Pharmacokinetic evaluation of paclitaxel, albumin-binding paclitaxel, and liposomal-encapsulated albumin-binding paclitaxel upon gastric subserosal administration.

Introduction: Systemic chemotherapy is typically administered following radical gastrectomy for advanced stage. To attenuate systemic side effects, we evaluated the effectiveness of regional chemotherapy using paclitaxel, albumin-paclitaxel, and liposome-encapsulated albumin-paclitaxel via subserosal injection in rat models employing nuclear medicine and molecular imaging technology. Method: Nine Sprague Dawley rats were divided into three groups: paclitaxel (n = 3), albumin-paclitaxel nano-particles (APNs; n = 3), and liposome-encapsulated APNs (n = 3). [123I]Iodo-paclitaxel ([123I]I-paclitaxel) was synthesized by conventional electrophilic radioiodination using tert-butylstannyl substituted paclitaxel as the precursor. Albumin-[123I]iodo-paclitaxel nanoparticles ([123I]APNs) were prepared using a desolvation technique. Liposome-encapsulated APNs (L-[123I]APNs) were prepared by thin-film hydration using DSPE-PEG2000, HSPC, and cholesterol. The rats in each group were injected with each test drug into the subserosa of the stomach antrum. After predetermined times (30 min, 2, 4, 8 h, and 24 h), molecular images of nuclear medicine were acquired using single-photon emission computed tomography/computed tomography. Results: Paclitaxel, APNs, and L-APNs showed a high cumulative distribution in the stomach, with L-APNs showing the largest area under the curve. Most drugs administered via the gastric subserosal route are distributed in the stomach and intestines, with a low uptake of less than 1% in other major organs. The time to reach the maximum concentration in the intestine for L-APNs, paclitaxel, and APNs was 6.67, 5.33, and 4.00 h, respectively. Conclusion: These preliminary results imply that L-APNs have the potential to serve as a novel paclitaxel preparation method for the regional treatment of gastric cancer.

Radiopharmaceuticals for Skeletal Muscle PET Imaging.

The skeletal muscles account for approximately 40% of the body weight and are crucial in movement, nutrient absorption, and energy metabolism. Muscle loss and decline in function cause a decrease in the quality of life of patients and the elderly, leading to complications that require early diagnosis. Positron emission tomography/computed tomography (PET/CT) offers non-invasive, high-resolution visualization of tissues. It has emerged as a promising alternative to invasive diagnostic methods and is attracting attention as a tool for assessing muscle function and imaging muscle diseases. Effective imaging of muscle function and pathology relies on appropriate radiopharmaceuticals that target key aspects of muscle metabolism, such as glucose uptake, adenosine triphosphate (ATP) production, and the oxidation of fat and carbohydrates. In this review, we describe how [18F]fluoro-2-deoxy-D-glucose ([18F]FDG), [18F]fluorocholine ([18F]FCH), [11C]acetate, and [15O]water ([15O]H2O) are suitable radiopharmaceuticals for diagnostic imaging of skeletal muscles.

Efficacy of preoperative lymphoscintigraphy in predicting surgical outcomes of lymphaticovenous anastomosis in lower extremity lymphedema: Clinical correlations in gynecological cancer-related lymphedema.

BACKGROUND: Lymphaticovenous anastomosis (LVA) is a promising microsurgical treatment for lower extremity lymphedema (LEL). Lymphoscintigraphy effectively assesses lower limb lymphatic systems before LVA, but its role in predicting the therapeutic outcomes of LVA is indeterminate. In this study we investigate the efficacy of preoperative lymphoscintigraphy using clinical findings to predict outcomes in gynecological cancer-related LEL patients who underwent LVA. METHODS: A retrospective review was conducted on consecutive gynecological cancer patients with LEL who had undergone LVA between June 2018 and June 2021. The therapeutic efficacy was assessed by measuring the change rate of the lower extremity lymphedema index (LELi) six months after surgery. Clinical data and lymphoscintigraphic findings were analyzed to assess therapeutic efficacy of LVA. RESULTS: Out of the 60 evaluated legs, 83.3% of the legs showed improved results after LVA. Univariable linear regression analysis revealed that higher preoperative LELi, and ovarian cancer were associated with superior LELi change rate (LC rate). Absence of dermal backflow (DBF) on lymphoscintigraphy was associated with inferior LC rate. Multivariable linear regression analysis identified ovarian cancer and higher preoperative LELi were independently correlated with favorable outcomes, while the absence of DBF was independently correlated with inferior outcomes. CONCLUSION: The results of this study emphasizes the effectiveness of preoperative lymphoscintigraphy, preoperative LELi, and primary malignancy as predictors of LVA outcomes in gynecological cancer-related LEL patients.

Value of Quantitative Salivary Gland SPECT/CT for the Detection of Saliva Leakage.

ABSTRACT: A 47-year-old woman presented to our emergency department with a 10-day history of pain, halitosis, and swelling below the left jaw. The patient was diagnosed with left sialadenitis and left submandibular abscess by tissue biopsy. An otolaryngologist performed transcervical incision and drainage of the abscess 1 day after admission. Postoperatively, the patient complained of a sensation of fluid leakage from the mouth, and a continuous purulent discharge was observed. One month postoperatively, a salivary gland scan and SPECT/CT were performed to investigate the sialorrhea and the cause of the discharge. Salivary gland SPECT/CT images localized the saliva leakage site.

The added value of SPECT/CT lymphoscintigraphy in the initial assessment of secondary extremity lymphedema patients.

An added value of SPECT/CT over planar lymphoscintigraphy for initial staging in patients with secondary extremity lymphedema was investigated. Furthermore, we developed a hybrid SPECT/CT classification combining dermal backflow (DBF) of SPECT and honeycomb pattern (HP) of CT, correlated it with lymphoscintigraphic staging and clinical severity. Forty-one patients with secondary extremity lymphedema who underwent lymphoscintigraphy with SPECT/CT were included retrospectively. The severity of extremity lymphedema was assessed using CT volumetry. Lymphoscintigraphic findings were evaluated using the Taiwan Lymphoscintigraphy Staging (TLS), and CT-based and SPECT-based quantitative analysis were performed. TLS was performed by planar scintigraphy only and with SPECT/CT, respectively. The SPECT/CT findings were classified into DBF-/HP-, DBF+/HP-, DBF+/HP+, and DBF-/HP+. Based on these findings, patients were categorized into five classes: Class 1 = DBF-HP- entire limb, Class 2 = DBF+/HP- proximal/distal limb without DBF+/HP+ or DBF-/HP+, Class 3 = DBF+/HP+ proximal/distal limb without DBF-/HP+, Class 4 = Mixed DBF+/HP+ and DBF-/HP+ in proximal/distal limb, Class 5 = DBF-/HP+ entire limb. Adding SPECT/CT to planar scintigraphy showed a 15.4% modification rate in lymphoscintigraphic staging. HP volume ratio significantly increased as clinical severity and lymphoscintigraphic staging increased, while DBF volume ratio increased with severity and followed expected patterns according to lymphoscintigraphic staging. Hybrid SPECT/CT lymphoscintigraphic classification showed strong positive correlation with clinical severity and TLS. Our results demonstrated substantial modification of lymphoscintigraphic staging by adding SPECT/CT to a conventional planar scintigraphy. In addition, a hybrid SPECT/CT is expected to provide new indicators reflecting lymphoscintigraphic staging and clinical severity by providing both of functional DBF and anatomical HP information.

A novel chalcone derivative exerts anticancer effects by promoting apoptotic cell death of human pancreatic cancer cells.

Aggressive pancreatic cancer is typically treated using chemotherapeutics to reduce the tumor pre-operatively and prevent metastasis post-operatively, as well as surgical approaches. In the present study, we synthesized a hydroxyl group-introduced chalcone derivative (1, IC50 = 32.1 µM) and investigated its potential as an anticancer drug candidate by evaluating its apoptosis-promoting effects on BXPC-3 cancer cells. The viability of BXPC-3 cells treated with 1 was measured using the water-soluble tetrazolium 1 reagent. BXPC-3 cells induced by 1 were stained with diverse probes or antibodies, such as ethidium homodimer-1, Hoechst, anti-Ki67, and MitoTracker. Protein expression was measured using an immunoblotting assay, and mRNA expression was determined using real-time polymerase chain reaction. Apoptotic molecular features, such as lipid accumulation and protein degradation, were monitored directly using stimulated Raman scattering microspectroscopy. Through incubation time- and concentration-dependent studies of 1, we found that it significantly reduced the proliferation and increased the number of apoptotic BXPC-3 cells. Compound 1 induced mitochondrial dysfunction, phosphorylation of p38, and caspase 3 cleavage. These results indicate that 1 is a potential therapeutic agent for pancreatic cancer, providing valuable insights into the development of new anticancer drug candidates.

In vivo tissue pharmacokinetics of ERBB2-specific binding oligonucleotide-based drugs by PET imaging.

Although aptamers have shown excellent target specificity in preclinical and clinical studies either by themselves or as aptamer-drug conjugates, their in vivo tissue pharmacokinetic (PK) analysis is still problematic. We aimed to examine the utility of image-based positron emission tomography (PET) to evaluate in vivo tissue PK, target specificity, and applicability of oligonucleotides. For this, fluorine-18-labeled aptamers with erb-b2 receptor tyrosine kinase 2 (ERBB2)-specific binding were synthesized by base-pair hybridization using a complementary oligonucleotide platform. To investigate the PKs and properties of in vivo tissue, usefulness of in vivo PET imaging in the development of an oligonucleotide-based drug as an assessment tool was evaluated in normal and tumor xenografted mice. ERBB2-cODN-idT-APs-[18 F]F ([18 F]1), injected intravenously showed significant and rapid uptake in most tissues except for the initial brain and muscle; the uptake was highest in the heart, followed by kidneys, liver, lungs, gall bladder, spleen, and stomach. The main route of excretion was through the renal tract ~77.8%, whereas about 8.3% was through the biliary tract of the total dose. The estimated effective dose for an adult woman was 0.00189 mGy/MBq, which might be safe. ERBB2-positive tumor could be well visualized in the KPL4 xenograft animal model by in vivo PET imaging. Consequently, the distribution in each organ including ERBB2 expression could be well determined and quantified by PET with fluorine-18-labeled aptamers. In vivo PK parameters such as terminal half-life, time to maximum concentration, area under the curve, and maximum concentration, were also successfully estimated. These results suggest that image-based PET with radioisotope-labeled aptamers could be provide valuable information on properties of oligonucleotide-based drugs in drug discovery of targeted therapeutics against various diseases.

Clinical Impact of SPECT/CT in Evaluation of Abdominothoracic Fistula.

ABSTRACT: Abdominothoracic fistula is rarely observed but can be life-threatening. Pleuroperitoneal communication, known to occur in 1.6% of all patients who undergo continuous ambulatory peritoneal dialysis, is an uncommon but well-recognized complication. The most common symptoms are dyspnea and right-sided pleural effusion. A biliopleural fistula is well-described as a complication of radiofrequency ablation and transcatheter arterial chemoembolization of hepatic lesions. It is important to diagnose the cause of pleural effusion early for proper treatment because if the abdominothoracic fistula effusion amount is not large, appropriate diagnosis may be difficult. Here, we introduce 2 cases showing the usefulness of SPECT/CT in evaluating pleuroperitoneal and biliopleural fistulas.

Clinical Usefulness of 18 F-FET PET in a Pediatric Patient With Suspected Demyelinating Disease.

ABSTRACT: An 11-year-old boy who presented with headache and progressive right-sided weakness exhibited cortical swelling in the parafalcine area of both frontoparietal high convexity and splenium portion of corpus callosum on brain MRI. This suggested the possibility of encephalopathy, but required differential diagnosis from brain tumor. 18 F-FET ( O -(2-[ 18 F]fluoroethyl)- l -tyrosine) PET/CT identified increased uptake along the parafalcine area of the frontoparietal lobes and the splenium portion of the corpus callosum. The relatively low target-to-background ratios were more indicative of inflammatory changes such as demyelinating disease. The patient recovered after empirical steroid and immunoglobulin treatment. Clinically, the patient was diagnosed with acute disseminated encephalomyelitis.

Potential anticancer effect of aspirin and 2'-hydroxy-2,3,5'-trimethoxychalcone-linked polymeric micelles against cervical cancer through apoptosis.

Although early diagnosis and treatment of cancers in women are achievable through continuous diagnostic tests, cervical cancer (CVC) still has a high mortality rate. In the present study, we investigated whether certain nanoparticles (NPs), comprising aspirin conjugated 2'-hydroxy-2,3,5'-trimethoxychalcone chemicals, could induce the apoptosis of cancer cells. HeLa cells were treated with NPs and the cell viability was evaluated using WST-1 assay. Protein expression of Ki-67 was measured using immunocytochemistry. In addition, the apoptotic effect of NPs was determined using TUNEL assay. To investigate the apoptosis signaling pathways, reverse transcription quantitative PCR was performed and lipid accumulation was observed via holotomographic microscopy. The IC50 value of the NPs was 4.172 µM in HeLa cells. Furthermore, 10 µM NPs significantly inhibited the cell proliferation and stimulated the apoptosis of HeLa cells. In addition, apoptosis and mitochondrial dysfunction were induced by the NPs through lipid accumulation in HeLa cells, leading to apoptotic signaling cascades. Taken together, the results from the present study demonstrated that the NPs developed promoted apoptosis though efficient lipid accumulation in HeLa cells, suggesting that they may provide a novel way to improve the efficacy of CVC anticancer treatment.

18F-FET PET/CT as a Diagnostic Tool for Brain Abscess.

ABSTRACT: A 49-year-old man presented with sudden right-sided weakness and seizure. Brain MRI identified a lobulated mass with diffusion restriction and irregular wall enhancement in the left parietal lobe. 18F-FET (O-(2-[18F]fluoroethyl)-l-tyrosine) PET/CT was performed, which identified a cystic mass in the left parietal lobe accompanied by FET uptake. Compartmentalized uptake was also confirmed throughout the left parietal lobe. Considering the relatively low target-to-background ratio and uptake observed in the entire left parietal lobe, the lesion was more likely to be a brain abscess than a tumor. The pathologic diagnosis after mass removal was acute and chronic inflammation with abscess.

Tissue pharmacokinetics of DHP107, a novel lipid-based oral formulation of paclitaxel, in mice and patients by positron emission tomography.

DHP107 is a newly developed lipid-based oral formulation of paclitaxel. We evaluated the in vivo tissue pharmacokinetics (PKs) of DHP107 in mice and patients using positron emission tomography (PET). Radioisotope-labeled [3 H]DHP107 and [18 F]DHP107 for oral administration were formulated in the same manner as the manufacturing process of DHP107. In vivo tissue PK were assessed in healthy ICR mice and breast cancer xenografted SCID mice. Two patients with metastatic breast cancer were clinically evaluated for absorption at the target lesion after internal absorbed dose estimation. Whole-body PET/computed tomography data were acquired in healthy and xenografted mice and in patients up to 10-24 h after administration. Tissue [18 F]DHP107 signals were plotted against time and PK parameters were determined. The amounts of radioactivity in various organs and excreta were determined using a beta-counter and are expressed as the percentage of injected dose (ID). Oral [18 F]DHP107 was well-absorbed and reached the target lesion in mice and patients with breast cancer. Significant amounts of radioactivity were found in the stomach, intestine, and liver after oral administration of [3 H]- and [18 F]DHP107 in healthy mice. The [18 F]DHP107 reached a peak distribution of 0.7-0.8%ID in the tumor at 5.6-7.3 h in the xenograft model. The [18 F]DHP107 distribution in patients with metastatic breast cancer was the highest at 3-4 h postadministration. Systemic exposures after administration of a DHP107 therapeutic dose were comparable with those in previous studies. PET using radioisotope-labeled drug candidates is useful for drug development and can provide valuable information that can complement plasma PK data, particularly in early phase clinical trials.

Lymphoscintigraphic Findings as Indicators of Lymphaticovenous Anastomosis Outcome in Patients With Extremity Lymphedema: A Retrospective Cohort Study.

PURPOSE: This study was performed to evaluate the usefulness of lymphoscintigraphy in predicting the surgical outcomes of lymphaticovenous anastomosis (LVA) in a patient with extremity lymphedema. PATIENTS AND METHODS: We retrospectively evaluated 133 patients with extremity lymphedema who underwent lymphoscintigraphy followed by LVA surgery from February 2018 to March 2020. Lymphoscintigraphic findings were evaluated on the following parameters: the extent of dermal backflow (small/large), lymphatic flow patterns (trunk flow pattern/proximal-restricted pattern/distal-restricted pattern), visualization of lymph nodes, and collateral lymphatic vessels. The mean circumferential difference change before and after surgery, circumferential reduction (CR) rate (%), was used as the clinical outcome variables. RESULTS: A decrease in circumference was observed in 93 (69.9%) of 133 patients after LVA. The extent of dermal backflow and lymphatic flow patterns was significantly correlated with improved clinical outcomes after LVA. The large extent of the dermal backflow group showed a more significant CR rate than the small extent (19.27% vs 1.24%, P = 0.005). The TP group showed the most significantly decreased CR rate to 21.46%, and the proximal-restricted pattern and distal-restricted pattern groups were -2.49% and -5.33%, respectively (P < 0.001). Multivariate analysis revealed that dermal backflow and lymphatic flow patterns were independent predictors of therapeutic outcome (P < 0.001). CONCLUSIONS: Our study demonstrates that pretreatment lymphoscintigraphy may help predict the therapeutic effect of LVA in patients with extremity lymphedema. Furthermore, dermal backflow and lymphatic flow patterns are independent predictors of CR rate after LVA surgery for extremity lymphedema.

Radioactive Iodine Treatment for Children and Young Adults with Thyroid Cancer in South Korea: A Population-based Study.

PURPOSE: This study investigated radioactive iodine treatment (RAIT) patterns and the secondary cancer incidence among children and young adults receiving RAIT after thyroidectomy for thyroid cancer. METHODS: This population-based cohort study used the Health Insurance Review and Assessment database of South Korea to identify a total of 18 617 children and young adults (0-29 years) who underwent thyroidectomy for thyroid cancer between 2008 and 2018. We recorded age at surgery, sex, the interval from surgery to RAIT, the doses of RAI, the number of RAIT sessions, and secondary cancer incidence. RESULTS: A total of 9548 (51.3%) children and young adults underwent 1 or more RAIT sessions. The initial dose of RAIT was 4.35 ±â€…2.19 GBq. The overall RAIT frequency fell from 60.9% to 38.5%, and the frequency of high-dose RAIT (>3.7 GBq) fell from 64.2% to 36.5% during the observational period. A total of 124 cases of secondary cancer developed during 120 474 person-years of follow-up; 43 (0.5%) in the surgery cohort and 81 (0.8%) in the RAIT cohort. Thus, the RAIT cohort was at an increased risk of secondary cancer (adjusted hazard ratio 1.52 [95% confidence interval 1.03-2.24], P = 0.035). CONCLUSION: The proportion of children and young adults receiving RAIT, and the RAI dose, fell significantly over the observational period. RAIT was associated with secondary cancers. This is of major concern in the context of child and young adult thyroid cancer survivors.

The impact of data-driven respiratory gating in clinical F-18 FDG PET/CT: comparison of free breathing and deep-expiration breath-hold CT protocol.

BACKGROUND: Respiratory motion can diminish PET image quality and lead to inaccurate lesion quantifications. Data-driven gating (DDG) was recently introduced as an effective respiratory gating technique for PET. In the current study, we investigated the clinical impact of DDG on respiratory movement in 18F-FDG PET/CT. METHOD: PET list-mode data were collected for each subject and DDG software was utilized for extracting respiratory waveforms. PET images was reconstructed using Q.clear and Q.clear + DDG, respectively. We evaluated SUVmax, SUVmean, the coefficient of variance (CoV), metabolic tumor volume (MTV), and tumor heterogeneity using the area under the curve of cumulative SUV histogram (AUC-CSH). Metabolic parameter changes were compared between each reconstruction method. The Deep-Expiration Breath Hold (DEBH) protocol was introduced for CT scans to correct spatial misalignment between PET and CT and compared with conventional free breathing. The DEBH and free breathing (FB) protocol comparison was made in a separate matching cohort using propensity core matching rather than the same patient. RESULTS: Total 147 PET/CT scans with excessive respiratory movements were used to study DDG-mediated correction. After DDG application, SUVmax (P < 0.0001; 8.15 ± 4.77 vs. 9.03 ± 5.02) and SUVmean (P < 0.0001; 4.91 ± 2.44 vs. 5.49 ± 2.68) of lung and upper abdomen lesions increased, while MTV significantly decreased (P < 0.0001; 7.07 ± 15.46 vs. 6.58 ± 15.14). In addition, the percent change of SUVs was greater in lower lung lesions compared to upper lobe lesions. Likewise, the MTV reduction was significantly greater in lower lobe lesions. No significant difference dependent on location was observed in liver lesions. DEBH-mediated CT breathing correction did not make a significant difference in lesion metabolic parameters compared to conventional free breathing. CONCLUSIONS: These results suggest that DDG correction enables more corrected quantification from respiratory movements for lesions located in the lung and upper abdomen. Therefore, we suggest that DDG is worth using as a standard protocol during 18F-FDG PET/CT imaging.

Camphene Attenuates Skeletal Muscle Atrophy by Regulating Oxidative Stress and Lipid Metabolism in Rats.

Sarcopenia- or cachexia-related muscle atrophy is due to imbalanced energy metabolism and oxidative stress-induced muscle dysfunction. Monoterpenes play biological and pharmacological reactive oxygen species (ROS) scavenging roles. Hence, we explored the effects of camphene, a bicyclic monoterpene, on skeletal muscle atrophy in vitro and in vivo. We treated L6 myoblast cells with camphene and then examined the ROS-related oxidative stress using Mito TrackerTM Red FM and anti-8-oxoguanine antibody staining. To investigate lipid metabolism, we performed real-time polymerase chain reactions, holotomographic microscopy, and respiratory gas analysis. Rat muscle atrophy in in vivo models was observed using 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography and immunocytochemistry. Camphene reversed the aberrant cell size and muscle morphology of L6 myoblasts under starvation and in in vivo models. Camphene also attenuated E3 ubiquitin ligase muscle RING-finger protein-1, mitochondrial fission, and 8-oxoguanine nuclear expression in starved myotubes and hydrogen peroxide (H2O2)-treated cells. Moreover, camphene significantly regulated lipid metabolism in H2O2-treated cells and in vivo models. These findings suggest that camphene may potentially affect skeletal muscle atrophy by regulating oxidative stress and lipid metabolism.

Suppressing breast cancer by exercise: consideration to animal models and exercise protocols.

PURPOSE: Exercise is thought to have a significant effect on chemotherapy, and previous studies have reported that exercise can increase patient survival. Thus, in this review, we aimed to summarize various animal models to analyze the effects of exercise on breast cancer. METHODS: We summarized types of breast cancer animal models from various reports and analyzed the effects of exercise on anti-cancer factors in breast cancer animal models. RESULTS: This review aimed to systematically investigate if exercise could aid in suppressing breast cancer. Our study includes (a) increase in survival rate through exercise; (b) the intensity of exercise should be consistent and increased; (c) a mechanism for inhibiting carcinogenesis through exercise; (d) effects of exercise on anti-cancer function. CONCLUSION: This review suggested the necessity of a variety of animal models for preclinical studies prior to breast cancer clinical trials. It also provides evidence to support the view that exercise plays an important role in the prevention or treatment of breast cancer by influencing anticancer factors.

99mTc-RBC SPECT/CT for Duodenal Bleeding Point Detection.

This is a case of a 63-year-old man who presented with acute melena and low hemoglobin. Upper and lower gastrointestinal evaluations failed to localize the bleeding focus. Tc-RBC planar scintigraphy identified 2 sites of suspected bleeding in the lower abdomen area. Subsequent SPECT/CT was performed and identified the precise main focus of active bleeding, the second and third parts of the duodenum, and also described the blood accumulation in the jejunum. Esophagogastroduodenoscopy was immediately performed, and results confirmed spurting blood from the small vessel with multiple ulcers in the second part of the duodenum.

Heat shock protein 90 inhibitor AUY922 attenuates platelet-derived growth factor-BB-induced migration and proliferation of vascular smooth muscle cells.

Luminespib (AUY922), a heat shock proteins 90 inhibitor, has anti-neoplastic and antitumor effects. However, it is not clear whether AUY922 affects events in vascular diseases. We investigated the effects of AUY922 on the platelet-derived growth factor (PDGF)-BB-stimulated proliferation and migration of vascular smooth muscle cells (VSMC). VSMC viability was detected using the XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reagent. To detect the attenuating effects of AUY922 on PDGF-BB-induced VSMCs migration in vitro, we performed the Boyden chamber and scratch wound healing assays. To identify AUY922-mediated changes in the signaling pathway, the phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) 1/2 was analyzed by immunoblotting. The inhibitory effects of AUY922 on migration and proliferation ex vivo were tested using an aortic ring assay. AUY922 was not cytotoxic at concentrations up to 5 nM. PDGF-BB-induced VSMC proliferation, migration, and sprout outgrowth were significantly decreased by AUY922 in a dose-dependent manner. AUY922 significantly reduced the PDGF-BB-stimulated phosphorylation of Akt and ERK1/2. Furthermore, PD98059 (a selective ERK1/2 inhibitor) and LY294002 (a selective Akt inhibitor) decreased VSMC migration and proliferation by inhibiting phosphorylation of Akt and ERK1/2. Greater attenuation of PDGF-BB-induced cell viability and migration was observed upon treatment with PD98059 or LY294002 in combination with AUY922. AUY922 showed anti-proliferation and anti-migration effects towards PDGF-BBinduced VSMCs by regulating the phosphorylation of ERK1/2 and Akt. Thus, AUY922 is a candidate for the treatment of atherosclerosis and restenosis.

Development of a Theranostic Convergence Bioradiopharmaceutical for Immuno-PET Based Radioimmunotherapy of L1CAM in Cholangiocarcinoma Model.

PURPOSE: Cholangiocarcinoma is a malignancy of bile duct with a poor prognosis. Conventional chemotherapy and radiotherapy are generally ineffective, and surgical resection is the only curative treatment for cholangiocarcinoma. L1-cell adhesion molecule (L1CAM) has been known as a novel prognostic marker and therapeutic target for cholangiocarcinoma. This study aimed to evaluate the feasibility of immuno-PET imaging-based radioimmunotherapy using radiolabeled anti-L1CAM antibody in cholangiocarcinoma xenograft model. EXPERIMENTAL DESIGN: We prepared a theranostic convergence bioradiopharmaceutical using chimeric anti-L1CAM antibody (cA10-A3) conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator and labeled with 64Cu or 177Lu and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with 64Cu-/177Lu-cA10-A3 in various cholangiocarcinoma xenograft models. Therapeutic efficacy and response monitoring were performed by 177Lu-cA10-A3 and 18F-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67. RESULTS: Radiolabeled cA10-A3 antibodies specifically recognized L1CAM in vitro, clearly visualized cholangiocarcinoma tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in cholangiocarcinoma xenograft models. 177Lu-cA10-A3 (12.95 MBq/100 µg) showed statistically significant reduction in tumor volumes (P < 0.05) and decreased glucose metabolism (P < 0.01). IHC analysis revealed 177Lu-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or 177Lu-isotype. CONCLUSIONS: Anti-L1CAM immuno-PET imaging using 64Cu-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting appropriate patients for radioimmunotherapy. Radioimmunotherapy using 177Lu-cA10-A3 may provide survival benefit in L1CAM-expressing cholangiocarcinoma tumor. Theranostic convergence bioradiopharmaceutical strategy would be applied as imaging biomarker-based personalized medicine in L1CAM-expressing patients with cholangiocarcinoma.