Animal Imaging Research Articles

Development of a digital zebrafish phantom and its application to dedicated small-fish PET

Objective. We are developing a small-fish positron emission tomography (PET) scanner dedicated to small aquatic animals relevant for biomedical and biological research, e.g. zebrafish. We plan to use Monte Carlo simulations to optimize its configuration and the required water-filled imaging chambers. Our objectives were: (1) to create a digital 3D zebrafish phantom using conventional micro-CT, (2) include the phantom into a simulated PET environment based on the framework GATE, and (3) investigate the effects of the water environment on the reconstructed images. Approach. To create the phantom, we performed ex vivo measurements of zebrafish specimen using a tabletop micro-CT and compared three methods to fixate the specimen. From segmented micro-CT images we created digital emission and transmission phantoms which were incorporated in GATE via tessellated volumes. Two chamber sizes were considered. For reference, a simulation with the zebrafish in air was implemented. The simulated data were reconstructed using CASToR. For attenuation correction, we used the exact attenuation information or a uniform distribution (only water). Several realizations of each scenario were performed; the reconstructed images were quantitatively evaluated. Main results. Fixation in formalin led to the best soft-tissue contrast at the cost of some specimen deformation. After attenuation correction, no significant differences were found between the reconstructed images. The PET images reflected well the higher uptake simulated in the brain and heart, despite their small size and surrounding background activity; the swim bladder (no activity) was clearly identified. The simplified attenuation map, consisting only of water, slightly worsened the images. Significance. A conventional micro-CT can provide sufficient image quality to generate numerical phantoms of small fish without contrast media. Such phantoms are useful to evaluate in-silico small aquatic animal imaging concepts and develop imaging protocols. Our results support the feasibility of zebrafish PET with an aqueous environment.

Advances and challenges in intravital imaging of craniofacial and dental progenitor cells.

Craniofacial and appendicular bone homeostasis is dynamically regulated by a balance between bone formation and resorption by osteoblasts and osteoclasts, respectively. Despite the developments in multiple imaging techniques in bone biology, there are still technical challenges and limitations in the investigation of spatial/anatomical location of rare stem/progenitor cells and their molecular regulation in tooth and craniofacial bones of living animals. Recent advances in live animal imaging techniques for the craniofacial and dental apparatus can provide new insights in real time into bone stem/progenitor cell dynamics and function in vivo. Here, we review the current inventions and applications of the noninvasive intravital imaging technique and its practical uses and limitations in the analysis of stem/progenitor cells in craniofacial and dental apparatus in vivo. Furthermore, we also explore the potential applications of intravital microscopy in the dental field.

20-MHz phased array ultrasound transducer for in vivo ultrasound imaging of small animals

In vivo ultrasound imaging with phased array transducers is of great importance for both clinical application and biomedical research. In this work, relaxor ferroelectric PMN-0.28PT single crystal with very high piezoelectric constant d33 ≥ 2000 pC/N and electromechanical coupling coefficient k33 ∼ 0.92 is used to fabricate high-frequency phased array transducers. A 128-element 20-MHz phased array transducer is successfully fabricated, and the optimized performance of −6 dB average bandwidth of ∼ 84 % and insertion loss of −43 dB are achieved. The axial and lateral imaging resolutions of the transducer are determined to be 81 µm and 243 µm, respectively. With Verasonics image platform, in vivo fisheye images are acquired, demonstrating the potential application of our developed high-frequency phased array transducer for biomedical research on small animals.

Lauric acid-grafted biopolymeric nanoparticles for efficient Melphalan delivery across the corneal layers for retinoblastoma: ex vivo and in vivo permeation study

Intravitreal injection of chemotherapy drugs for intraocular retinoblastoma, for the prevalent pediatric malignancy treatment with the side effects of severe infection. This study tried to synthesize the novel approach to deliver Melphalan to the vitreous cavity through the cornea to increase drug efficacy with non-invasive effects. For this purpose, lauric acid-grafted chitosan-alginate and chitosan-alginate loaded by Melphalan nanoparticles were fabricated. Fourier-transform infrared spectroscopy (FTIR) and x-ray diffraction (XRD) were the basic characterizations of chitosan modification. Scanning electron microscopy (SEM) and dynamic light scattering (DLS) are the other assessments of synthesized nanoparticles. Drug encapsulation and in vitro release were studied using UV-spectroscopy, also ex vivo and in vivo corneal permeation was studied using Franz diffusion cell, fluorescence microscopy, and in vivo animal imaging. FTIR and XRD confirm the successful grafting of lauric acid and spherical shape with the average size of 50 nm and 80 nm observed for modified and chitosan-alginate nanoparticles respectively. In the release study, encapsulation efficiency of 98% with sustained drug release of 80% for 100 h with the Fickian drug diffusion mechanism was reported. Ex vivo corneal permeation exhibited an improved drug penetration rate in the sample of lauric acid-grafted-chitosan-alginate nanoparticles with the results of 5.8 times higher than chitosan-alginate nano-carriers and 15.5-fold compared to drug solution. Also, in vivo study shows that the designed nanoparticles containing Melphalan reached the vitreous cavity with high efficacy. Current investigations illustrate the novel Melphalan delivery with sustained behavior through the cornea with the high potential of corneal layer penetration for retinoblastoma management.

Head holder and cranial window design for sequential magnetic resonance imaging and optical imaging in awake mice.

Medical imaging techniques are widely used in preclinical research as diagnostic tools to detect physiological abnormalities and assess the progression of neurovascular disease in animal models. Despite the wealth of imaging options in magnetic resonance imaging (MRI), interpretation of imaging-derived parameters regarding underlying tissue properties is difficult due to technical limitations or lack of parameter specificity. To address the challenge of interpretation, we present an animal preparation protocol to achieve quantitative measures from both MRI and advanced optical techniques, including laser speckle contrast imaging and two-photon microscopy, in murine models. In this manner, non-translatable methods support and improve interpretation of less specific, translatable methods, i.e., MRI. Combining modalities for improved clinical interpretation involves satisfying the requirements of various methods. Furthermore, physiology unperturbed by anesthetics is a prerequisite for the strategy to succeed. Awake animal imaging with restraint provides an alternative to anesthesia and facilitates translatability of cerebral measurements. The method outlines design requirements for the setup and a corresponding reproducible surgical procedure for implanting a 3D printed head holder and cranial window to enable repeated multimodal imaging. We document the development, application, and validation of the method and provide examples confirming the usefulness of the design in acquiring high quality data from multiple modalities for quantification of a wide range of metrics of cerebral physiology in the same animal. The method contributes to preclinical small animal imaging, enabling sequential imaging of previously mutually exclusive techniques.

A Mouse Holder for Awake Functional Imaging in Unanesthetized Mice: Applications in 31P Spectroscopy, Manganese-Enhanced Magnetic Resonance Imaging Studies, and Resting-State Functional Magnetic Resonance Imaging.

Anesthesia is often used in preclinical imaging studies that incorporate mouse or rat models. However, multiple reports indicate that anesthesia has significant physiological impacts. Thus, there has been great interest in performing imaging studies in awake, unanesthetized animals to obtain accurate results without the confounding physiological effects of anesthesia. Here, we describe a newly designed mouse holder that is interfaceable with existing MRI systems and enables awake in vivo mouse imaging. This holder significantly reduces head movement of the awake animal compared to previously designed holders and allows for the acquisition of improved anatomical images. In addition to applications in anatomical T2-weighted magnetic resonance imaging (MRI), we also describe applications in acquiring 31P spectra, manganese-enhanced magnetic resonance imaging (MEMRI) transport rates and resting-state functional magnetic resonance imaging (rs-fMRI) in awake animals and describe a successful conditioning paradigm for awake imaging. These data demonstrate significant differences in 31P spectra, MEMRI transport rates, and rs-fMRI connectivity between anesthetized and awake animals, emphasizing the importance of performing functional studies in unanesthetized animals. Furthermore, these studies demonstrate that the mouse holder presented here is easy to construct and use, compatible with standard Bruker systems for mouse imaging, and provides rigorous results in awake mice.

Recent Progress Toward Imaging Application of Multifunction Sonosensitizers in Sonodynamic Therapy.

Sonodynamic therapy (SDT) is a rapidly developing non-surgical therapy that initiates sensitizers’ catalytic reaction using ultrasound, showing great potential for cancer treatment due to its high safety and non-invasive nature. In addition, recent research has found that using different diagnostic and therapeutic methods in tandem can lead to better anticancer outcomes. Therefore, as essential components of SDT, sonosensitizers have been extensively explored to optimize their functions and integrate multiple medical fields. The review is based on five years of articles evaluating the combined use of SDT and imaging in treating cancer. By developing multifunctional sonosensitive particles that combine imaging and sonodynamic therapy, we have integrated diagnosis into the treatment of precision medicine applications, improving SDT cell uptake and antitumor efficacy utilizing different tumour models. This paper describes the imaging principle and the results of cellular and animal imaging of the multifunctional sonosensitizers. Efforts are made in this paper to provide data and design references for future SDT combined imaging research and clinical application development and to provide offer suggestions.

Iron oxide and iron oxyhydroxide nanoparticles impair SARS-CoV-2 infection of cultured cells

BackgroundCoronaviruses usually cause mild respiratory disease in humans but as seen recently, some human coronaviruses can cause more severe diseases, such as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the global spread of which has resulted in the ongoing coronavirus pandemic.ResultsIn this study we analyzed the potential of using iron oxide nanoparticles (IONPs) coated with biocompatible molecules like dimercaptosuccinic acid (DMSA), 3-aminopropyl triethoxysilane (APS) or carboxydextran (FeraSpin™ R), as well as iron oxyhydroxide nanoparticles (IOHNPs) coated with sucrose (Venofer®), or iron salts (ferric ammonium citrate -FAC), to treat and/or prevent SARS-CoV-2 infection. At non-cytotoxic doses, IONPs and IOHNPs impaired virus replication and transcription, and the production of infectious viruses in vitro, either when the cells were treated prior to or after infection, although with different efficiencies. Moreover, our data suggest that SARS-CoV-2 infection affects the expression of genes involved in cellular iron metabolism. Furthermore, the treatment of cells with IONPs and IOHNPs affects oxidative stress and iron metabolism to different extents, likely influencing virus replication and production. Interestingly, some of the nanoparticles used in this work have already been approved for their use in humans as anti-anemic treatments, such as the IOHNP Venofer®, and as contrast agents for magnetic resonance imaging in small animals like mice, such as the FeraSpin™ R IONP.ConclusionsTherefore, our results suggest that IONPs and IOHNPs may be repurposed to be used as prophylactic or therapeutic treatments in order to combat SARS-CoV-2 infection.Graphical

Video-rate full-ring ultrasound and photoacoustic computed tomography with real-time sound speed optimization.

Full-ring dual-modal ultrasound and photoacoustic imaging provide complementary contrasts, high spatial resolution, full view angle and are more desirable in pre-clinical and clinical applications. However, two long-standing challenges exist in achieving high-quality video-rate dual-modal imaging. One is the increased data processing burden from the dense acquisition. Another one is the object-dependent speed of sound variation, which may cause blurry, splitting artifacts, and low imaging contrast. Here, we develop a video-rate full-ring ultrasound and photoacoustic computed tomography (VF-USPACT) with real-time optimization of the speed of sound. We improve the imaging speed by selective and parallel image reconstruction. We determine the optimal sound speed via co-registered ultrasound imaging. Equipped with a 256-channel ultrasound array, the dual-modal system can optimize the sound speed and reconstruct dual-modal images at 10 Hz in real-time. The optimized sound speed can effectively enhance the imaging quality under various sample sizes, types, or physiological states. In animal and human imaging, the system shows co-registered dual contrasts, high spatial resolution (140 µm), single-pulse photoacoustic imaging (< 50 µs), deep penetration (> 20 mm), full view, and adaptive sound speed correction. We believe VF-USPACT can advance many real-time biomedical imaging applications, such as vascular disease diagnosing, cancer screening, or neuroimaging.

Aperture Modulation of Isoreticular Metal Organic Frameworks for Targeted Antitumor Drug Delivery.

The introduction of different pore diameters in metal organic frameworks (MOFs) could adjust their drug delivery performance. MOFs with customized structures have potential application value in targeted drug delivery. However, no research on this topic has been found so far. In this report, isoreticular metal organic frameworks (IRMOFs) have been taken as a typical case of tailor-made MOFs, the pore size of which is enlarged (average BJH pore sizes of about 2.43, 3.06, 5.47, and 6.50 nm were determined for IRMOF-1, IRMOF-8, IRMOF-10, and IRMOF-16, respectively), emphasizing the relationship between pore size and model drugs (Oridonin, ORI) and clarifying its potential working mechanism. IRMOF-1, whose pore size matches the size of ORI, has an outstanding drug loading capacity (57.93% by wt) and release profile (about 90% in 24 h at pH 7.4). IRMOF-1 was further coated with polyethylene glycol (PEG) modified with a cell penetrating peptide (CPP44) bound to M160 (CD163L1) protein for targeting of hepatic tumor lines. This nanoplatform (CPP44-PEG@ORI@IRMOF-1) exhibited acid-responsive drug release behavior (37.86% in 10 h at pH 7.4 and 66.66% in 10 h at pH 5.5) and significantly enhanced antitumor effects. The results of cell targeting and in vivo animal imaging indicated that CPP44-PEG@ORI@IRMOF-1 may serve as a tumor-selective drug delivery nanoplatform. Toxicity assessment confirmed that PEGylated IRMOF-1 did not cause organ or systemic toxicity. Furthermore, it is encouraging that the IRMOF-based targeted drug delivery system with pore size modulation showed rapid clearance (most administered NPs are metabolized from urine and feces within 1 week) and avoided accumulation in the body, indicating their promise for biomedical applications. This MOF-based aperture modulation combined with a targeted modification strategy might find broad applications in cancer theranostics. Thus, it is convenient to customize personalized MOFs according to the size of drug molecules in future research.

The Use of Panitumumab-IRDye800CW in a Novel Murine Model for Conjunctival Squamous Cell Carcinoma.

PurposeConjunctival squamous cell carcinoma (SCC) is a sight-threatening ocular surface malignancy with the primary treatment modality being surgical resection. To evaluate surgical imaging modalities to improve surgical resection, we established a novel murine model for conjunctival SCC to demonstrate the utility of panitumumab-IRDye800, a fluorescently labeled anti-epidermal growth factor receptor (EGFR) antibody.MethodsNOD-scid IL2Rgammanull (NSG) mice received subconjunctival injection of UM-SCC-1 or SCC-9, head and neck SCC cell lines. On tumor growth, mice were injected with Panitumumab-IRDye800CW, and imaged with a small animal imaging system and optical coherence tomography (OCT). Immunohistochemistry for SCC markers were used to confirm tumor origin.ResultsSeventy-five percent (N = 4) of the UM-SCC-1 group developed aggressive, rapidly growing tumors that were P40 and EGFR positive within two weeks of inoculation. The SCC-9 tumors failed to demonstrate any growth (N = 4). Ocular tumors demonstrated high fluorescence levels with a tumor to background ratio of 3.8.ConclusionsSubconjunctival injections are an appropriate technique to create in vivo models for assessing treatment modalities and novel therapies in conjunctival SCC.Translational RelevanceThis model demonstrates Panitumumab-IRDye800CW's utility in the ophthalmic setting and suggests that clinical trials may be warranted.

Radionuclide 131I-labeled albumin-indocyanine green nanoparticles for synergistic combined radio-photothermal therapy of anaplastic thyroid cancer.

ObjectivesAnaplastic thyroid cancer (ATC) cells cannot retain the radionuclide iodine 131 (131I) for treatment due to the inability to uptake iodine. This study investigated the feasibility of combining radionuclides with photothermal agents in the diagnosis and treatment of ATC.Methods 131I was labeled on human serum albumin (HSA) by the standard chloramine T method. 131I-HSA and indocyanine green (ICG) were non-covalently bound by a simple stirring to obtain 131I-HSA-ICG nanoparticles. Characterizations were performed in vitro. The cytotoxicity and imaging ability were investigated by cell/in vivo experiments. The radio-photothermal therapy efficacy of the nanoparticles was evaluated at the cellular and in vivo levels.ResultsThe synthesized nanoparticles had a suitable size (25–45 nm) and objective biosafety. Under the irradiation of near-IR light, the photothermal conversion efficiency of the nanoparticles could reach 24.25%. In vivo fluorescence imaging and single-photon emission CT (SPECT)/CT imaging in small animals confirmed that I-HSA-ICG/131I-HSA-ICG nanoparticles could stay in tumor tissues for 4–6 days. Compared with other control groups, 131I-HSA-ICG nanoparticles had the most significant ablation effect on tumor cells under the irradiation of an 808-nm laser.ConclusionsIn summary, 131I-HSA-ICG nanoparticles could successfully perform dual-modality imaging and treatment of ATC, which provides a new direction for the future treatment of iodine-refractory thyroid cancer.

NLRP3 downregulation enhances engraftment and functionality of adipose-derived stem cells to alleviate erectile dysfunction in diabetic rats.

BackgroundThe transplantation of adipose-derived stem cells (ASCs) is a most promising treatment for diabetic erectile dysfunction (DMED). However, the effect of high glucose on the post-transplantation survival of stem cells limits the efficacy of ASCs transplantation. Prolonging the survival time of ASCs in vivo after transplantation is a key issue in the utilization of ASCs for DMED. Herein, we aimed to investigate the therapeutic effect of ASCs by downregulating NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) as well as its mechanism of action in DMED.MethodsASCs were obtained by isolating subcutaneous fat from SD rats and were identified using lipogenic and osteogenic differentiation assays, as well as flow cytometric analysis. The shNLRP3 lentivirus with the best downregulating effect was screened, and shNLRP3 lentivirus (LV-shNLRP3) was transfected into ASCs (ASCsshNLRP3) to detect apoptosis and the reactive oxygen species (ROS) levels in each group under high glucose conditions. In DMED rats, ASCsLV-shNLRP3, ASCsLV-control, or phosphate buffered saline (PBS) were administrated via intra-cavernous injection, and normal rats served as normal controls. One week post-injection, animal imaging was performed to track the ASCs. Four weeks post-injection, erectile function was evaluated by measuring the intra-cavernosal pressure and mean arterial pressure. Corpus cavernosum pyroptosis and endothelial function were examined by western blotting and immunofluorescence.ResultsNLRP3-mediated pyroptosis might be a pathogenic mechanism of ED and DMED. ASCs were isolated successfully. Thereafter, the LV-shNLRP3 with the highest transfection efficiency was selected and used to modify ASCs successfully. LV-shNLRP3 could protect ASCs paracrine function under hyperglycemia through anti-apoptosis and anti-ROS deposition mechanisms. Furthermore, ASCsLV-shNLRP3 showed an advantage in the suppression of pyroptosis compared to ASCsLV-control. The ASCsLV-shNLRP3 group had improved cavernous endothelial function and smooth muscle injury, thus reversing erectile function, and was superior to the ASCsLV-control group.ConclusionsNLRP3 Inflammasome-mediated pyroptosis might be involved in DMED formation. Intra-cavernous injection of ASCsLV-shNLRP3 could suppress cavernosal pyroptosis, contributing to improved erectile function in DMED rats.

A novel and easy to prepare azo-based bioreductive linker and its application in hypoxia-sensitive cationic liposomal doxorubicin: Synthesis, characterization, in vitro and in vivo studies in mice bearing C26 tumor

This study designed and synthesized a cost-effective azo-based hypoxia-sensitive linker (AHSL) using commercially accessible, inexpensive raw materials and simple methods to apply in cationic nanoliposomes. Then, AHSL was post-inserted into the cationic liposome (Cat-lip), and PEG-Azo-Cat-lip was prepared and characterized using DLS. The decrease in the zeta-potential of formulation from + 18.4 mV for Cat-lip to + 6.1 mV and the increase in the size of the PEG-Azo-Cat-lip indicated the successful post insertion of AHSL into the liposomes. The Doxorubicin (Dox) release study showed that PEGylation results in a more stable PEG-Azo-Cat-lip than the Cat-lip. The increased cytotoxicity of the PEG-Azo-Cat-lip in the hypoxic condition also indicated the cleavage of the AHSL in the hypoxic environment. In vivo biodistribution using animal imaging has shown higher tumor accumulation of the MPEG-Azo-Cat-lip than Cat-lip during the 120 h of the study. The results of anti-tumor activities and biosafety of the formulations also showed the higher efficiency of the MPEG-Azo-Cat-lip compared with the Cat-lip. The results of this study indicated the antitumor efficacy of this hypoxia-sensitive which merits further investigation.

Whole-Body Photoacoustic Imaging Techniques for Preclinical Small Animal Studies.

Photoacoustic imaging is a hybrid imaging technique that has received considerable attention in biomedical studies. In contrast to pure optical imaging techniques, photoacoustic imaging enables the visualization of optical absorption properties at deeper imaging depths. In preclinical small animal studies, photoacoustic imaging is widely used to visualize biodistribution at the molecular level. Monitoring the whole-body distribution of chromophores in small animals is a key method used in preclinical research, including drug-delivery monitoring, treatment assessment, contrast-enhanced tumor imaging, and gastrointestinal tracking. In this review, photoacoustic systems for the whole-body imaging of small animals are explored and summarized. The configurations of the systems vary with the scanning methods and geometries of the ultrasound transducers. The future direction of research is also discussed with regard to achieving a deeper imaging depth and faster imaging speed, which are the main factors that an imaging system should realize to broaden its application in biomedical studies.

Meclizine and Metabotropic Glutamate Receptor Agonists Attenuate Severe Pain and Ca2+ Activity of Primary Sensory Neurons in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) affects ∼68% of patients undergoing chemotherapy, causing debilitating neuropathic pain and reducing quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing and pain mitigation. Meclizine is an H1 histamine receptor antagonist known to have neuroprotective effects, including an anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN using male and female mice to test agonists of mGluR8 and Group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests, and we imaged Ca2+ activity of the large population of dorsal root ganglia (DRG) neurons in vivo For the latter, we used a genetically-encoded Ca2+ indicator, Pirt-GCaMP3, which enabled us to monitor different drug interventions at the level of the intact DRG neuronal ensemble. We found that CIPN increased spontaneous Ca2+ activity in DRG neurons, increased number of Ca2+ transients, and increased hyper-responses to mechanical, thermal, and chemical stimuli. We found that mechanical and thermal pain caused by CIPN was significantly attenuated by the mGluR8 agonist, (S)-3,4-DCPG, the Group II mGluR agonist, LY379268, and the H1 histamine receptor antagonist, meclizine. DRG neuronal Ca2+ activity elevated by CIPN was attenuated by LY379268 and meclizine, but not by (S)-3,4-DCPG. Furthermore, meclizine and LY379268 attenuated cisplatin-induced weight loss. These results suggest that Group II mGluR agonist, mGluR8 agonist, and meclizine are promising candidates as new treatment options for CIPN, and studies of their mechanisms are warranted.SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy (CIPN) is a painful condition that affects most chemotherapy patients and persists several months or longer after treatment ends. Research on CIPN mechanism is extensive but has produced only few clinically useful treatments. Using in vivo GCaMP Ca2+ imaging in live animals over 1800 neurons/dorsal root ganglia (DRG) at once, we have characterized the effects of the chemotherapeutic drug, cisplatin and three treatments that decrease CIPN pain. Cisplatin increases sensory neuronal Ca2+ activity and develops various sensitization. Metabotropic glutamate receptor (mGluR) agonist, LY379268 or the H1 histamine receptor antagonist, meclizine decreases cisplatin's effects on neuronal Ca2+ activity and reduces pain hypersensitivity. Our results and experiments provide insights into cellular effects of cisplatin and drugs preventing CIPN pain.

ROS-sensitive calcipotriol nano-micelles prepared by methoxypolyethylene glycol (mPEG) – modified polymer for the treatment of psoriasis

Oxidative stress due to excessive reactive oxygen species (ROS) production in the skin microenvironment is one of the main mechanisms in psoriasis pathogenesis. A nano drug delivery system based on ROS-responsive release can enhance drug release at the target site. In this study, a ROS-sensitive material methoxypolyethylene glycol-thioether-thiol (mPEG-SS) was synthesized using mPEG as the parent structure with sulfide structural modification. An mPEG-SS-calcipotriol (mPEG-SS-CPT, PSC) nano-micelle percutaneous delivery system was prepared by encapsulating CPT. A small animal imaging system was used to study PSC’s the ROS-sensitive drug release process. It is shown that endogenous ROS mainly affects PSC and releases drugs. Finally, the therapeutic effect of PSC on psoriasis was explored by animal experiments. Ultimately, it ameliorates imiquimod-induced psoriasis-like inflammation. Overall, PSC is an effective ROS-sensitive transdermal drug delivery system that is expected to provide a new strategy for treating psoriasis.

Epithelial Cell Adhesion Molecule-Functionalized Fe3O4@Au Nanoparticles for Coregistered Optoacoustic and Magnetic Resonance Imaging and Photothermal Therapy of Hepatocellular Carcinoma

Early diagnosis and management of hepatocellular carcinoma (HCC) is important for improving the 5-year survival rate. Multimodal imaging is of great significance for obtaining complementary information, improving the efficacy of tumor detection, and monitoring HCC recurrence. The rational development of targeted nanoprobes with excellent performance is of great significance for the accurate diagnosis of HCC and image-guided photothermal therapy (PTT). In the present study, we synthesized a hybrid nanoprobe containing epithelial cell adhesion molecule-functionalized Fe3O4@Au nanoparticles as an HCC-targeted nanoprobe, which served as a dual-modal contrast agent for optoacoustic tomography (OAT) and magnetic resonance imaging (MRI) and as a photothermal sensitizer for PTT. Using this nanoprobe, we evaluated the application of coregistered OAT–MRI for the diagnosis and therapy of HCC to resolve an image alignment problem. Body-position variation in OAT and MRI was minimized using a specially designed 3D-printed dual-modality animal imaging bed constructed from polylactic acid. The registration accuracy of OAT–MRI data was further improved by a robust image registration protocol. Dual-modality coregistered imaging was performed for the early diagnosis of HCC and monitoring of curative effects. To our knowledge, this is the first study to apply a combination of a targeted nanoprobe and coregistration of OAT–MRI for the diagnosis and management of abdominal diseases.

Abstract 6288: Evaluation of therapeutic strategy for the treatment of kidney cancer using multimodal imaging

Abstract INTRODUCTION: As the most common type of kidney cancer, renal cell carcinoma (RCC) emerges in the form of highly vascularized tumors. Our team has recently demonstrated the therapeutic effects of two novel heme-targeting agents (heme-sequestering peptide 2 (HSP2) and cyclopamine tartrate (CycT)) which effectively suppress angiogenic activities and normalize tumor vasculatures in non-small cell lung cancer (NSCLC) cells and mouse tumor models [1,2]. We have now applied non-invasive multimodal imaging to evaluate these heme related treatments of kidney cancer. METHODS: Magnetic Resonance Imaging (MRI) and MultiSpectral Optoacoustic Tomography (MSOT) are ideally suited for investigations of the kidney and RCC given their extensive vasculature. MRI was performed at 9.4-T using high-resolution axial T2-weighted multi-slice images encompassing the entire kidney tumor were obtained with a fat suppressed fast spin-echo sequence in about 8 minutes. The MSOT system illuminates the mouse from all sides, providing effective excitation (700, 780, 800, 820, 850 nm) even at depth, revealing rudimentary anatomy, as well as functional oxy- and deoxyhemoglobin. We used MSOT and MRI modalities to determine the degree to which CycT modified hypoxia in orthotopic PDX renal XP 334 tumor xenografts in mice. RESULTS: Both MSOT and MRI showed anatomical differences between treated and control tumors with treated tumors being significantly smaller (p &amp;lt; 0.002). Dynamic hemoglobin changes to oxygen-breathing challenge through MSOT as a response to control and CycT group in kidney tumors. CONCLUSION: MR and MSOT imaging allowed us to monitor and evaluate the effects of the novel heme targeting drugs CycT, which significantly suppressed orthotopic kidney PDX 334 tumor growth. MSOT demonstrates dynamic hemoglobin changes to oxygen-breathing challenge in response to CycT and untreated control groups in kidney tumors. Combining MR imaging with other non-invasive imaging modalities provides a clear guide on monitoring and targeting treatments for tumors in mice. REFERENCES: [1] S. Sohoni, et al., Elevated Heme Synthesis and Uptake Underpin Intensified Oxidative Metabolism and Tumorigenic Functions in Non-Small Cell Lung Cancer Cells, Cancer Res, 79 (2019) 2511-2525. [2] P. Ghosh, et al., Oxygen-Enhanced Optoacoustic Tomography Reveals the Effectiveness of Targeting Heme and Oxidative Phosphorylation at Normalizing Tumor Vascular Oxygenation, Cancer Research, 80 (2020) 3542. Acknowledgments: CPRIT RP200021 &amp; RP160617 and Infrastructure of Kidney SPORE Brugarolas for PDX tissues well as small animal imaging resource of P30 CA142543 and Shared Instrumentation grants S10 OD018094-01A1, 1S10 RR024757 and S10 RR031859 Citation Format: Li Liu, Hashini Wanniarachchi, Tianyuan Wang, Xiaojing Wang, Dean Sherry, Ralph P. Mason, Li Zhang. Evaluation of therapeutic strategy for the treatment of kidney cancer using multimodal imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6288.

MRI and US imaging reveal evolution of spatial heterogeneity of murine tumor vasculature

The tumor microenvironment, especially the vasculature, undergoes dynamic remodeling during tumor growth and progression. The aim of this study was to investigate changes in the structure and function of tumor microenvironment (TME), with a special focus on vasculature, during the growth of the Lewis Lung Carcinoma tumor (LLC). We have used several MRI techniques and ultrasound imaging of live animals to assess how heterogenous TME features change in time.Lewis lung carcinoma bearing C57BL/6 mice were examined for three weeks. During this time, assessment of tumor vasculature was performed with Time of Flight (TOF) angiography, Dynamic Contrast Enhanced (DCE) MRI and Power Doppler Ultrasound. Additionally, diffusion and perfusion were analyzed using Diffusion Weighted MRI (DWI).Consecutive measurements of the same animals revealed an approximately twofold decrease in the density of LLC vessels in time. Heterogeneity of vasculature was best uncovered by changes in histogram based DCE analysis and revealed deterioration of tumor vessels during its progression. The tumor vasculature became less dense and with slower blood flow, with larger and more permeable vessels. As a rule, tumor tissue perfusion and diffusion parameters decreased in time, but locally increase was observed. Time- and spatial heterogeneity of tumor microenvironment, including vasculature, was revealed by 3D imaging, demonstrating that local changes are often contradictory to parameters averaged over the whole tumor volume.