A rationally designed nuclei-targeting FAPI 04-based molecular probe with enhanced tumor uptake for PET/CT and fluorescence imaging.

PURPOSE: Fibroblast activation protein inhibitor (FAPI) -based probes have been widely studied in the diagnosis of various malignant tumors with positron emission tomography/computed tomography (PET/CT). However, current imaging studies of FAPI-based probes face challenges in rapid clearance rate and potential false-negative results. Furthermore, FAPI has been rarely explored in optical imaging. Considering this, further modifications are imperative to improve the properties of FAPI-based probes to address existing limitations and broaden their application scenarios. In this study, we rationally introduced methylene blue (MB) to FAPIs, thereby imparting nuclei-targeting and fluorescence imaging capabilities to the probes. Furthermore, we evaluated the added value of FAPI-based fluorescence imaging to traditional PET/CT, exploring the potential application of FAPI-based probes in intraoperative fluorescence imaging. METHODS: A new FAPI-based probe, namely NOTA-FAPI-MB, was designed for both PET/CT and fluorescence imaging by conjugation of MB. The targeting efficacy of the probe was evaluated on fibroblast activation protein (FAP)-transfected cell line and human primary cancer-associated fibroblasts (CAFs). Subsequently, PET/CT and fluorescence imaging were conducted on tumor-bearing mice. The tumor detection and boundary delineation were assessed by fluorescence imaging of tissues from hepatocellular carcinoma (HCC) patients. RESULTS: NOTA-FAPI-MB demonstrated exceptional targeting ability towards FAP-transfected cells and CAFs in comparison to NOTA-FAPI. This benefit arises from the cationic methylene blue (MB) affinity for anionic nucleic acids. PET/CT imaging of tumor-bearing mice revealed significantly higher tumor uptake of [18F]F-NOTA-FAPI-MB (standard uptake value of 2.20 ± 0.31) compared to [18F]F-FDG (standard uptake value of 1.66 ± 0.14). In vivo fluorescence imaging indicated prolonged retention at the tumor site, with retention lasting up to 24 h. In addition, the fluorescent probes enabled more precise lesion detection and tumor margin delineation than clinically used indocyanine green (ICG), achieving a 100.0% (6/6) tumor-positive rate for NOTA-FAPI-MB while 33.3% (2/6) for ICG. These findings highlighted the potential of NOTA-FAPI-MB in guiding intraoperative surgical procedures. CONCLUSIONS: The NOTA-FAPI-MB was successfully synthesized, in which FAPI and MB simultaneously contributed to the targeting effect. Notably, the nuclear delivery mechanism of the probes improved intracellular retention time and targeting efficacy, broadening the imaging time window for fluorescence imaging. In vivo PET/CT demonstrated favorable performance of NOTA-FAPI-MB compared to [18F]F-FDG. This study highlights the significance of fluorescence imaging as an adjunct technique to PET/CT. Furthermore, the encouraging results obtained from the imaging of human HCC tissues hold promise for the potential application of NOTA-FAPI-MB in intraoperative fluorescent surgery guidance within clinical settings.

In vivo visualization of tumor-associated macrophages re-education by photoacoustic/fluorescence dual-modal imaging with a metal-organic frames-based caspase-1 nanoreporter.

Tumor-associated macrophages (TAMs) are vital in the tumor microenvironment, contributing to immunosuppression and therapy tolerance. Despite their importance, the precise re-education of TAMs in vivo continues to present a formidable challenge. Moreover, the lack of real-time and efficient methods to comprehend the spatiotemporal kinetics of TAMs repolarization remains a significant hurdle, severely hampering the accurate assessment of treatment efficacy and prognosis. Herein, we designed a metal-organic frameworks (MOFs) based Caspase-1 nanoreporter (MCNR) that can deliver a TLR7/8 agonist to the TAMs and track time-sensitive Caspase-1 activity as a direct method to monitor the initiation of immune reprogramming. This nanosystem exhibits excellent TAMs targeting ability, enhanced tumor accumulation, and stimuli-responsive behavior. By inducing the reprogramming of TAMs, they were able to enhance T-cell infiltration in tumor tissue, resulting in inhibited tumor growth and improved survival in mice model. Moreover, MCNR also serves as an activatable photoacoustic and fluorescent dual-mode imaging agent through Caspase-1-mediated specific enzyme digestion. This feature enables non-invasive and real-time antitumor immune activation monitoring. Overall, our findings indicate that MCNR has the potential to be a valuable tool for tumor immune microenvironment remodeling and noninvasive quantitative detection and real-time monitoring of TAMs repolarization to immunotherapy in the early stage.

In vivo liver function reserve assessments in alcoholic liver disease by scalable photoacoustic imaging.

We present a rapid and high-resolution photoacoustic imaging method for evaluating the liver function reserve (LFR). To validate its accuracy, we establish alcoholic liver disease (ALD) models and employ dual-wavelength spectral unmixing to assess oxygen metabolism. An empirical mathematical model fits the photoacoustic signals, obtaining liver metabolism curve and LFR parameters. Liver oxygen metabolism significantly drops in ALD with the emergence of abnormal hepatic lobular structure. ICG half-life remarkably extends from 241 to 568 s in ALD. A significant decline in LFR occurs in terminal region compared to central region, indicated by a 106.9 s delay in ICG half-life, likely due to hepatic artery and vein damage causing hypoxia and inadequate nutrition. Reduced glutathione repairs LFR with a 43% improvement by reducing alcohol-induced oxidative damage. Scalable photoacoustic imaging shows immense potential for assessing LFR in alcoholic-related diseases, providing assistance to early detection and management of liver disease.

Tumor Microenvironment Activated Photoacoustic-Fluorescence Bimodal Nanoprobe for Precise Chemo-immunotherapy and Immune Response Tracing of Glioblastoma.

Synergistic therapy strategy and prognostic monitoring of glioblastoma's immune response to treatment are crucial to optimize patient care and advance clinical outcomes. However, current systemic temozolomide (TMZ) chemotherapy and imaging methods for in vivo tracing of immune responses are inadequate. Herein, we report an all-in-one theranostic nanoprobe (PEG/αCD25-Cy7/TMZ) for precise chemotherapy and real-time immune response tracing of glioblastoma by photoacoustic-fluorescence imaging. The nanoprobe was loaded with TMZ and targeted regulatory T lymphocyte optical dye αCD25-Cy7 encapsulated by glutathione-responsive DSPE-SS-PEG2000. The results showed that the targeted efficiency of the nanoprobe to regulatory T lymphocytes is up to 92.3%. The activation of PEG/αCD25-Cy7/TMZ by glutathione enhanced the precise delivery of TMZ to the tumor microenvironment for local chemotherapy and monitored glioblastoma's boundary by photoacoustic-fluorescence imaging. Immunotherapy with indoleamine 2,3-dioxygenase inhibitors after chemotherapy could promote immunological responses and reduce regulatory T lymphocyte infiltration, which could improve the survival rate. Photoacoustic imaging has in real-time and noninvasively depicted the dynamic process of immune response on a micrometer scale, showing that the infiltration of regulatory T lymphocytes after chemotherapy was up-regulated and would down-regulate after IDO inhibitor treatment. This all-in-one theranostic strategy is a promising method for precisely delivering TMZ and long-term dynamically tracing regulatory T lymphocytes to evaluate the immune response in situ for accurate tumor chemo-immunotherapy.

In situ fluorescence-photoacoustic measurement of the changes of brown adipose tissue in mice under hindlimb unloading.

Space travel causes rapid weight loss of astronauts, but the underlying reasons are still obscure. Brown adipose tissue (BAT) is a well-known thermogenesis tissue that is innervated by sympathetic nerves, and norepinephrine stimulation can promote the thermogenesis and angiogenesis of BAT. Herein, the structural and physiological changes of BAT as well as serological indicators were investigated in mice under hindlimb unloading (HU) to simulate a weightless environment in space. The results showed that long-term HU could induced the thermogenic activation of BAT by upregulating the mitochondrial uncoupling protein. Further, peptide-conjugated indocyanine green was developed to target the vascular endothelial cells of BAT. Noninvasive fluorescence-photoacoustic imaging presented the neovascularization of BAT on the micron scale in the HU group, accompanying by the increase of vessel density. Downward trend of serum triglyceride and glucose level of mice treated with HU proved the more heat production and energy consumption in BAT compared with the control group. This study suggested that HU may be an effective strategy to curb the occurrence of obesity, whereas fluorescence-photoacoustic dual-modal imaging showed capability of assessing BAT activity.NEW & NOTEWORTHY We found that the mechanism of weight loss of astronauts in space flight may be that hindlimb unloading (HU) promotes the activation of brown adipose tissue (BAT) and the increase of uncoupling protein (UCP1) expression, which accelerates the body's heat production. Meanwhile, the activation of BAT is accompanied by the proliferation of blood vessels. With the help of peptide CPATAERPC conjugated indocyanine green targeting to vascular endothelial cells, fluorescence-photoacoustic imaging has selectively tracked the vascular structure of BAT on the micron scale, which provided noninvasive imaging tools to in situ measure the changes of BAT.

In vivo characterization and analysis of glioblastoma at different stages using multiscale photoacoustic molecular imaging.

Simultaneous spatio-temporal description of tumor microvasculature, blood-brain barrier, and immune activity is pivotal to understanding the evolution mechanisms of highly aggressive glioblastoma, one of the most common primary brain tumors in adults. However, the existing intravital imaging modalities are still difficult to achieve it in one step. Here, we present a dual-scale multi-wavelength photoacoustic imaging approach cooperative with/without unique optical dyes to overcome this dilemma. Label-free photoacoustic imaging depicted the multiple heterogeneous features of neovascularization in tumor progression. In combination with classic Evans blue assay, the microelectromechanical system based photoacoustic microscopy enabled dynamic quantification of BBB dysfunction. Concurrently, using self-fabricated targeted protein probe (αCD11b-HSA@A1094) for tumor-associated myeloid cells, unparalleled imaging contrast of cells infiltration associated with tumor progression was visualized by differential photoacoustic imaging in the second near-infrared window at dual scale. Our photoacoustic imaging approach has great potential for tumor-immune microenvironment visualization to systematically reveal the tumor infiltration, heterogeneity, and metastasis in intracranial tumors.

Label-free differential imaging of cellular components in mouse brain tissue by wide-band photoacoustic microscopy.

Mapping diverse cellular components with high spatial resolution is important to interrogate biological systems and study disease pathogenesis. Conventional optical imaging techniques for mapping biomolecular profiles with differential staining and labeling methods are cumbersome. Different types of cellular components exhibit distinctive characteristic absorption spectra across a wide wavelength range. By virtue of this property, a lab-made wide-band optical-resolution photoacoustic microscopy (wbOR-PAM) system, which covers wavelengths from the ultraviolet and visible to the shortwave infrared regions, was designed and developed to capture multiple cellular components in 300-µm-thick brain slices at nine different wavelengths without repetitive staining and complicated processing. This wbOR-PAM system provides abundant spectral information. A reflective objective lens with an infinite conjugate design was applied to focus laser beams with different wavelengths, avoiding chromatic aberration. The molecular components of complex brain slices were probed without labeling. The findings of the present study demonstrated a distinctive absorption of phospholipids, a major component of the cell membrane, brain, and nervous system, at 1690 nm and revealed their precise distribution with microscopic resolution in a mouse brain, for the first time. This novel imaging modality provides a new opportunity to investigate important biomolecular components without either labeling or lengthy specimen processing, thus, laying the groundwork for revealing cellular mechanisms involved in disease pathogenesis.

Photoacoustic Microscopic Imaging of Cerebral Vessels for Intensive Monitoring of Metabolic Acidosis.

PURPOSE: Metabolic acidosis as one of the most common perioperative complications has been associated with increased risks for poor prognosis. Routine monitoring methods include blood gas analysis and electrocardiogram, which are limited by time delay effects. And the existing intravital imaging modalities are difficult to achieve in one step. Here, we present a dual-wavelength photoacoustic imaging approach to overcome this dilemma. The aim of this study was to develop a rapid approach for intensive monitoring of acid-base imbalance and cerebral oxygen metabolism. PROCEDURES: We characterized the cerebrovascular structure by label-free dual-wavelength (532 and 559 nm) photoacoustic microscopy in healthy and diabetic mouse models with metabolic acidosis. Concurrently, we developed a single-vessel analysis method to accurately delineate the differential responses of small vessels and quantify the cerebral oxygenation following experimental alteration of pH. RESULTS: We demonstrated that there was an increasing trend in changes of vascular measurements (density, diameter, and relative hemoglobin concentration) and cerebral microvascular oxygen metabolism with the aggravation of acidosis. Furthermore, we established a clinical nomogram for the diagnosis of disease severity and yielded good discrimination ability with area under the curve of 0.920-0.967 and accuracy of 81.9-93.0%. The nomogram was also validated well in the diabetic mouse model with metabolic acidosis. CONCLUSIONS: Our photoacoustic imaging approach has great potential for rapid detection of metabolic acidosis and brain oxygen metabolism, which could potentially be applied as a bedside monitoring method for brain protection and timely treatment of acid-base abnormalities.

Anomalous kinetics of galactose-deficient IgA incurring nephropathy revealed by cross-scale optical imaging.

IgA nephropathy (IgAN) is the most common glomerulonephritis, characterized by the presence of predominant IgA deposits in the mesangium. Deposition of pathogenic IgA in kidney tissue is a fundamental initiating process that has not been fully studied. Here, we employed optical imaging to directly visualize kidney deposition of IgA with optimized spatial and temporal resolution in BALB/c nude mice. Real-time fluorescence imaging revealed that IgA isolated from patients with IgAN preferentially accumulated in the kidneys, compared with IgA purified from healthy individuals. There was no difference in the distribution of either IgA preparation by the liver. Photoacoustic computed tomography dynamically demonstrated and quantified the enhanced retention of pathological IgA in the kidney cortex. Photoacoustic microscopy tracked IgA deposition in the glomeruli with a resolution down to three microns in a mouse model. Notably, longitudinal fluorescent imaging revealed that galactose-deficient IgA (Gd-IgA), which was elevated in the circulation of patients with IgAN, persisted in the kidney for longer than two weeks, and stable deposition of Gd-IgA induced kidney impairment, including albuminuria and mesangial proliferation. Thus, our study highlights that the aberrant kidney depositional kinetics of Gd-IgA is involved in the pathogenesis of IgAN. Hence, cross-scale optical imaging has potential applications in assessing immune-mediated kidney diseases and uncovering underlying mechanisms of disease.

Small Animal In Situ Drug Delivery Effects via Transdermal Microneedles Array versus Intravenous Injection: A Pilot Observation Based on Photoacoustic Tomography.

Intravenous injection is a rapid, low-cost, and direct method that is commonly used to deliver multifarious biotherapeutics and vaccines. However, intravenous injection often causes trauma or tissue injury that requires professional operation. Transdermal drug delivery overcomes the aforementioned defects, and the microneedles (MNs) array is one of the most promising transdermal drug delivery platforms. Timely, precise, and non-invasive monitoring and evaluation of the effects of MNs in transdermal administration is significant to the research of drug efficiency response to specific diseases. In this sense, photoacoustic computed tomography (PACT), which provides wavelength-selective and deep-penetrating optical contrast, could be a promising imaging tool for in situ evaluation of the treatment effects. In this work, we propose the use of PACT to non-invasively assess the effects of real-time drug delivery in glioma tumors through transdermal administration with degradable indocyanine green-loaded hyaluronic acid MNs (ICG-HA-MNs). The outcome is systematically and quantitatively compared with that via intravenous injection. It is found that the photoacoustic signals of ICG in the tumor site express a faster elevation and shorter duration time in the intravenous injection group; by contrast, the photoacoustic signals demonstrate a lower intensity but prolonged duration time in the MNs group. The observed phenomenon indicates faster response but shorter drug duration for intravenous injection, which is in contrast with the lower loading but prolonged performance for transdermal drug delivery with MNs. These results exhibit good consistency with the earlier, common-sense findings reported from other aspects, confirming that PACT can serve as a potential imaging tool to precisely, non-invasively, and quickly evaluate in situ drug delivery effects and provide constructive guidance for the design and fabrication of microneedles.

In vivo quantitative photoacoustic evaluation of the liver and kidney pathology in tyrosinemia.

Hereditary tyrosinemia type Ⅰ (HT1) is a severe autosomal recessive inherited metabolic disease, which can result in severe damage of liver and kidney. Photoacoustic imaging (PAI) uses pulsed laser light to induce ultrasonic signals to facilitate the visualization of lesions that are strongly related to disease progression. In this study, the structural and functional changes of liver and kidney in HT1 was investigated by cross-scale PAI. The results showed that the hepatic lobule and renal tubule were severely damaged during HT1 progression. The hemoglobin content, vessel density, and liver function reserve were decreased. The metabolic half-life of indocyanine green declined from 59.8 s in health to 262.6 s in the advanced stage. Blood oxygen saturation was much lower than that in health. This study highlights the potential of PAI for in vivo evaluation of the liver and kidney lesions in HT1.

Tumor-Homing and Immune-Reprogramming Cellular Nanovesicles for Photoacoustic Imaging-Guided Phototriggered Precise Chemoimmunotherapy.

Many studies have focused on developing effective therapeutic strategies to selectively destroy primary tumors, eliminate metastatic lesions, and prevent tumor recurrence with minimal side effects on normal tissues. In this work, we synthesized engineered cellular nanovesicles (ECNVs) with tumor-homing and immune-reprogramming functions for photoacoustic (PA) imaging-guided precision chemoimmunotherapy. M1-macrophage-derived cellular nanovesicles (CNVs) were loaded with gold nanorods (GNRs), gemcitabine (GEM), CpG ODN, and PD-L1 aptamer. The good histocompatibility and tumor-homing effect of CNVs improved drug retention in the bloodstream and led to their enrichment in tumor tissues. Furthermore, the photothermal ability of GNRs enabled PA imaging-guided drug release. GEM induced tumor immunogenic cell death (ICD), and CpG ODN promoted an immune response to the antigens released by ICD, leading to long-term specific antitumor immunity. In addition, the PD-L1 aptamer relieved the inhibitory effect of the PD1/PD-L1 checkpoint on CD8+ T-cells and augmented the immunotherapeutic effect. The synergistic innate and adaptive immune responses enhanced the antitumor effect of ECNVs. In summary, this nanoplatform integrates local targeted photothermal therapy with extensive progressive chemotherapy and uses ICD to reshape the immune microenvironment for tumor ablation.

Engineered extracellular vesicles as intelligent nanosystems for next-generation nanomedicine.

Extracellular vesicles (EVs), as natural carriers of bioactive cargo, have a unique micro/nanostructure, bioactive composition, and characteristic morphology, as well as fascinating physical, chemical and biochemical features, which have shown promising application in the treatment of a wide range of diseases. However, native EVs have limitations such as lack of or inefficient cell targeting, on-demand delivery, and therapeutic feedback. Recently, EVs have been engineered to contain an intelligent core, enabling them to (i) actively target sites of disease, (ii) respond to endogenous and/or exogenous signals, and (iii) provide treatment feedback for optimal function in the host. These advances pave the way for next-generation nanomedicine and offer promise for a revolution in drug delivery. Here, we summarise recent research on intelligent EVs and discuss the use of "intelligent core" based EV systems for the treatment of disease. We provide a critique about the construction and properties of intelligent EVs, and challenges in their commercialization. We compare the therapeutic potential of intelligent EVs to traditional nanomedicine and highlight key advantages for their clinical application. Collectively, this review aims to provide a new insight into the design of next-generation EV-based theranostic platforms for disease treatment.

Multiphoton microscopy providing pathological-level quantification of myocardial fibrosis in transplanted human heart.

Multiphoton microscopy (MPM), a high-resolution laser scanning technique, has been shown to provide detailed real-time information on fibrosis assessment in animal models. But the value of MPM in human histology, especially in heart tissue, has not been fully explored. We aimed to evaluate the association between myocardial fibrosis measured by MPM and that measured by histological staining in the transplanted human heart. One hundred and twenty samples of heart tissue were obtained from 20 patients consisting of 10 dilated cardiomyopathies (DCM) and 10 ischemic cardiomyopathies (ICM). MPM and picrosirius red staining were performed to quantify collagen volume fraction (CVF) in explanted hearts postoperatively. Cardiomyocyte and myocardial fibrosis could be clearly visualized by MPM. Although patients with ICM had significantly greater MPM-derived CVF than patients with DCM (25.33  ± 12.65 % vs. 19.82  ± 8.62 %, p = 0.006), there was a substantial overlap of CVF values between them. MPM-derived CVF was comparable to that derived from picrosirius red staining based on all samples (22.58 ± 11.13% vs. 21.19 ± 11.79%, p = 0.348), as well as in DCM samples and ICM samples. MPM-derived CVF was correlated strongly with the magnitude of staining-derived CVF in both all samples and DCM samples and ICM samples (r = 0.972, r = 0.963, r = 0.973, respectively; all p < 0.001). Intra- and inter-observer reproducibility for MPM-derived CVF and staining-derived CVF were 0.995, 0.989, 0.995, and 0.985, respectively. Our data demonstrated that MPM can provide a pathological-level assessment of myocardial microstructure in transplanted human heart.

A microenvironment-responsive FePt probes for imaging-guided Fenton-enhanced radiotherapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) continues to be one of the most fatal malignancies with increasing morbidity, and potent therapeutics are urgently required given its insensitivity to traditional treatments. Here, we have developed a microenvironment-responsive FePt probes for the highly efficient Fenton-enhanced radiotherapy (FERT) of HCC. The selective release of Fe2+ in the acidic tumor microenvironment, but not in normal tissue, together with enhanced levels of hydrogen peroxide produced through the Pt radiosensitization effect, facilitates the generation of an enormous amount of hydroxyl radicals through the Fenton reaction, thereby extending the radiotherapeutic cascade and realizing a powerful therapeutic efficacy for HCC. Moreover, the "burst" release of Fe2+ contributes to the T2-to-T1 magnetic resonance imaging (MRI) switching effect, which informs the release of Fe2+, making imaging-guided cancer therapy feasible. This work not only breaks the bottleneck of traditional radiotherapy for HCC while minimally affecting normal tissues, but also provides a new strategy for FERT imaging guidance.

Ultrashort-Pulse-Microwave Excited Whole-Breast Thermoacoustic Imaging With Uniform Field of Large Size Aperture Antenna for Tumor Screening.

Microwave-induced thermoacoustic imaging (MTAI) has been widely used in biomedical science, and has the potential as an auxiliary measure for clinical diagnosis and treatment. Recently, there are increasing interests in using ultrashort microwave-pumped thermoacoustic imaging techniques to obtain high-efficiency, high-resolution images. However, the traditional imaging system can only provide uniform radiation in a relatively small area, which limits their large field of view in clinical applications (such as whole-breast imaging, brain imaging). To address this problem, we propose an ultrashort pulse microwave thermoacoustic imaging device with a large size aperture antenna. The system can provide a microwave radiation area of 40 cm × 27 cm and a uniform imaging view of 14 cm × 14 cm. With 7 cm imaging depth and a 290 µm resolution. The practical feasibility of the system for breast tumor screening is tested in phantoms with different shapes and in an ex vivo human breast tumor which is embedded in the excised breast of an ewe (π × 5 cm × 5 cm). The tumor can be identified with a contrast of about 1:2. The results demonstrate that the dedicated MTAI system with the uniform large field of view, high imaging resolution, and large imaging depth have the potential for clinical routine breast screening.

RGD-functionalised melanin nanoparticles for intraoperative photoacoustic imaging-guided breast cancer surgery.

PURPOSE: Obtaining tumour-free margins is critical for avoiding re-excision and reducing local recurrence following breast-conserving surgery; however, it remains challenging. Imaging-guided surgery provides precise detection of residual lesions and assists surgical resection. Herein, we described water-soluble melanin nanoparticles (MNPs) conjugated with cyclic Arg-Gly-Asp (cRGD) peptides for breast cancer photoacoustic imaging (PAI) and surgical navigation. METHODS: The cRGD-MNPs were synthesised and characterized for morphology, photoacoustic characteristics and stability. Tumour targeting and toxicity of cRGD-MNPs were determined by using either breast cancer cells, MDA-MB-231 tumour-bearing mice or the FVB/N-Tg (MMTV-PyVT) 634Mul/J mice model. PAI was used to locate the tumour and guide surgical resection in MDA-MB-231 tumour-bearing mice. RESULTS: The cRGD-MNPs exhibited excellent in vitro and in vivo tumour targeting with low toxicity. Intravenous administration of cRGD-MNPs to MDA-MB-231 tumour-bearing mice showed an approximately 2.1-fold enhancement in photoacoustic (PA) intensity at 2 h, and the ratio of the PA intensity at the tumour site to that in the surrounding normal tissue was 3.2 ± 0.1, which was higher than that using MNPs (1.7 ± 0.3). Similarly, the PA signal in the spontaneous breast cancer increased ~ 2.5-fold at 2 h post-injection of cRGD-MNPs in MMTV-PyVT transgenic mice. Preoperative PAI assessed tumour volume and offered three-dimensional (3D) reconstruction images for accurate surgical planning. Surgical resection following real-time PAI showed high consistency with histopathological analysis. CONCLUSION: These results highlight that cRGD-MNP-mediated PAI provide a powerful tool for breast cancer imaging and precise tumour resection. cRGD-MNPs with fine PA properties have great potential for clinical translation.

Instant Ultrasound-Evoked Precise Nanobubble Explosion and Deep Photodynamic Therapy for Tumors Guided by Molecular Imaging.

Nanobubbles (NBs) have recently gained interest in cancer imaging and therapy due to the fact that nanoparticles with the size range of 1-1000 nm can extravasate into permeable tumor types through the enhanced permeability and retention (EPR) effect. However, the therapeutic study of NBs was only limited to drug delivery or cavitation. Herein, we developed ultrasound-evoked massive NB explosion to strikingly damage the surrounding cancer. The dual-function agent allows synergistic mechanical impact and photodynamic therapy of the tumors and enhances imaging contrast. Moreover, the mechanical explosion improved the light delivery efficiency in biological tissue to promote the effect of photodynamic therapy. Under ultrasound/photoacoustic imaging guidance, we induced on-the-spot bubble explosion and photodynamic therapy of tumors at a depth of centimeters in vivo. The mechanical impact of the explosion can enhance delivery of the photosensitizers. Ultrasound explicitly revealed the cancer morphology and exhibited fast NB perfusion. Generated mechanical damage and release of mixture agents demonstrated remarkable synergetic anticancer effects on deep tumors. This finding also offers a new approach and insight into treating cancers.