Berberin sustained-release nanoparticles were enriched in infarcted rat myocardium and resolved inflammation.

Inflammatory regulation induced by macrophage polarization is essential for cardiac repair after myocardial infarction (MI). Berberin (BBR) is an isoquinoline tetrasystemic alkaloid extracted from plants. This study analyzes the most likely mechanism of BBR in MI treatment determined via network pharmacology, showing that BBR acts mainly through inflammatory responses. Because platelets (PLTs) can be enriched in the infarcted myocardium, PLT membrane-coated polylactic-co-glycolic acid (PLGA) nanoparticles (BBR@PLGA@PLT NPs) are used, which show enrichment in the infarcted myocardium to deliver BBR sustainably. Compared with PLGA nanoparticles, BBR@PLGA@PLT NPs are more enriched in the infarcted myocardium and exhibit less uptake in the liver. On day three after MI, BBR@PLGA@PLT NPs administration significantly increases the number of repaired macrophages and decreases the number of inflammatory macrophages and apoptotic cells in infarcted rat myocardium. On the 28th day after MI, the BBR@PLGA@PLT group exhibits a protective effect on cardiac function, reduced cardiac collagen deposition, improved scar tissue stiffness, and an excellent angiogenesis effect. In addition, BBR@PLGA@PLT group has no significant impact on major organs either histologically or enzymologically. In summary, the therapeutic effect of BBR@PLGA@PLT NPs on MI is presented in detail from the perspective of the resolution of inflammation, and a new solution for MI treatment is proposed.

Triptolide with hepatotoxicity and nephrotoxicity used in local delivery treatment of myocardial infarction by thermosensitive hydrogel.

Myocardial infarction (MI) resulting from coronary artery occlusion is the leading global cause of cardiovascular disability and mortality. Anti-inflammatory treatment plays an important role in MI treatment. Triptolide (TPL), as a Chinese medicine monomer, has a variety of biological functions, including anti-inflammatory, anti-tumor, and immunoregulation. However, it has been proved that TPL is poorly water soluble, and has clear hepatotoxicity and nephrotoxicity, which seriously limits its clinical application. Herein, we designed a long-acting hydrogel platform (TPL@PLGA@F127) for MI treatment by intramyocardial injection. First, we found that the inflammatory response and immune regulation might be the main mechanisms of TPL against MI by network pharmacology. Subsequently, we prepared the hydrogel platform (TPL@PLGA@F127) and tested its effects and toxicity on normal organs in the early stage of MI (3 days after MI-operation). The results showed that TPL@PLGA@F127 could not only promote "repair" macrophages polarization (to M2 macrophage) by day 3 after MI, but also has a long-lasting anti-inflammatory effect in the later stage of MI (28 days after MI-operation). Additionally, we proved that TPL@PLGA@F127 could attenuate the toxicity of TPL by releasing it more slowly and stably. Finally, we observed the long-term effects of TPL@PLGA@F127 on MI and found that it could improve cardiac function, depress the myocardial fibrosis and protect the cardiomyocytes. In summary, this study indicated that TPL@PLGA@F127 could not only enhance the therapeutic effects of TPL on MI, but also attenuate the hepatotoxicity and nephrotoxicity, which established a strong foundation for the clinical application of TPL for MI.

Visualizing γδ T cells by very late antigen-4-targeted positron emission tomography.

PURPOSE: γδ T cell-based immunotherapy has been rolled out as a promising treatment strategy for malignant tumors due to their potent anti-tumor cytotoxicity, ease of expansion, and unrestricted MHC feature. However, the dynamics and outcomes of γδ T cells in tumor sites are poorly understood. Reported strategies rely on ex vivo biolabeling, significantly limiting the application of γδ T cell molecular imaging. Herein, we investigated whether VLA-4 (very late antigen-4), a crucial component in the effective trafficking of lymphocytes, could serve as a biomarker to non-invasively visualize γδ T cells. METHODS: VLA-4-targeted tracer, 68 Ga-LLP2A, was evaluated in MDA-MB-231- and A549-bearing mice with adoptive transfer of γδ T cells by longitudinal PET/CT imaging. Imaging data were verified by ex vivo biodistribution studies, and the co-localization of CD3 and VLA-4 was validated by immunohistochemistry studies. RESULTS: 68 Ga-LLP2A showed high specificity to VLA-4-expressing γδ T cells in both in vitro and tumor-bearing mice with adoptive transfer of γδ T cells. Longitudinal PET imaging of 68 Ga-LLP2A in tumor-bearing mice with adoptive transfer of γδ T cells showed an increasing tumor tracer uptake, revealing the tumor-specific homing of γδ T cells. The presence of VLA-4-expressing γδ T cells in tumors was confirmed via histological analysis. CONCLUSION: To the best of our knowledge, we reported the first molecular probe, 68 Ga-LLP2A, for in vivo imaging of γδ T cells in live tumors, which advances PET imaging of γδ T cells and supports the translation of imaging agents for immunotherapeutic monitoring.

Conductive nanocomposite hydrogel and mesenchymal stem cells for the treatment of myocardial infarction and non-invasive monitoring via PET/CT.

BACKGROUND: Injectable hydrogels have great promise in the treatment of myocardial infarction (MI); however, the lack of electromechanical coupling of the hydrogel to the host myocardial tissue and the inability to monitor the implantation may compromise a successful treatment. The introduction of conductive biomaterials and mesenchymal stem cells (MSCs) may solve the problem of electromechanical coupling and they have been used to treat MI. In this study, we developed an injectable conductive nanocomposite hydrogel (GNR@SN/Gel) fabricated by gold nanorods (GNRs), synthetic silicate nanoplatelets (SNs), and poly(lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA). The hydrogel was used to encapsulate MSCs and 68Ga3+ cations, and was then injected into the myocardium of MI rats to monitor the initial hydrogel placement and to study the therapeutic effect via 18F-FDG myocardial PET imaging. RESULTS: Our data showed that SNs can act as a sterically stabilized protective shield for GNRs, and that mixing SNs with GNRs yields uniformly dispersed and stabilized GNR dispersions (GNR@SN) that meet the requirements of conductive nanofillers. We successfully constructed a thermosensitive conductive nanocomposite hydrogel by crosslinking GNR@SN with PLGA2000-PEG3400-PLGA2000, where SNs support the proliferation of MSCs. The cation-exchange capability of SNs was used to adsorb 68Ga3+ to locate the implanted hydrogel in myocardium via PET/CT. The combination of MSCs and the conductive hydrogel had a protective effect on both myocardial viability and cardiac function in MI rats compared with controls, as revealed by 18F-FDG myocardial PET imaging in early and late stages and ultrasound; this was further validated by histopathological investigations. CONCLUSIONS: The combination of MSCs and the GNR@SN/Gel conductive nanocomposite hydrogel offers a promising strategy for MI treatment.

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-4-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth. METHODS: Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-4-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated. RESULTS: Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. CONCLUSION: mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-4-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.

Expert consensus on the safety prevention and control of nuclear medicine diagnosis and treatment during the outbreak of COVID-19 (1st edition): (translated from Chinese version).

In December 2019, an infectious disease caused by a new type of coronavirus infection was prevalent in Wuhan and across the country. On January 20, 2020, the National Health Commission of the People's Republic of China issued No.1 Announcement, which incorporated the novel coronavirus pneumonia into the Class B infectious disease according to the Law on Prevention and Control of Infectious Disease, but the disease should be adopted in the management of Class A infectious disease. In order to effectively control the source of infection, cut off the transmission route, protect the susceptible population, ensure the medical quality and medical safety, perform epidemic prevention and control, and comprehensively guarantee the life safety and physical health of medical staff, patients, and family members, it is very important to organize and carry out nuclear medicine diagnosis and treatment scientifically and safely. According to the national prevention and control policy, Chinese Society of Nuclear Medicine and editorial board of the Chinese Journal of Nuclear Medicine and Molecular Imaging organized professionals to formulate the expert consensus on the safety prevention process of nuclear medicine imaging and nuclide therapy during the period of new coronavirus infection.

18F-FDG PET/CT in diagnostic and prognostic evaluation of patients with cardiac masses: a retrospective study.

PURPOSE: Correct diagnosis and prognostic assessment of cardiac masses are crucial before therapy. We evaluated the diagnostic and prognostic value of 18F-FDG PET/CT in patients with cardiac masses. METHODS: 18F-FDG PET/CT images of 64 patients with 65 cardiac masses were retrospectively analysed (34 men, 30 women; average age, 51.2 ± 17.5 years). Comparisons of CT features and 18F-FDG metabolic indices between benign and malignant entities, as well as among primary and secondary malignancies and lymphoma, were performed. The diagnostic values of PET/CT for distinguishing benign versus malignant masses were calculated. PET/CT data were further assessed for the predictive value for overall survival (OS) using the Cox proportional hazards model to assess potential independent predictors. Kaplan-Meier curves were generated to assess the value of PET/CT for prognostication. RESULTS: Statistically significant differences in various morphological features and metabolic indices between benign and malignant masses were found. An SUVmax of 6.75 was the optimal cutoff value to differentiate between benign and malignant masses, and the diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 92.11%, 88.89%, 90.77%, 92.11%, and 88.89%, respectively. Taking CT features and SUVmax ≥ 6.75 as a criterion, the values were 76.32%, 100.00%, 86.15%, 100.00%, and 75.00%, respectively; taking ≥ 3 CT features or SUVmax ≥ 6.75 as a criterion, the values were 94.74%, 88.89%, 92.31%, 92.31%, and 92.31%, respectively, indicating optimal diagnostic performance when paired with the anatomic information provided by the CT component. A univariate analysis of OS determined that surrounding tissue infiltration, epicardial infiltration, necrosis, multiple chambers or vessel involvement, distant metastasis, SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were significant predictors of survival. In the multivariate analysis, only SUVmax ≥ 6.715 was significant (P < 0.01). Median OS was 1460 days for SUVmax < 6.715 and 342 days for SUVmax ≥ 6.715 (P < 0.01). CONCLUSION: 18F-FDG PET/CT is helpful in the diagnosis of cardiac masses before treatment and has value in detecting extracardiac primary or secondary tumours. 18F-FDG PET/CT could also be a promising tool to provide prognostic information for these patients, especially SUVmax displaying independent prognostic value.

Drilling Condition Identification Based on Sound Pressure Signal in Anterior Cervical Discectomy Surgery.

BACKGROUND In anterior cervical discectomy and fusion (ACDF) surgery, drilling operation causes a high risk of tissue injury. This study aimed to present a novel feedback system based on sound pressure signals to identify drilling condition during ACDF. MATERIAL AND METHODS ACDF surgery was performed on the C4/5 segments of 6 porcine cervical specimens. The annulus fibrosus, endplate cartilage, sub-endplate cortical bone, and posterior longitudinal ligament (PLL) were drilled until penetration using a 2-mm high-speed burr. Sound pressure signals were collected using a microphone and dynamic signal analyzer. The recorded signals of different tissues were proceeded with lifting wavelet transform for extracting harmonic components. The frequencies of harmonic components are 1, 2, 3, 4, and 5 times higher than the motor frequency. The magnitude of harmonic components was calculated to identify different drilling conditions, along a broad spectrum of frequencies (1-5 kHz). For statistical analysis, one-way ANOVA (analysis of variance) and post hoc test (Dunnett's T3) were performed. RESULTS Very good demarcation was found among the signal magnitudes of different drilling conditions. Different drilling conditions do not present the same rate of variation of frequency. Differences in magnitude among all drilling conditions were statistically significant at certain frequency points (p<0.05). In 3 cases, one tissue could not be identified with respect to another (annulus fibrosus and endplate cartilage at 2 kHz, PLL and penetration at 3 kHz, annulus fibrosus and sub-endplate cortical bone at 5 kHz, p>0.05). CONCLUSIONS Sound pressure signals may provide an auxiliary feedback system for enhancing drilling operation in ACDF surgery, especially in minimally invasive surgery.

"Hepatic Superscan" Revealed on 18 F-FDG PET Due to Drug-Induced Fulminant Hepatitis.

ABSTRACT: "Hepatic superscan" could be caused by a variety of etiologies. Here we report a 68-year-old woman with a medication history of cefoperazone and azithromycin for pneumonia recently who underwent 18 F-FDG PET/CT to detect underlying malignancy due to unexplained liver damage and fever of unknown origin. Unexpectedly, "hepatic superscan" without morphologic changes was noted. Unfortunately, aggressive treatment did not reverse the damaged liver function, and the patient rapidly died. Drug-induced fulminant hepatitis was diagnosed clinically. Our case demonstrates that fulminant hepatitis could result in "hepatic superscan" on 18 F-FDG PET despite negative findings on the ultrasonography, CT, and MRI.

Congenital Mesoblastic Nephroma Mimic Wilms Tumor on 18 F-FDG PET/CT and PET/MR.

ABSTRACT: Congenital mesoblastic nephroma is an extremely rare, low-grade malignant renal tumor in children. A 10-month-old boy and a 4-month-old girl were admitted to our hospital with a huge abdominal mass. For staging of the mass, 18 F-FDG PET/CT and PET/MR were performed showing a huge heterogeneous abdominal mass accompanied by extensive heterogeneous aggregation. Both of them were highly suspected to be Wilms tumor, the most common renal malignant tumor in children. However, histopathological examination after surgery confirmed congenital mesodermal nephroma.

[68Ga]FAPI PET for Imaging and Treatment Monitoring in a Preclinical Model of Pulmonary Fibrosis: Comparison to [18F]FDG PET and CT.

PURPOSE: This study aimed to evaluate the feasibility of using [68Ga]-fibroblast-activating protein inhibitor (FAPI) positron emission tomography (PET) imaging for diagnosing pulmonary fibrosis in a mouse model. We also examined its value in monitoring treatment response and compared it with traditional [18F]-fluorodeoxyglucose (FDG) PET and computed tomography (CT) imaging. METHODS: A model of idiopathic pulmonary fibrosis was established using intratracheal injection of bleomycin (BLM, 2 mg/kg) into C57BL/6 male mice. For the treatment of IPF, a daily oral dose of 400 mg/kg/day of pirfenidone was administered from 9 to 28 days after the establishment of the model. Disease progression and treatment efficacy were assessed at different stages of the disease every week for four weeks using CT, [18F]FDG PET, and [68Ga]FAPI PET (baseline imaging performed at week 0). Mice were sacrificed and lung tissues were harvested for hematoxylin-eosin staining, picrosirius red staining, and immunohistochemical staining for glucose transporter 1 (GLUT1) and FAP. Expression levels of GLUT1 and FAP in pathological sections were quantified. Correlations between imaging parameters and pathological quantitative values were analyzed. RESULTS: CT, [18F]FDG PET and [68Ga]FAPI PET revealed anatomical and functional changes in the lung that reflected progression of pulmonary fibrosis. In untreated mice with pulmonary fibrosis, lung uptake of [18F]FDG peaked on day 14, while [68Ga]FAPI uptake and mean lung density peaked on day 21. In mice treated with pirfenidone, mean lung density and lung uptake of both PET tracers decreased. Mean lung density, [18F]FDG uptake, and [68Ga]FAPI uptake correlated well with quantitative values of picrosirius red staining, GLUT1 expression, and FAP expression, respectively. Conclusions: Although traditional CT and [18F]FDG PET reflect anatomical and metabolic status in fibrotic lung, [68Ga]FAPI PET provides a means of evaluating fibrosis progression and monitoring treatment response.

Solitary Accessory Spleen-Like Metastasis Coexisted With Splenic Infarction Reveled on 18F-FDG PET/CT in a Hepatocellular Carcinoma Patient.

ABSTRACT: Solitary parasplenic metastatic carcinoma may be misinterpreted as accessory spleen on CT images. In addition, elevated FDG uptake in the spleen may also mimic metastasis in patient with a history of carcinoma. Here we present a case of parasplenic metastasis coexisted with splenic infarction reveled on 18F-FDG PET/CT in a 51-year-old man with history of hepatocellular carcinoma.

Vertical Appearance of Urinary Bladder on Bone Scintigraphy Might Not Always Suggest Adjacent Pathology.

ABSTRACT: Previous publications suggested that vertical appearance of the urinary bladder on 99m Tc-MDP whole-body bone scintigraphy was likely due to an adjacent abnormality. Here we report bone scan findings of a vertical appearance of the urinary bladder in a 66-year-old man with lung cancer without corresponding pathology nearby.

Coexistence of FDG-Avid and FDG-Negative Aneurysms in a Patient With Fever of Unknown Origin.

ABSTRACT: A 68-year-old man with intermittent fever of unknown origin for 5 months underwent 18F-FDG PET/CT to detect causative lesion. An 18F-FDG-avid lesion was revealed in the left pelvic iliac vessel region and was highly suggestive of malignancy. One and a half months later, a giant left internal iliac artery aneurysm was identified by CT angiography, corresponding to the 18F-FDG-avid lesion. Combined with elevated inflammatory markers, he was finally diagnosed as having inflammatory internal iliac artery aneurysm. An abdominal aortic aneurysm with low 18F-FDG uptake was also identified.

Enhancing Photothermal Therapy Efficacy by In Situ Self-Assembly in Glioma.

The residence time of some small molecular imaging and therapeutic agents in tumor tissue is short and the molecules can be easily dispersed, which decreases treatment efficacy. Therefore, methods that enhance oncotherapy performance are of significant importance. Here, we report an in situ self-assembly strategy aimed at enhancing the photothermal therapy of glioblastomas. The probe, ICG-PEP-c(RGD)fk, consisted of a glutathione-reactive self-assembling polypeptide as the skeleton, indocyanine green (ICG) as a theranostic agent, and cyclic Arg-Gly-Asp [c(RGD)fk] peptides as the targeting group. ICG-PEP-c(RGD)fk was synthesized and found to be assembled in the glutathione environment at 9.446 µM in vitro. Human glioblastoma cell line U87MG-luc with high integrin αvß3 expression was applied to invivo experiments. ICG-PEP-c(RGD)fk provided clearer tumor imaging and had a tumor retention time of 6.12 times longer than that of ICG-c(RGD)fk. In therapeutic experiments, ICG-PEP-c(RGD)fk significantly suppressed glioblastoma growth and the tumor volume was 2.61 times smaller than in the ICG-c(RGD)fk group at the end of the observation period. Moreover, the median survival time of ICG-PEP-c(RGD)fk group was significantly improved by 2.78 times compared with that of the control group. In conclusion, glutathione-reactive self-assembling peptides are capable of increasing the tumor retention time and improving the photothermal therapeutic effect. The in situ self-assembly strategy is a potential and feasible method to enhance oncotherapy.