Sonosensitizers with Various Imaging Functions: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Mingxin Zhang.

With the rapid development of sonodynamic therapy (SDT), sonosensitizers have evolved from traditional treatments to comprehensive diagnostics and therapies. Sonosensitizers play a crucial role in the integration of ultrasound imaging (USI), X-ray computed tomography (CT), and magnetic resonance imaging (MRI) diagnostics while also playing a therapeutic role.

  • sonodynamic therapy
  • sonosensitizers
  • clinical

1. Contrast-Enhanced Ultrasound (CEUS)

Ultrasound (US) is a sound wave with a frequency of more than 20,000 Hz that is inaudible to the human ear. Ultrasound has the advantages of low-cost, simple, rapid, non-invasive, non-radioactive, accurate, continuous, dynamic, and repeatable scans [43,56,57][1][2][3]. Using the physical properties of ultrasound, various cross-sectional images of organs and surrounding organs can be displayed, which is close to the anatomical real structure. Therefore, ultrasound is often used as the first choice for the examination of solid organs and fluid-containing organs. In particular, ultrasound elastography and contrast-enhanced ultrasound (CEUS) are well established as being used for diagnosis. In CEUS, intravenously injected microbubbles are excited by longitudinal ultrasound in the examined area, producing nonlinear oscillations. The corresponding contrast agent software can distinguish the diseased tissues from the received contrast agent signals [58][4]. However, currently, 78.5% of radiology departments use diagnostic ultrasound imaging as a routine diagnostic imaging method, while only 26% of them use contrast-enhanced ultrasound [58][4]. The excessively expensive price of ultrasound contrast agents and their lower selectivity limited the clinical application of CEUS. It was found that some sonosensitizers used for SDT treatment also showed promising results in CEUS. Table 1 lists the sonosensitizers and imaging capabilities used for CEUS imaging. Sonosensitizers produce stable microbubbles (MBs) or nanobubbles (NBs) under CEUS cavitation to achieve enhanced imaging [59,60,61][5][6][7]. Sonosensitizers achieve synergistic drug delivery and tumor therapy by affecting the lesion’s tissue structure. Therefore, with the development of sonosensitizers, the clinical application of contrast-enhanced ultrasound is becoming more and more broad.
Table 1.
US Imaging Characteristics of the Multifunctional Sonosensitizers.
Sonosensitizers Probes Biological Model SDT Result Imaging Effect Ref.
Molecules 28 06484 i001

PCF-MBs		 PCF HT-29 cancer-bearing Balb/c

nude mice		 tumor

inhibition rate of more than 50%		 20 s post-injection,

the US imaging signal reached the maximum; and the contrast

enhancement could last for more than 3 min		 [49][8]
Molecules 28 06484 i002

FMSN-DOX		 FMSNs TRAMP

tumor-bearing nude mice		 The gradual reduction in tumor growth from day 1 to day 9 with significant contrast enhancement within the tumor. [45][9]
Molecules 28 06484 i003

HMME/MCC-HA		 MCC NPs MCF-7 tumor-bearing nude mice successfully suppressed the tumor volume

with the V/V0 of 0.87 ± 0.13		 strong US signals in tumor site at 3 h post-injection,

and particularly after exposure to US stimulus		 [8][10]
Molecules 28 06484 i004

Lip-AIPH		 AIPH
]. CT has become a popular noninvasive clinical imaging method because of its reproducibility, low price, and ease of use [74][24]. CT scans are divided into conventional and enhanced scans according to whether contrast media is used or not. Since plain CT cannot distinguish between tissues with similar mass attenuation coefficients (e.g., normal organs and tumors), exogenous X-ray attenuating CT contrast materials need to be injected intravenously to identify diseased tissues. Iodine contrast is commonly used in clinical practice but has the following limitations: (1) susceptibility to allergic reactions and nephrotoxicity; (2) low dose-efficiency ratio; and (3) lack of targeting. Studies have investigated the utilization of sonosensitizers as CT imaging agents to overcome the shortcomings of commonly used clinical contrast agents. Table 2 lists the sonosensitizers and imaging capabilities used for CT imaging.
Table 2.
CT Imaging Characteristics of the Multifunctional Sonosensitizers.
Sonosensitizers Probes Biological Model Treatment Result Imaging Effect Ref.
Molecules 28 06484 i016

MnWOX-PEG		 W(CO)6 4T1 tumor-bearing mice Tumor weight drop CT imaging signal intensity was almost 2.4 times higher than that of the control group [44][25]
Molecules 28 06484 i017

AgBiS2@DSPE-PEG2000-FA		 AgBiS2 HeLa tumor-bearing mice Tumor size drop The CT signal intensity at the tumor site gradually increased and peaked at 6h after the injection [48][26]
Molecules 28 06484 i018

Au-TiO2-A-TPP		 Au-TiO2 MCF-7 tumor-bearing mice Tumor weight drop The CT signal in the tumor area reached its maximum at 24 h [51][27]
MCF-7 tumor-bearing mice a highly significant antitumor effect was achieved in

mice in the group of Lip-AIPH with US irradiation a highly significant antitumor effect was achieved in

mice in the group of Lip-AIPH with US irradiation		 [62]
Molecules 28 06484 i019

GMCDS-FA@CMC		[11 Au@mSiO2]
orthotopic colorectal tumor Decreased number and smaller diameter of colorectal tumors The nanoprobe remained in the colorectal

region [
[26] developed an AgBiS2@DSPE-PEG2000-FA (ABS-FA) with good biosafety and active targeted CT imaging capability that combined photothermal and ultrasound kinetic treatment capabilities. It was found that ABS-FA had significant targeting in tumor tissues in vivo, and the CT signals at the site of the tumor were steadily enhanced after ABS-FA (300 μL, 5 mg/mL) injection, reaching a peak at 6–12 h. However, the non-targeted ABS-NH2 signals did not change at different time points at the tumor site. The results of low-power (0.35 W/cm2) infrared thermography were consistent with those of CT, which showed that the thermal signal appeared 2 h after drug injection and reached its maximum 10 h after injection.
Zhang et al. [75][28] constructed a novel oral nanoparticle, Au@mSiO2/Ce6/DOX/SLB-FA@CMC (GMCDS-FA@CMC), that endowed the pH/ultrasonic dual-response to realize the combination of SDT with chemotherapy for colorectal cancer treatment. After oral delivery of GMCDS-FA@CMC, a well-defined tumor CT signal was observed in situ in colorectal cancer model mice and persisted for 7–9 h. It was found that the enteric-coated particles possessed good CT imaging effects in vivo by oral delivery and could be used to direct SDT-chemotherapy for colorectal cancer treatment.

3. Magnetic Resonance Imaging (MRI)

Since the first implementation of MRI in 1973 as a non-invasive and multi-contrast detection method, MR imaging has been widely used in various biomedical fields [76][29]. MRI can reflect tissue lesions by combining parameters such as flow effects and electromagnetic wave-related proton density after the excitation of strong magnetic field pulses and the formation of magnetic resonance phenomena through hydrogen atoms in human water molecules [77][30]. The images are also processed with the aid of computer technology to obtain an excellent diagnosis of the pathology, which has high spatial and tissue resolution [78,79,80][31][32][33]. Therefore, it is extensively utilized clinically in the diagnosis and prognostic status of various diseases. Magnetic resonance imaging is not sensitive, but this obstacle can be overcome by exogenous contrast agents by decreasing the relaxation time of bulk water [80,81][33][34]. It was found that appropriate contrast agents are important for enhancing the susceptibility and specificity of diagnosis, enhancing the degree of signal contrast, and improving the resolution of soft tissue images for clinical application [76][29]. For example, with the help of gadolinium (Gd)-based T1 agents, information about the boundaries of brain tumors can be observed more clearly [82][35]. In recent years, some new nuclear magnetic sensitizers containing Mn and Fe have been applied to MRI tumor imaging [83,84][36][37]. Table 3 lists the sonosensitizers and imaging capabilities used for MRI imaging.
Table 3.
MR Imaging Characteristics of the Multifunctional Sonosensitizers.
Sonosensitizers Probes Biological Model SDT Result Imaging Effect Ref.
Molecules 28 06484 i020

UPFB		 MOFs (Fe3+) U14 tumor-bearing Kunming mice increased inhibition of tumor growth enhanced T2 contrast signal [84][37]
Molecules 28 06484 i021

Fe-TiO2 NDs		 Fe3+ 4T1 tumor-bearing mice better

tumor inhibition		 The brightening effect through the T1-weighted MR images [85][38]
Molecules 28 06484 i022

Fe-VS2-PEG		 Fe3+ 4T1 cells

subcutaneously in BALB/c mice		 better treatment

effect and a longer survival period		 the tumor had an obvious brightening effect 24 h after i.v. injection (T1) [83][36]
75][28]
Molecules 28 06484 i023

OCN-PEG-(Ce6-Gd3+)/BNN6		 Ga3+ 4T1 tumor-bearing mice the tumor suppression rate reached 63.2% The T1-weighted contrast effect was significantly enhanced [52][39] Molecules 28 06484 i005

mTiO2@PPY-HNK
Molecules 28 06484 i024

mTiO2 4T1 tumor model significantly inhibit the tumor growth as the concentration increases, the ultrasound signal is more intense and the image is clearer MnSiO3[63][12]
-Pt@BSA-Ce6(MPBC) Mn2+ U14 tumor-bearing Balb/c mice tumor growth inhibition the T1−MR signal of the tumor enhanced [86][40] Molecules 28 06484 i006

OIX_NPs		 PFP ID8

cells into the left shoulder (the primary tumor)		 significant inhibition of tumor volume peaking at 4 h post-injection. [64][13]
Molecules 28 06484 i025

MG@P NPs		 PMnC (Mn) 4T1 tumor-bearing mice the tumor growth of

Mice remarkably suppressed		 T1 signal of the tumor region showed an increasing trend within 24 h and then decreased [87][41] Molecules 28 06484 i007

TPZ/HMTNPs-SNO		 HMTNPs-SNO MCF-7 tumor-bearing nude mice exhibited an effective therapeutic

effect		 compared with the saline group, showed local enhancement at the tumor site.
Molecules 28 06484 i026

F3-PLGA@MB/Gd NPs		[65][14]
Gd-DTPA-BMA the nude mice bearing MDA-MB-231 tumors induce tumor cell apoptosis Linear signal dependence of T1 intensity values [46][42] Molecules 28 06484 i008

IR780-NDs		 PFP
Molecules 28 06484 i027breast cancer 4T1 nude mice

Tumor weight drop Ang-IR780-MnO24 h after the injection of IR780-NDs a bright US signal occurred at the

tumor site.		 2-PLGA (AIMP) MnO2 U87MG

tumor-bearing mice		 enhanced SDT effect A linear relationship was shown between the 1/T1

values and Mn concentration[47][15]
[88][43 Molecules 28 06484 i009

SMISO NPs		 SMISO 4T1 tumor-bearing nude mice the

inhibition rate of tumor growth in the SMISO + US group

reached 88.2%		 the grayscale values of US images increase with them.

concentration increases		 [66][16]
]
Molecules 28 06484 i028

DOX/Mn-TPPS@RBCS		 Mn-TPPS MCF-7 tumor-bearing nude mice Inhibit tumor growth T1-weighted MR imaging results in enhancement [89][44] Molecules 28 06484 i010

RPPs&SPIOs		 RPPs 4T1 tumors a 100% survival rate of mice at 90 days Shift in RPPs after thermal stimulation results in significant contrast enhancement
Molecules 28 06484 i029

MnTTP-HSA		[ MnTTP (Mn)67][ MCF-7 tumor-bearing nude mice17]
the best in completely inhibiting tumor a T1

the positive signal at the tumor showed an increasing trend within

3 h and then gradually decreased		 [90][45] Molecules 28 06484 i011

FA-PEG-PLGA-Ptx@ICG-Pfh NPs		 Pfh MDA-MB231 tumor-bearing mice tumor growth was significantly inhibited images were greatly improved [68][18]
Molecules 28 06484 i030

mZMD		 MnO2 HeLa tumor xenograft-bearing nude mice significant suppression

effects		 the concentration of the NCs increased, the T1 MR images became brighter and brighter [91][46] Molecules 28 06484 i012

RBC-HPBs/HMME/PFH
Molecules 28 06484 i031

PFH GdHF-NDs Ga4T1 tumor-bearing female

mice		 enhancing tumor treatment effects of HMME 3+ CT26 tumor-bearing miceA clear US signal was observed at 4 h after injection, and the strongest signal appeared at 8 h. GdHF-NDs/PEG + US

shows the most potent efficiency in tumor suppression (73.7%)		 T1 signal strength increased[69][19]
Molecules 28 06484 i013

Ce6-PFP-DTX/PLGA		 PFP breast cancer 4T1 nude mice much higher inhibition rate of the CPDP NPs + LIFU group after LIFU irradiation, the corresponding intensity

of CPDP NPs was elevated compared with the

pre-irradiation group		 [70][20]
Molecules 28 06484 i014

AS1411-DOX-PFH-PEG@PLGA		 PFH breast cancer 4T1 nude mice the tumor volumes significantly decreased Increased imaging ability of ADPPs in vivo within 24 h after intravenous injection [71][21]
Molecules 28 06484 i015

RB-MBs		 MBs HT-29 tumor mouse

model		 - a contrast-enhanced ultrasound imaging mode at a frequency of 5 MHz [72][22]
Chen M. et al. [49][8] reported a liposomal nanoparticle based on porphyrin/camptothecin-floxuridine triad microbubbles (PCF-MBs). The novel PCF-MB not only realized ultrasound imaging but also achieved chemo-photodynamic combination therapy. After intravenously injecting 1 mg/mL of PCF-MBs into Balb/c nude mice bearing HT-29 colon cancer, the ability of PCF-MBs to potentiate ultrasound imaging was investigated by a fixed-frequency ultrasound transducer. The results showed that before the injection, there was hardly any sonographic signal in the tumor. The ultrasound imaging signals peaked 20 s after injection, and the peak state lasted more than 3 min.
Zhang et al. [66][16] synthesized a composite system in which Mn-doped In2S3/InOOH (SMISO) is loaded in spinodal silica (r-SiO2) to integrate ultrasound imaging and SDT for the detection and treatment of breast cancer. The live Type B US imaging results showed that the grayscale was changed after injection of SiO2, MISO, or SMISO solutions in the 4T1 breast tumor model, and there was a statistical difference between SMISO and the control group (p < 0.01), suggesting SMISO could achieve ultrasound imaging. Further, it was found that the signal intensity increased after SMISO NPs injection and peaked at 12 h, guiding the optimal time for ultrasound irradiation. And then, 12 h after the NPs injection, the signal intensity gradually decreased until it disappeared, indicating that the NPs were eliminated from the tumor. Under US irradiation, the SMISO NPs effectively inhibited tumor growth. In summary, the nanoplatform simultaneously had therapeutic efficacy and imaging capability.
Zhang L et al. [47][15] fabricated an innovative nanoplatform capable of multimodal (FLI/PAI/USI) imaging using IR780 and perfluoropentane (PFP), as well as guiding SDT for tumor treatment. After intravenous injection of IR780-NDs, researchers acquired enhanced ultrasound images of xenograft tumors in nude mice with 4T1 breast cancer. At 24 h after administration in the caudal i.v., the US signal in CEUS mode showed brightness. In addition, the quantification data indicated that the echo intensity was much stronger in the post-injection group than in the pre-injection group.

2. X-ray Computed Tomography (CT)

CT scanning utilizes a computer to process a combination of several X-ray images acquired from different angulations to develop an anatomical picture of the scanned object [73][23
Cao et al. [51][27] designed and synthesized titanium oxide (TiO2) nanosheets with triphenylphosphine (TPP) and AS1411 aptamer structure to realize mitochondria-targeted, CT imaging, and sonodynamic-chemotherapy for cancer treatment. Relative to the control group, Au-TiO2-A-TPP-treated mice displayed significant CT signals at the tumor sites, which validated the capability of Au-TiO2-A-TPP to diagnose tumors by CT imaging in vivo. As the concentration of Au-TiO2-A-TPP increased, the brightness and CT values of CT images increased, suggesting a linear relationship between CT grayscale values and concentration. As mentioned previously, contrast agents commonly used in clinical practice may not be appropriate for patients with renal insufficiency, who may be better suited for contrast agents with a short half-life in vivo and low nephrotoxicity. Surprisingly, the half-life of Au-TiO2-A-TPP in the blood circulation of mice was only 4.71 h, indicating Au-TiO2-A-TPP was very promising for patients with renal insufficiency.
Cheng K et al. [48]
[
78
]
[
31
]
Lei et al. [83][36] recommended iron-doped vanadium disulfide nanosheets (Fe-VS2 NSs) as novel sonosensitizers modified with polyethylene glycol (PEG) to achieve the combination of SDT with chemodynamic therapy (CDT) for cancer therapy. Fe-VS2-PEG NSs have magnetic resonance imaging capability and strong tumor inhibility in vivo. At 24 h after intravenous administration of Fe-VS2-PEG, MR imaging of the tumor demonstrated significant enhancement, and the quantitative analysis showed that signal strength was 2.04 times stronger than that before administration. In addition, the concentration of Fe-VS2-PEG NSs was positively correlated with MR signal intensity.
Wang et al. [84][37] designed and constructed Janus nanostructures called UPFB, consisting of upconversion nanoparticles (UCNPs) (NaYF4:20%Yb, 1%Tm@NaYF4:10% Yb@NaNdF4) and porphyrin-based metal organic frameworks (MOFs) (PCN-224(Fe)). UPFB promoted ROS production by GSH depletion and oxygen supply and realized the integration of SDT and chemodynamic therapy (CDT) for oncology treatment under MRI guidance. Compared with the UPF group, the UPFB group darkened overtime at the tumor site, indicating that the T2 contrast signal was enhanced and the accumulation of UPFB was in a time-related manner. UPFB was highly enriched in tumor tissues by quantitative analysis of the biodistribution of Zr and Fe elements by inductively coupled plasma mass spectrometry (ICP-MS)). Furthermore, the circulation half-life of UPFB was calculated to be 3.381 h. All these results suggested that the UPFB possessed excellent tumor target ability and could be utilized as a contrast agent for T2-weighted.
Guan et al. [91][46] reported a novel biodegradable nanomaterial derived from a mesoporous zeolitic-imidazolate framework@MnO2/doxorubicin hydrochloride (ZIF-90@MnO2/DOX, mZMD NCs) to achieve T1-weighted MRI-guided SDT/CDT/chemotherapy. It was found that the MR image brightness increased with the concentration of mZMD NCs. After 8 h of intravenous administration, the tumor region was significantly brighter for imaging, indicating that mZMD NCs can effectively aggregate at the tumor site and release Mn2+ for T1-weighted MR imaging. The mZMD NCs showed good biocompatibility and biosafety and effectively suppressed the growth of tumor cells.

4. Multi-Modal Imaging

All imaging methods have their disadvantages: MRI has the characteristics of long acquisition time and low space coverage; CT has the risk of ionizing radiation; and the US has limited penetration ability [92,93,94,95][47][48][49][50]. Single-modality imaging cannot meet the growing demand for accuracy and reliability in clinical diagnostics or clinical research [96][51]. The combined application of multiple testing techniques has become a hot research topic, complementing each other’s advantages and realizing more precise diseases [97][52]. Compared with single-mode imaging, multimode imaging achieves multiple imaging functions through a single nanomaterial, providing a basis for accurate cancer diagnosis [98][53]. To date, several nanoparticle-based bimodal co-imaging materials have been reported to achieve better imaging and treatment.
Wang et al. [99][54] prepared hollow CoP@N-carbon@PEG (CPCs@PEG) nanospheres (∼60 nm) as sonosensitizers to inhibit tumor growth by promoting ROS production under US irradiation. With the incorporation of cobalt ions, which had magnetic properties and X-ray attenuation coefficients, CPCs@PEG were capable of both CT and MRI. Further, the authors also performed MRI imaging studies in vivo using 4T1 tumor-bearing mice as a model. After the injection of CPC10@PEG, the contrast of the cancer site became darker. In addition, the researchers conducted a CT imaging capability study. With the increase in CPC10@PEG concentration, the CT signal was gradually enhanced. The researchers also investigated the in vivo CT imaging capabilities of CPC10@PEG, which showed a significant increase in the brightness of the cancer site after intravenous injection compared with pre-injection.
Gong et al. [44][25] designed and prepared a novel high-performance multifunctional sonosensitizer built on ultramicroscopic oxygen-deficient bimetallic oxide MnWOX nanoparticles for multimodal imaging-guided SDT for cancer therapy. The MnWOX-PEG nanoparticles exhibited effective SDT effects by producing 1O2 and ·OH and possessed the glutathione depletion capability to enhance the SDT efficacy. MnWOX-PEG exhibited good biosafety and excellent tumor growth suppression in mice under ultrasound irradiation. Due to the high attenuation of X-rays by the W element, MnWOX-PEG can also be applied in CT imaging and as a reduction agent for T1 in magnetic resonance imaging. The findings indicated that after 24 h of intravenous injection of MnWOX-PEG 4T1, the tumor-bearing mice showed significant CT (2.4 times) and MRI (1.8 times) signals in the tumor site. These multimodal imaging results demonstrated that MnWOX-PEG can efficiently accumulate in tumors, and sonosensitizers had diagnostic imaging capabilities and assisted in the precise treatment of tumors with SDT.

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