used for biomedical applications such as PA-imaging contrast agents. One such example is that Cheng et al. prepared the AuNRs with a length of 40 ± 5 nm and a width of 8 ± 3 nm, which have near-infrared absorption at 800 nm and can be used as a contrast agent for PA imaging (Fig. 3A).71 In vivo experiments conducted by Cheng and colleagues showed that this nanomaterial effectively targeted triple negative breast cancer sites and the process could be monitored through PA imaging. Changing the size of NPs, interparticle distance, etc., can adjust optical scattering and absorption, resulting in the enhancement of PA contrast.9 Li et al. reported poly(ethylene glycol) coated (PEGylated) hollow AuNSps with a size of 40–50 nm,72 whose optical absorption at 520 nm was shifted to 800 nm by adjusting the structure and size of AuNSps. These AuNSps have been verified to be highly efficient PA contrast agents for blood vessel imaging (Fig. 3B). AuNSts are another PA contrast agent with tunable LSPR in the visible-NIR range (Fig. 3C).73 Lu et al. designed long-chain amine/carboxy-terminated polyethylene glycol (PEG)-modified AuNSts with an LSPR band at 780 nm.74 These AuNSts have preeminent biocompatibility and can be used as a PA contrast agent. AuNCs are gold nanomaterials with hollow interiors and porous thin-walled structures that possess light absorption ability in the range of 600–1200 nm (Fig. 3D).75 Tao et al. constructed AuNC-based nanoagents for targeting lymph nodes (LNs), which can also act as a suitable contrast agent for PA imaging. Additionally, in vivo PA imaging allowed for the real-time visualization of AuNC build-up to track the immune process. Therefore, metallic and semimetallic nanomaterials, especially gold nanomaterials, have shown promising potential for use as contrast agents for PA imaging in biomedical applications.
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Fig. 3 SEM and TEM images of different inorganic NIR-I PA contrast agents. (A) Nanorods, (B) nanospheres, (C) nanostars, (D) nanocages, (E) WS2-PEG, (F) CuS, (G) CuInS/ZnS, (H) CNTR@AuNPs, and (I) r-GO-AuNR. (A) Reproduced with permission.71 Copyright 2018, Wiley-VCH. (B) Reproduced with permission.72 Copyright 2010, Elsevier. (C) Reproduced with permission.73 Copyright 2012, IOP Publishing Ltd. (D) Reproduced with permission.75 Copyright 2008, American Chemical Society. (E) Reproduced with permission.76 Copyright 2014, Wiley-VCH. (F) Reproduced with permission.77 Copyright 2017, American Chemical Society. (G) Reproduced with permission.78 Copyright 2016, American Chemical Society. (H) Reproduced with permission.79 Copyright 2015, American Chemical Society. (I) Reproduced with permission.80 Copyright 2016, American Chemical Society. |
Transition metal chalcogenides are semiconductor nanocrystals with strong NIR absorption due to energy band transitions that have demonstrated great application potential in the fields of physics, chemistry, and materials science.81–83 Chalcogenides/MXene-based nanomaterials, such as copper sulfide (CuS), tungsten sulfide (WS2), and molybdenum sulfide (MoS2), are widely used in PA imaging as contrast agents, ascribed to their strong absorbance in the NIR region.84–86 For instance, Liu and colleagues fabricated a PEGylated WS2 nanosheet (WS2-PEG) with a strong absorbance in the NIR region (700–950 nm) for PA imaging (Fig. 3E).76 CuS has high photothermal conversion efficiency, low cytotoxicity, simple fabrication procedure, and is considerably cost-effective, thus becoming a contrast agent with high popularity for PA-imaging research (Fig. 3F).77 Additionally, the combination of two different transition metal compounds can also be used for PA imaging. Being well proved, CuInS/ZnS quantum dots (QDs) can achieve tumor site monitoring via PA imaging and meanwhile mediate photoinduced tumor ablation (Fig. 3G).78
Conversely, carbon nanomaterials, such as graphene-based nanomaterials and carbon nanotubes (CNTs), have been widely used as contrast agents in the biomedical field due to their superior photostability, biocompatibility, and ease of manufacture compared to gold nanomaterials.87–92 Carbon-based nanomaterials also have broad absorbance in the ultraviolet to NIR region, making them ideal candidates for PA imaging. For instance, Lim et al. prepared a carbon nanotube ring (CNTR)-based PA contrast agent (CNTR@AuNPs), whose PA intensity was about two orders of magnitude higher than that of CNTR due to the enhanced absorption of NIR light by the heterogeneous system, and the heat transfer resistance of gold nanoparticles to the surrounding signal generating medium was greatly reduced (Fig. 3H).79 In addition, Chen et al. designed a new type of rGO-coated AuNR (rGO-AuNR) PA contrast agent (Fig. 3I).80 Under laser irradiation, the interaction between the plasmonic AuNPs and the rGO led to an enhancement of the photocurrent of the rGO, thereby enhancing its photothermal properties and enabling strong NIR absorption and good PA-imaging capabilities.
Furthermore, quantum dots have garnered extensive attention due to their merits such as an ultrathin structure, high specific surface area, distinctive photoelectric characteristics, and favorable biological safety. Sun et al. fabricated titanium ligand (TiL4) coordinated black phosphorus quantum dots (BPQDs) as an efficient PA agent for cancer bioimaging.93 After the injection of TiL4@BPQDs, the PA signals in the tumor are conspicuously enhanced. The PA signal intensities in the tumor area are 21.49 ± 3.16 and 31.58 ± 2.42 a.u. At 4 h post-injection, robust PA signals as high as 120.80 ± 5.40 a.u. can be detected from the tumor.
Metal–organic frameworks (MOFs), composed of metal ions coordinated by organic linkers, have emerged as a promising category of functional materials and garnered extensive attention in numerous distinct areas including PA contrast agents. From the perspective of biomedicine, nanoscale MOFs with excellent biocompatibility, biodegradability, ultrahigh porosity, and tunable pore size are ideal nanocarriers for transporting chemotherapy drugs and photosensitizers. Zhou et al. developed a nanoscale porphyrin–palladium metal–organic framework (PdH-MOF) with highly dispersed Pd atoms serving as hydrogen carriers to effectively load highly reductive hydrogen for the tumor-targeted PA-imaging-guided hydrogenothermal therapy of cancer.94 After the intravenous injection of PdH-MOF nanoparticles for 1 h, an obvious PA signal emerged within the tumor region, and the signal intensity remained at a relatively high and stable level for 24 h, demonstrating great potential for the subsequent PA-imaging guidance of hydrogenothermal therapy.
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Fig. 4 Schematic diagrams and representative characterization images of organic NIR-I PA contrast agents. (A) Schematic diagram for the preparation of HSA-ICG NPs. (B) TEM image of HSA-ICG NPs. (C) Schematic diagram of the self-assembled macromolecular probes (PCBP) for PA imaging. (D) Schematic diagram for the preparation of cRGD-PDI NPs. (E) TEM image of cRGD-PDI NPs. (F) Schematic illustration of the preparation of SPNs via nanoprecipitation. (G) PA images of SPNs in solution. (A and B) Reproduced with permission.98 Copyright 2014, American Chemical Society. (C) Reproduced with permission.100 Copyright 2017, Wiley-VCH. (D and E) Reproduced with permission.101 Copyright 2017, American Chemical Society. (F and G) Reproduced with permission.102 Copyright 2015, Wiley-VCH. |
Semiconducting polymers with conjugated structures have been developed for use as PA contrast agents. Compared to small molecule organic dyes, these semiconducting polymers have better photothermal stability and can be readily combined with other imaging modalities and therapeutic approaches.103–105 Formerly, Pu et al. reported a semiconductor macromolecular probe (PCBP), which had NIR-absorbing hydrophobic phthalocyanine and four hydrophilic PEG chains. The probe had a ROS-responsive linker, causing a significantly enhanced PA signal in the presence of ROS (Fig. 4C).100 Organic semiconductor NPs, such as perylene-diimide (PDI), are also favourable for PA imaging, benefiting from their high stability and excellent optoelectronic properties.106,107 Fan and his team designed cRGD-PDI NPs with an extinction coefficient of 2.58 × 108 M−1 cm−1, an organic semiconductor NP consisting of amphiphilic perylene-3,4,9,10-tetracarboxylic diimide molecules and cyclic Arg–Gly–Asp (cRGD) (Fig. 4D and E).101 These NPs were used for contrast-enhanced PA imaging of thrombus in living mice and produced a significant increase in PA intensity at the thrombus sites after intravenous injection.
Semiconductor polymer nanoparticles (SPNs) are a novel class of optically and electronically active nanomaterials consisting mainly of semiconductor polymers (SPs). SPNs have high absorption coefficients and controllable size,108,109 and are unique candidates for development as contrast agents for PA imaging. SPNs can expeditiously transform photonic energy into acoustic waves.110 For example, Pu et al. reported a series of low-bandgap diketopyrrolopyrrole-based SPNs for in vivo PA imaging (Fig. 4F).102 The differences in backbone structures among SPN1-4 lead to changes in the nature of the electron donor, which, in turn, affects the PA intensity variation. SPN4 showed the highest PA intensity, primarily due to the electron-donating ability of its corresponding structural unit (Fig. 4G), suggesting that SPN4 has great potential for in vivo tumor imaging.
The longer wavelength of NIR-I results in less absorption and scattering by biological tissues compared with visible light.111,112 As a result, NIR-I region PA-imaging contrast agents are suitable for imaging biological tissues like the skin and produce high-quality images. However, NIR-I region PA-imaging contrast agents have certain limitations, such as the presence of significant background noise that can adversely affect both imaging depth and contrast.55,113 In comparison to NIR-I PA contrast agents, NIR-II PA contrast agents demonstrate enhanced efficacy in mitigating the scattering and absorption of incident light by biological tissues.114 Thus, NIR-II PA contrast agents have become a current research hotspot since they can significantly improve imaging contrast.
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Fig. 5 TEM images and schematic diagrams of different inorganic NIR-II PA contrast agents. (A) AuPBs, (B) AuNRs, (C) ZrO2-x-B@SiO2-HA, (D) Bi NPs, (E) CuS@BSA-RGD NPs, and (F) Meso-CNs. (G) Preparation process of MNPs and schematic diagram for multimodal imaging. (H) Schematic diagram of P1 formation. (I) Chemical structure of various NPs and preparation method of SPN. (A) Reproduced with permission.117 Copyright 2018, American Chemical Society. (B) Reproduced with permission.118 Copyright 2023, Wiley-VCH. (C) Reproduced with permission.119 Copyright 2020, Royal Society of Chemistry. (D) Reproduced with permission.120 Copyright 2017, American Chemical Society. (E) Reproduced with permission.121 Copyright 2018, Royal Society of Chemistry. (F) Reproduced with permission.122 Copyright 2018, Ivyspring. (G) Reproduced with permission.123 Copyright 2014, American Chemical Society. (H) Reproduced with permission.28 Copyright 2018, Wiley-VCH. (I) Reproduced with permission.124 Copyright 2019, Wiley-VCH. |
NIR-II PA contrast agents have outstanding potential for cancer diagnosis and treatment. Consequently, researchers have devoted a great amount of effort to exploring different types of contrast agents that can be used for PA-imaging-guided tumor-targeted phototherapy in the NIR-II window. Studies have shown that metallic element Zr and semimetallic element Bi are both effective PA contrast agents with low toxicity and few side effects. For instance, Shen et al. reported a ZrO2-based phototheranostic agent (ZrO2-x-B@SiO2-HA) that enables PA-imaging-guided tumor-targeted phototherapy in the NIR-II window (Fig. 5C).119 The ZrO2-x-B had a high NIR-II PA-imaging ability and photothermal conversion efficiency owing to its composition of oxygen vacancies and boron doping. Therefore, it had the potential to perform precise NIR-II radiation-activated PA-imaging-guided cancer treatment. For another example, Li and co-workers constructed ultrasmall semimetal NPs of bismuth (Bi-LyP-1 NPs) with high tumor aggregation (Fig. 5D).120 The Bi-LyP-1 NPs with brilliant photothermal conversion efficiency could be used for PA imaging and efficient treatment. The results not only indicated that Bi-based nanomaterials can also be used as contrast agents for PA imaging, but also demonstrated the great promise of semimetallic NPs in biomedical applications.
CuS NPs with high SNR are also an excellent PA contrast agent candidate due to their excellent NIR-II absorption property, low toxicity, and competent biodegradability.125–127 Zhang et al. designed CuS@BSA-RGD NPs by conjugating the ultrasmall CuS NPs with the cyclic arginine–glycine–aspartate (cRGD) peptide and extraordinary optical absorption in the NIR-II window could be achieved (Fig. 5E).121 After intravenous injection of the NPs, the area of hepatocellular carcinoma in situ in mice was visualized with highly sensitive PA images, indicating that CuS has great potential to be applied in cancer diagnosis and treatment.
In addition to metallic and semimetallic nanomaterials, as well as transition metal-based nanomaterials, carbon-based nanomaterials have also received much consideration in the biomedical field for their excellent optical properties.128,129 Wu et al. reported successful construction of mesoporous carbon nanospheres (Meso-CNs) with wideband and strong absorption in NIR-I and NIR-II windows (Fig. 5F).122 The Meso-CNs exhibited good photothermal conversion and PA signal generation ability and could potentially serve as a PA contrast agent for cancer diagnosis.
Additionally, conjugated polymers (CP) have been popularly used in PA-imaging-guided therapy as an attractive PA contrast agent, with superior optical features for photo-controlled drug delivery.130 Liu et al. synthesized a CP-based NIR-II PA contrast agent (P1) that showed good biocompatibility and superior PA stability in orthotopic brain tumor imaging (Fig. 5H).28 Furthermore, SPNs are a novel optical contrast agent with excellent photothermal conversion efficiency and photostability.131 Therefore, Pu and colleagues reported a kind of SPN-based metabolizable NIR-II nanoagent for in vivo biomarker detection and cancer therapy (Fig. 5I).124 The SPNs showed outstanding NIR-II PA-imaging performance for deep brain vasculature and subcutaneous tumors of live mice.
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Fig. 6 Representative ratiometric PA contrast agents. (A) TEM images of Au–Pd@Ag. (B) Proposed mechanism of Au–Pd@Ag for the detection of H2O2. (C) Chemical structures of hCy7 and hCy7′. (D) Proposed mechanism of LP-hCy7 for the detection of H2O2. (E) Chemical structure of the CS, ORM, OIM, and RSPN sensing mechanisms. (A) and (B) Reproduced with permission.132 Copyright 2020, Wiley-VCH. (C) and (D) Reproduced with permission.133 Copyright 2017, Wiley-VCH. (E) Reproduced with permission.134 Copyright 2021, American Chemical Society. |
Universally, dye-based nanomaterials have been used as one of the PA contrast agents because of their good biocompatibility and biodegradability.56 Huang et al. developed a PA sensor (LP-hCy7) consisting of liposomes (LP) and MeHg+-responsive NIR anabolic dye (hCy7) that exhibited high sensitivity and selectivity for MeHg+ (Fig. 6C).133 MeHg+ entered the lipid layer of LP-hCy7 and converted hCy7 to hCy7′ via a mercury-promoted cyclization reaction. The absorbance of the nanoprobe increased and decreased at 690 nm and 860 nm, respectively (Fig. 6D). Thus, the PA signal ratio (PA860/PA690) can be used as an indicator for MeHg+ detection in vitro and in vivo.
SPNs, being broadly explored as PA contrast agents for their good biocompatibility, can also be utilized as a ratiometric PA contrast agent.135 Zhang and co-workers synthesized a novel ratiometric semiconductor polymer nanoparticle (RSPN) (Fig. 6E), which provided a noninvasive tool for the diagnosis of atherosclerosis.134 In vivo experiments showed that the PA signal ratio of the RSPN (PA690/PA800) was positively correlated with the level of oxidative stress in mice. These results proved that the RSPN enabled the accurate measurement of O2˙− levels in complex physiological environments.
Classification | Merits | Drawbacks | Advantages of PA image-guided therapies | Ref. |
---|---|---|---|---|
PTT | Oxygen independent; tumor tissue thermal ablation; spatiotemporal selectivity. | Heat-shock response; inadequate tissue-penetration of light results in an unsatisfactory therapeutic efficacy for deep tumors; potential for thermal damage to surrounding healthy tissues. | Provides rapid and efficient tumor ablation accompanied by real-time imaging monitoring. | 141–145 |
PDT | High spatiotemporal precision; minimal damage to normal tissue; limited or no potential for resistance. | Limited light penetration; oxygen dependence and hypoxic in TME restrict treatment efficiency. | Provides real-time and high-resolution imaging of tumor oxygenation and photosensitizer distribution; facilitates precise treatment planning and monitoring of therapeutic response. | 146–150 |
SDT | Compared with PDT, SDT has a deeper penetration depth; overcomes the oxygen dependence of PDT, rendering it effective for hypoxic tumors. | Lack of suitable sonosensitizers due to most sonosensitizers having low bioavailability. | Imaging information determines the starting time point of SDT. | 151–155 |
Synergistic therapy | Improve the therapeutic effect; remove the limitations of using monotherapy. | The augmentation of complexity in treatment planning and optimization. | Imaging-guided synergistic therapy is beneficial for enhancing treatment efficiency. | 156–160 |
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Fig. 7 PA-imaging-guided PTT. (A) Synthesis pathway of Ru-Phen CPNs and schematic diagram of PTT therapy. (B) With the change of the concentration of Ru-Phen CPNs, the corresponding PA intensity changes. (C) PA images of tumors at various time points after intravenous administration of Ru-Phen CPNs in 4T1 tumor-bearing mice. (D) Infrared thermography of mice after intravenous injection of CPNs under 808 nm irradiation. (E) Changes of tumor volume in mice after various treatments. (F) Schematic diagram of biosynthetic melanin NPs for PA-imaging-guided PTT. (G) PA images of tumor areas in 4T1 tumor-bearing mice before and after intravenous administration of melanin NPs and (H) corresponding PA signal intensities at various time points. (I) The change of cancer tissue temperature with time after different treatments. (J) Images of tumor-bearing mice after different treatments and (K) corresponding tumor growth curves of 4T1 tumor-bearing mice. (L) Survival curve of 4T1 tumor-bearing mice. (A–E) Reproduced with permission.167 Copyright 2019, Ivyspring. (F–L) Reproduced with permission.168 Copyright 2022, Wiley-VCH. |
SPNs, which are also excellent PTT agents apart from their PA-imaging contrast agent property, are widely employed in PA-imaging-guided photothermal therapy.167,169 Lee et al. constructed a brand-new type of electron donor (5,5′-dibromo 4,4′-bis(2-octyldodecyl)-2,2′-dithiophene)–acceptor (5,6-difluoro-4,7-bis5-(trimethylstannyl)thiophen-2-ylbenzo-2,1,3-thiadiazole) conjugated SPN (PPorPEG NPs).170 The PA-imaging data showed that PPorPEG NPs accumulated efficiently at the tumor site, and reached a maximum signal intensity at 12 h post-injection, giving the optimal time to utilize their photothermal properties for PTT. Consequently, the tumors regressed completely due to the PA-imaging-guided PTT.
Personalized precision medicine using nanotherapeutic agents has attracted great interest and enthusiasm for its applications in the diagnosis of diseases. In addition, the use of melanin as a contrast agent in PA imaging is a significant development in the field of biomedicine.171 Yan et al. developed a melanin NP, which displayed high photothermal conversion efficiency (48.9%) and NIR region absorption for PA-imaging-guided PTT in vivo (Fig. 7F).172 Intravenous injection of melanin NPs followed by two hours of 808 nm laser irradiation resulted in excellent PA-imaging performance and PTT effects. As shown in Fig. 7G and H, the PA signal intensity of the cancer cell site was maximum after two hours of injection, indicating a maximum enrichment and the best time for PTT. The cancer cell region of the mouse was irradiated with an 808 nm laser at 2 h post-injection based on the location information provided by PA imaging. After 10 minutes of laser irradiation, the tumor temperature in the melanin + laser group was remarkably higher than that in the control group, and the cancer cell was entirely abated at 22 days after treatment (Fig. 7I–K). Moreover, the survival rate of mice improved significantly after intravenous injection of melanin NPs under NIR laser irradiation (Fig. 7L). Hence, melanin NPs offer us a new approach for developing phototherapeutic agents with excellent PA-imaging performance and PTT effect under 808 nm laser irradiation.
An ideal photothermal agent is expected to possess a high photothermal conversion effect, low biological toxicity, and degradability. The development of novel photothermal therapy agents featuring these properties is highly demanded. Guo et al. synthesized boron quantum dots (BQDs) with an ultrasmall hydrodynamic diameter for photoacoustic imaging-guided photothermal therapy. The BQDs demonstrate high photoacoustic imaging contrast performance due to their significant absorption in the near-infrared region. BQDs also exhibit good photothermal conversion capability, which can effectively convert near-infrared light into heat to eliminate cancer cells.173 Zhou et al. designed an activatable NIR-II plasmonic theranostic system founded on silica-encapsulated self-assembled gold nanochains (AuNCs@SiO2) for precise tumor diagnosis and efficacious treatment. This transformable chain configuration transcends the conventional molecular imaging window, and its absorption can be redshifted from the visible to the NIR-II region due to the fusion among adjacent gold nanoparticles within the restricted local space of AuNCs@SiO2, which is triggered by the elevated H2O2 level in the tumor microenvironment, resulting in the formation of a new string-like structure with robust NIR-II absorption. This is further confirmed by finite-difference-time-domain (FDTD) simulation. With the tumor microenvironment-activated transformable chain structure, AuNCs@SiO2 demonstrated outstanding properties for photoacoustic imaging and a high photothermal conversion efficiency of 82.2% at 1064 nm, leading to severe cell death and remarkable tumor growth inhibition in vivo.168
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Fig. 8 PA-imaging-guided PDT. (A) Schematic illustration of IrCy NPs for PA-imaging-guided PDT. (B) PA imaging in tumors at different time points before and after intravenous injection of IrCy NPs. (C) Fluorescence spectrum of ABDA changes in the presence of IrCy NPs under laser irradiation. (D) Changes in tumor volume with time after different treatments. (E) Proposed mechanism of DBBC-UiO for photoinduced PDT. (F) ESR spectra of TEMP for O2˙− detection. (G) ESR spectra of DMPO for 1O2 detection. (H) DBBC-UiO concentration is positively correlated with PA signal intensity. (I) Changes in PA imaging in vivo before and after DBBC-UiO injection. (J) Change curve of tumor volume in mice after 16 days of different treatments. (A–D) Reproduced with permission.176 Copyright 2019, Ivyspring. (E–J) Reproduced with permission.177 Copyright 2022, Wiley-VCH. |
However, one of the major characteristics of solid tumors in the tumor microenvironment (TME) is hypoxia, which can lead to unsatisfactory PDT outcomes.178,179 To address these drawbacks, Zhang et al. prepared a multifunctional metal–organic framework (MOF) nanosheet (DBBC-UiO) that could effectively alleviate the problem of hypoxia in the TME.177 DBBC-UiO acted as a photosensitizer (PS) to produce 1O2 under NIR light irradiation and could generate a large amount of O2˙− in the severe hypoxic microenvironment through the type I mechanism (Fig. 8E). Using 2,2,6,6-tetramethylpiperidine (TEMP) and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as 1O2 and O2˙− indicators, respectively, the ESR spectra showed good 1O2 and O2˙− generating ability of DBBC-UiO under light irradiation (Fig. 8F and G). After intravenous injection of DBBC-UiO, the PA signal intensity in the cancer tissue of mice was remarkably enhanced with the increasing concentration of the DBBC-UiO (Fig. 8H). Moreover, the peak value of the PA signal was reached at 12 h post-injection due to the accumulation of DBBC-UiO at the tumor site, which was considered as the optimal treatment time point (Fig. 8I). Moreover, given the PA-imaging result, the precise release of 1O2 and O2˙− and efficient reduction of tumor volume were accomplished by the DBBC-UiO + light treatment group (Fig. 8J), where the hypoxic environment was effectively mitigated and the tumor growth was obviously inhibited.
Boron dipyrromethene (Bodipy) dyes, as a type of representative organic small molecule, have been extensively utilized as fluorescent probes due to their high absorption coefficients and fluorescent quantum yields, low dark toxicity, and excellent photostability. Liu et al. developed an NIR excitable PS (Bodipy–Ir) with the PAI property by coupling a Bodipy derivative with Ir(III). Under 808 nm excitation, Bodipy–Ir could generate a considerable amount of singlet oxygen and exhibit photoacoustic properties. Bodipy–Ir NPs were intravenously administered into the A549 tumor-bearing mice via the tail vein. Two hours after injection, the PAI of the tumor was observed, and the signal increased over time, reaching a maximum at 12 h.180 Hypoxia, a prominent characteristic of hepatocellular carcinoma (HCC), undermines therapeutic outcomes, elevates recurrence rates, and promotes metastasis, particularly during PDT in clinical scenarios. Zeng et al. developed a biomimetic oxygen delivery system denoted as BLICP@O2, which employs hybrid tumor cell membranes and thermosensitive liposomes as oxygen carriers, incorporating the NIR-II dye IR1048, the photosensitizer Ce6, and perfluorohexane. Upon sequential irradiation at 1064 and 690 nm, BLICP@O2 demonstrates significant photothermal and photodynamic effects. Photothermal heating triggers oxygen release, enhancing the photodynamic effect of Ce6. Blood oxygen alterations during PDT are monitored by multispectral PA imaging. The enhanced PDT efficacy, mediated by hypoxia alleviation, is convincingly demonstrated both in vitro and in vivo. This work presents an imaging-guided, dual-wavelength programmed cascaded treatment strategy for tumor-targeted oxygen delivery and controlled release, with real-time efficacy surveillance using PA imaging, providing valuable insights for surmounting the challenges in PDT-based cancer therapy.181
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Fig. 9 PA-imaging-guided SDT. (A) Schematic illustration of FHMP NPs for PA-imaging-guided SDT of cancer cells. (B) Changes in DPBT consumption under different treatments. (C) Relationship between PA signal intensity and different particle concentrations. (D) Changes in PA image of mouse tumor area with time after different treatments and (E) corresponding PA signal value. (F) Changes in tumor volume after different treatments. (G) Proposed mechanism of the nano-prodrug for PA imaging enhanced SDT against tumor cells. (H) Percentage of SO2 produced by different concentrations of P-DOA NPs. (I) PA images of tumors in mice at various time points after different treatments and (J) corresponding PA signal. (K) Changes in melanin volume in mice after different treatments. Changes in (L) tumor volume and (M) weight in squamous cell carcinoma mice after 17 days of different treatments. (A–F) Reproduced with permission.184 Copyright 2018, Ivyspring. (G–M) Reproduced with permission.185 Copyright 2022, Wiley-VCH. |
Reductive effect of the GSH content in the tumor region has become a primary problem that must be solved, as GSH can attenuate SDT-mediated ROS damage, which in turn reduces the efficacy of SDT. Inspired by this, Xiao et al. reported a nano-prodrug (P-DOA NPs) for PA-imaging-guided SDT of malignant melanoma and squamous cell carcinoma (SCC) (Fig. 9G).185 The nano-prodrug, consisting of dual prodrug molecules (DOA), was capable of releasing sulfide dioxide (SO2), 5-aminolevulinic acid (ALA), and methoxyl poly(ethylene glycol)-b-poly(L-lysine) (mPEG-b-PLL). In the TME, P-DOA NPs disintegrated and DOA could react with overexpressed GSH to release SO2 and ALA (Fig. 9H). On the one hand, ALA can be specifically transformed to protoporphyrin IX (PpIX) in the TME via the heme synthesis pathway in mitochondria for SDT and PA imaging. On the other hand, the release of SO2 and the consumption of GSH can dramatically enhance the intracellular ROS level in the tumor location, leading to enhanced SDT. After intravenous injection, P-DOA NPs efficiently accumulated at 12 h post-injection in tumor guided by PA imaging, which was selected as the optimal time point for SDT (Fig. 9I and J). Then, in vivo anti-tumor experiment results further proved that the P-DOA NPs + US treated group showed effectively suppressed tumor growth (Fig. 9K–M). Therefore, under the direction of real-time PA imaging, P-DOA NPs can achieve distinguished elimination of melanoma and SCC xenografts in mice, and ultimately realize the purpose of malignant cancer treatment.
SDT holds considerable promise as a therapeutic modality for treating atherosclerotic plaque. Nevertheless, the therapeutic efficacy of SDT is impeded by the limited tissue-penetration depth and the insufficient generation of reactive oxygen species (ROS) associated with conventional sonosensitizers. Moreover, determining the optimal timing for US irradiation subsequent to the administration of sonosensitizers poses a significant technical challenge. Addressing these issues is of paramount importance for enhancing the effectiveness of SDT in clinical applications. Fu et al. fabricated hyaluronic acid-modified US-propelled Janus mesoporous SiO2 partially coated gold nanorods loaded with 2,2-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH), along with functionalized Ag/Ag2S nanoparticles (HA-JASAA), for NIR-II fluorescence imaging-guided SDT of atherosclerotic plaque.186 After intravenous administration of HA-JASAA, the hyaluronic acid modification enables specific targeting of proinflammatory macrophages within atherosclerotic plaques. Subsequently, upon reaction with H2O2 in the atherosclerotic microenvironment, the NIR-II fluorescence signal is activated. When the intensity of the NIR-II fluorescence signal reaches its peak, US irradiation is applied; the AIPH loaded in HA-JASAA is converted into nitrogen, propelling HA-JASAA to deeply penetrate into plaque tissue. Moreover, under US activation, two sonosensitizers, AIPH and Ag2S, respectively, generate oxygen-independent and oxygen-dependent ROS to induce the apoptosis of lesional macrophages, thereby significantly inhibiting the progression of atherosclerotic plaque. These results demonstrated the translational potential of HA-JASAA-mediated NIR-II fluorescence imaging-guided SDT for the treatment of atherosclerotic plaques.
Phototherapy plays an important role in cancer treatment and includes PTT and PDT.196,197 However, the PSs used in PDT often have poor water solubility and photostability, and PTT hyperthermia can cause heat shock, causing unsatisfactory therapeutic efficacy and failure to achieve the intended treatment outcome.198,199 Facing these challenges, a growing number of researchers proposed that the combination of PTT and PDT using similar light-triggered conditions can significantly improve the therapeutic effect.200 Dong et al. demonstrated this synergistic effect by developing donor–acceptor–donor (D–A–D) structured NPs (DPP-TPA NPs), which take advantage of the thiophene group-containing diketopyrrolopyrrole (DPP) to enhance NIR-absorption and semiconducting functions, and also make use of triphenylamine (TPA) to improve bathochromic shift absorption and charge transport capacity by reprecipitation (Fig. 10A).201 Intriguingly, the DPP-TPA NPs exhibited enhanced PA-imaging ability and PA signal intensity (Fig. 10B), and demonstrated excellent 1O2 generation ability (ΦΔ = 33.6%) and photothermal conversion efficiency (η = 34.5%). After intravenous injection, the DPP-TPA NPs were found to accumulate at the tumor location, which was verified by PA-imaging information (Fig. 10C and D), enabling highly effective tumor therapy upon NIR light irradiation. The integration of PTT and PDT well reduced the tumor volume (Fig. 10E and F), illustrating the effectiveness, safety, and accuracy of the DPP-TPA NP platform in PA-imaging-guided phototherapy, along with the broad promise of DPP-TPA NPs for future use.
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Fig. 10 PA-imaging-guided synergistic therapy. (A) Schematic representation of DPP-TPA NP-guided PDT/PTT therapy via PA imaging. (B) PA image changes as the concentration of DPP-TPA NPs rises. (C) Following intravenous injection of DPP-TPA NPs, the PA images of tumor locations in tumor-bearing animals altered over time and (D) corresponding PA intensity. (E) Infrared thermal images of mice after different treatments. (F) Changes in tumor volume over time in different treatment groups. (G) Schematic diagram of CuS@BSA-HMONs-DOX in vivo PA-imaging-guided PTT/chemotherapy synergistic therapy. (H) Relationship between Cu concentration and PA signal intensity. (I) PA images of tumor-bearing animals taken before and after intravenous administration of CuS@BSA-HMONs-DOX NPs. (J) DOX release curves before and after GSH addition of CuS@BSA-HMONs-DOX at various pH levels. (K) Changes in tumor site temperature over time after intravenous administration of CuS@BSA-HMONs-DOX NPs. (L) Changes in tumor volume after different treatments. (A–F) Reproduced with permission.201 Copyright 2016, American Chemical Society. (G–L) Reproduced with permission.202 Copyright 2022, Elsevier. |
CDT represents an emerging anti-cancer strategy that has the ability to inhibit tumor growth and metastasis.203 Nonetheless, there are still limitations such as the high GSH content in the TME that leads to insufficient endogenous H2O2, and the unmatched optimal reaction pH of Fenton-like reaction with the TME, making it difficult to eliminate tumors.204,205 Consequently, the combination of CDT with other therapies has become a future direction in cancer treatment. It is noteworthy that Wei et al. developed a new kind of CoFeMn dichalcogenide nanosheet (CFMS NSs), which had excellent PA-imaging capability for guiding PTT/CDT synergistic therapy.206 CFMS NSs also exhibited brilliant photothermal properties, and the solutions’ temperature increased with the increase of material concentration under laser irradiation. Due to the conversion of overexpressed H2O2 to toxic ˙OH in tumor cells in the presence of Co and Fe and the reduction of intracellular GSH by Mn, cytotoxic ROS were massively produced in CFMS NS-treated tumor cells. Around 8 h after intravenous injection, the CFMS NSs reached maximal accumulation at the tumor site, as shown by in vivo PA imaging. Based on the PA-imaging results, the NIR and CFMS NS-treated group demonstrated notable tumor growth inhibition compared to other tested controls. This PA-imaging-guided-PTT/CDT synergistic therapy using CFMS NSs not only can significantly inhibit the proliferation of cancer cells, but also presents a new effective approach for cancer treatment.
In recent years, nanoplatforms for simultaneous cancer imaging and synergistic therapy have emerged as a new trend in cancer therapeutics.207 Even if chemotherapy has been widely used in many cancer therapeutic strategies, it also faces some drawbacks such as nonspecific distribution and rapid degradation of drugs,208,209 which may be eliminated by combining chemotherapy with other treatment modalities. For instance, studies have shown that when blood flow and oxygenation within the tumor were increased by mild hyperthermia treatments, tumor cells would become more sensitive to chemotherapy drugs, achieving better treatment effects.210 Gu and co-workers reported a biodegradable mesoporous organic silica NP (CuS@BSA-HMONs-DOX) based on biocompatible heterochemical (CuS@BSA) decorated mesoporous NPs for efficient PA-imaging-guided PTT/chemotherapy synergistic treatment of human osteosarcoma cancer (Fig. 10G).202 PA imaging showed that the PA signal was enhanced as the concentration of CuS@BSA-HMONs-DOX NPs increased (Fig. 10H). In particular, an acidic microenvironment will greatly increase the DOX release rate of CuS@BSA-HMONs-DOX NPs (Fig. 10J). Meanwhile, CuS@BSA-HMONs NPs have high photothermal conversion efficiency and could be used as a photothermal agent, which can obviously raise the temperature of the tumor site under 808 nm laser irradiation (Fig. 10K). This way, the PA signal of the tumor area was significantly brightened 4 h after the intravenous injection of CuS@BSA-HMONs-DOX NPs, reaching a maximum at 12 h after injection, which was clearly distinguishable from the surrounding normal tissues (Fig. 10I), indicating that CuS@BSA-HMONs-DOX NPs could accumulate in the tumor tissue via the enhanced permeability and retention (EPR) effect. In a Saos-2 tumor-bearing mouse model, the relative tumor volume has remarkably dwindled in the laser + CuS@BSA-HMONs NPs group when compared to the control group (Fig. 10L).
Despite the significant progress in disease diagnosis and treatment using PA contrast agents, considerable potential remains for further development. The development of PA contrast agents has ushered in a new era for the noninvasive diagnosis and treatment of diseases. By combining the advantages of different imaging technologies, PA-based multimodal contrast agents can non-invasively, in real-time, and specifically display complex biochemical processes in the body with high-resolution, providing more comprehensive and accurate information and achieving multimodal imaging-guided synergistic cancer treatment. Developing biomarker-targeted PA agents through specific biomarker optimization could enhance tumor precision while reducing nonspecific uptake by the reticuloendothelial system, particularly when utilizing TME biomarkers as responsive units. Endogenous biomarker-responsive PA agents show particular promise. Considering these developmental directions, attention must also be given to the biosafety, distribution, and biodegradability of PA contrast agents. Therefore, before clinical application, it is necessary to study the toxicity of PA contrast agents, improve their biocompatibility, and promote their clinical translation and regulatory approval.
In summary, with the extensive and systematic study of nanomaterials, we have reason to believe that PA contrast agents and PA-imaging-guided cancer therapy have broad application prospects in the biomedical field.
Footnote |
† Xiao Yang and Zeyu Jiang contributed equally to this work. |
This journal is © The Royal Society of Chemistry 2025 |