Nanobubbles: A Novel Targeted Drug Delivery System

Abstract Nanobubbles are nanometer size bubbles having different constituents of varying physicochemical characteristic for the inner core and outer shell. Nanobubbles are mainly fabricated to improve the stability, bioavailability and improve the biodistribution of the delivered drug to the specific targeted site. Their small sizes bubbles allow the possibility of extravasation from blood vessels into the surrounding tissues and ultrasound-targeted site-specific release with minimal invasiveness. Nanobubbles are developing as important contrast agents for imaging and carriers for drug delivery at targeted region. Sonication is the primary method for preparation of nanobubbles followed by thin-layer evaporation, high shear emulsification, mechanical agitation and coacervation or coalescence. With exposure to ultrasound/extracorporeal shock waves, the drug is liberated from the nanobubbles into the target cells. This review paper is an effort to reveal the different formulation development techniques briefly and varying shell and core content for developing nanobubbles.

Untargeted contrast-enhanced ultrasound versus contrast-enhanced computed tomography: a differential diagnostic performance (DDP) study for kidney lesions

OBJECTIVES: Histopathology is the 'gold standard' for diagnosing renal cell carcinoma but is limited by sample size. Contrast-enhanced ultrasound can differentiate malignant and benign lesions, but the Chinese guidelines on the management of renal cell carcinoma do not include this method. The purpose of this study was to compare the diagnostic parameters of contrast-enhanced ultrasound against those of contrast-enhanced computed tomography for detecting kidney lesions, with histopathology considered the reference standard. METHODS: Patients with suspected kidney lesions from prior grayscale ultrasonography and computed tomography were included in the analysis (n=191). The contrast-enhanced ultrasound, contrast-enhanced computed tomography, and histopathology data were collected and analyzed. A solid, enhanced mass was considered a malignant lesion, and an unenhanced mass or cyst was considered a benign lesion. The Bosniak criteria were used to characterize the lesions. RESULTS: Contrast-enhanced ultrasound and contrast-enhanced computed tomography both detected that 151 patients had malignant tumors and 40 patients had benign tumors. No significant differences in the tumors and their subtypes were reported between contrast-enhanced ultrasound and histopathology (p=0.804). Chromophobe renal cell carcinoma was detected through contrast-enhanced computed tomography (n=1), but no such finding was reported by contrast-enhanced ultrasound. A total of 35 cases of papillary renal cell carcinoma were reported through contrast-enhanced ultrasound while 32 were reported through histopathology. CONCLUSIONS: Contrast-enhanced ultrasound might be safe and as accurate as histopathology in diagnosing kidney lesions, especially renal cell carcinoma. Additionally, this study provides additional information over histopathology and has an excellent safety profile. Level of evidence: III.

Natural oral contrast agents for gastrointestinal magnetic resonance imaging

Magnetic resonance imaging is an exclusive imaging method which can distinguish injured tissues from the healthy tissues or organs without using ionizing radiation. Magnetic resonance imaging is able to provide quantitative data regarding the anatomical and physiological features of each specific organ. Magnetic resonance imaging is a non-invasive method, but contrast agents are necessary to enhance the visualization of inaccessible organs in some organs such as gastrointestinal [GI] imaging. Various types of contrast agents have been used in studies including intravascular administration and oral materials. Oral contrast agents can be the artificial materials or natural factors. Natural contrast agents consist of fruit juice or pulps. Some advantages have been reported regarding the natural types of contrast agents over the artificial agents including better taste and tolerability. We briefly reviewed the different types of contrast agents and focused on the studies in which natural oral contrast agents used to investigate their efficacy in increasing the gastrointestinal magnetic resonance imaging clarity

Use of nanoparticles to monitor human mesenchymal stem cells transplanted into penile cavernosum of rats with erectile dysfunction

PURPOSE: This study was performed to examine the treatment of erectile dysfunction by use of superparamagnetic iron oxide nanoparticles-labeled human mesenchymal stem cells (SPION-MSCs) transplanted into the cavernous nerve injured cavernosa of rats as monitored by molecular magnetic resonance imaging (MRI). MATERIALS AND METHODS: Eight-week-old male Sprague-Dawley rats were divided into three groups of 10 rats each: group 1, sham operation; group 2, cavernous nerve injury; group 3, SPION-MSC treatment after cavernous nerve injury. Immediately after the cavernous nerve injury in group 3, SPION-MSCs were injected into the cavernous nerve injured cavernosa. Serial T2-weighted MRI was done immediately after injection and at 2 and 4 weeks. Erectile response was assessed by cavernous nerve stimulation at 2 and 4 weeks. RESULTS: Prussian blue staining of SPION-MSCs revealed abundant uptake of SPION in the cytoplasm. After injection of 1x10(6) SPION-MSCs into the cavernosa of rats, T2-weighted MRI showed a clear hypointense signal induced by the injection. The presence of SPION in the corpora cavernosa was confirmed with Prussian blue staining. At 2 and 4 weeks, rats with cavernous nerve injury had significantly lower erectile function than did rats without cavernous nerve injury (p<0.05). The group transplanted with SPION-MSCs showed higher erectile function than did the group without SPION-MSCs (p<0.05). The presence of SPION-MSCs for up to 4 weeks was confirmed by MRI imaging and Prussian blue staining in the corpus cavernosa. CONCLUSIONS: Transplanted SPION-MSCs existed for up to 4 weeks in the cavernous nerve injured cavernosa of rats. Erectile dysfunction recovered and could be monitored by MRI.

Correlations of Dynamic Contrast-Enhanced Magnetic Resonance Imaging with Morphologic, Angiogenic, and Molecular Prognostic Factors in Rectal Cancer

PURPOSE: To investigate the correlations between parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and prognostic factors in rectal cancer. MATERIALS AND METHODS: We studied 29 patients with rectal cancer who underwent gadolinium contrast-enhanced, T1-weighted DCE-MRI with a three Tesla scanner prior to surgery. Signal intensity on DCE-MRI was independently measured by two observers to examine reproducibility. A time-signal intensity curve was generated, from which four semiquantitative parameters were calculated: steepest slope (SLP), time to peak (Tp), relative enhancement during a rapid rise (Erise), and maximal enhancement (Emax). Morphologic prognostic factors including T stage, N stage, and histologic grade were identified. Tumor angiogenesis was evaluated in terms of microvessel count (MVC) and microvessel area (MVA) by morphometric study. As molecular factors, the mutation status of the K-ras oncogene and microsatellite instability were assessed. DCE-MRI parameters were correlated with each prognostic factor using bivariate correlation analysis. A p-value of <0.05 was considered significant. RESULTS: Erise was significantly correlated with N stage (r=-0.387 and -0.393, respectively, for two independent data), and Tp was significantly correlated with histologic grade (r=0.466 and 0.489, respectively). MVA was significantly correlated with SLP (r=-0.532 and -0.535, respectively) and Erise (r=-0.511 and -0.446, respectively). MVC was significantly correlated with Emax (r=-0.435 and -0.386, respectively). No significant correlations were found between DCE-MRI parameters and T stage, K-ras mutation, or microsatellite instability. CONCLUSION: DCE-MRI may provide useful prognostic information in terms of histologic differentiation and angiogenesis in rectal cancer.

Evaluation of Porcine Pancreatic Islets Transplanted in the Kidney Capsules of Diabetic Mice Using a Clinically Approved Superparamagnetic Iron Oxide (SPIO) and a 1.5T MR Scanner

OBJECTIVE: To evaluate transplanted porcine pancreatic islets in the kidney capsules of diabetic mice using a clinically approved superparamagnetic iron oxide (SPIO) and a 1.5T MR scanner. MATERIALS AND METHODS: Various numbers of porcine pancreatic islets labeled with Resovist, a carboxydextran-coated SPIO, were transplanted into the kidney capsules of normal mice and imaged with a 3D FIESTA sequence using a 1.5T clinical MR scanner. Labeled (n = 3) and unlabeled (n = 2) islets were transplanted into the kidney capsules of streptozotocin-induced diabetic mice. Blood glucose levels and MR signal intensities were monitored for 30 days post-transplantation. RESULTS: There were no significant differences in viability or insulin secretion between labeled and unlabeled islets. A strong correlation (r2 > 0.94) was evident between the number of transplanted islets and T2 relaxation times quantified by MRI. Transplantation with labeled or unlabeled islets helped restore normal sustained glucose levels in diabetic mice, and nephrectomies induced the recurrence of diabetes. The MR signal intensity of labeled pancreatic islets decreased by 80% over 30 days. CONCLUSION: The transplantation of SPIO-labeled porcine islets into the kidney capsule of diabetic mice allows to restore normal glucose levels, and these islets can be visualized and quantified using a 1.5T clinical MR scanner.

Oxidant stress due to non ionic low osmolar contrast medium in rat kidney.

Background & objectives: Contrast media may cause contrast-induced nephropathy (CIN) in risk group. This study was taken up to establish possible effects of non ionic low osmolar contrast medium administration on oxidant/antioxidant status and nitric oxide (NO) levels in rat kidney tissues. Methods: Fourteen female, 14 wk old Wistar-albino rats were divided into 2 groups of 7 rats each (control and contrast groups). Non ionic low osmolar contrast medium was administered iv to the animals in the contrast group. The day after, animals were sacrificed and malondialdehyde (MDA) and NO levels and activities of antioxidant [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)] and oxidant [xanthine oxidase (XO)] enzymes were measured in kidney tissues. Serum creatinine levels were measured to evaluate kidney functions. Results: Contrast medium administration caused an increase in MDA levels and a decrease in NO levels in kidney tissues. Interpretation & conclusions: The results suggest that non ionic low osmolar contrast medium administration leads to accelerated oxidant reactions and decreased NO level in rat kidney tissues. Further studies need to be done to assess the role of these changes in CIN.

Induction of Upregulation and Downregulation of the T-Cell Activation Marker CD98 in Patients Undergoing Contrast-Enhanced CT with Iodinated Non-Ionic Dimeric Contrast Medium

OBJECTIVE: This study was designed to determine prospectively the expression of the multifunctional CD98 protein in peripheral white blood cells in patients receiving iodinated contrast media (CM) for a computed tomography (CT) examination. MATERIALS AND METHODS: In 12 adult patients that received non-ionic dimeric CM (iosimenol or iodixanol), the expression of CD98 was analyzed from samples of peripheral white blood cells obtained prior to, one hour, and 24 hours after CM injection by the use of flow cytometry analysis and the use of the direct immunofluorescence technique. RESULTS: Overall, expression of CD98 was significantly downregulated 24 hours after CM injection (51.9% +/- 10.8% vs. 38.8% +/- 16.9%; p < 0.04). Patients that received iosimenol exhibited a more pronounced but not significant decrease of CD98 expression both one hour and 24 hours after CM injection. In an analysis of specific patient responses, CD98 downregulation occurred in eight patients. In two patients, CD98 was upregulated, and in the remaining two patients, expression remained unchanged. No patient acquired an adverse CM reaction. CONCLUSION: This is the first demonstration that CM may be a regulator of CD98 expression. To determine if upregulation is associated with an increased risk for the acquisition of an adverse CM-induced hypersensitivity reaction and if downregulation is associated without a risk for the acquisition of an adverse CM-induced hypersensitivity reaction, further studies with a larger population of patients are required.

Evaluation of partial cranial cruciate ligament rupture with positive contrast computed tomographic arthrography in dogs

Computed tomographic arthrography (CTA) of four cadaveric canine stifles was performed before and after partial cranial cruciate ligament rupture in order to verify the usefulness of CTA examination for the diagnosis of partial cranial cruciate ligament rupture. To obtain the sequential true transverse image of a cranial cruciate ligament, the computed tomography gantry was angled such that the scanning plane was parallel to the fibula. True transverse images of cranial cruciate ligaments were identified on every sequential image, beginning just proximal to the origin of the cranial cruciate ligament distal to the tibial attachment, after the administration of iodinated contrast medium. A significant decrease in the area of the cranial cruciate ligament was identified on CTA imaging after partial surgical rupture of the cranial cruciate ligament. This finding implies that CTA can be used for assessing partial cranial cruciate ligament ruptures in dogs.

Three-dimensional CT angiography of the canine hepatic vasculature

Eight Beagle dogs were anesthetized and were imaged using a single channel helical CT scanner. The contrast medium used in this study was iohexol (300 mg I/ml) and doses were 0.5 ml/kg for a cine scan, 3 ml/kg for an enhanced scan. The flow rate for contrast material administration was 2 ml/sec for all scans. This study was divided into three steps, with unenhanced, cine and enhanced scans. The enhanced scan was subdivided into the arterial phase and the venous phase. All of the enhanced scans were reconstructed in 1 mm intervals and the scans were interpreted by the use of reformatted images, a cross sectional histogram, maximum intensity projection and shaded surface display. For the cine scans, optimal times were a 9-sec delay time post IV injection in the arterial phase, and an 18-sec delay time post IV injection in the venous phase. A nine-sec delay time was acceptable for the imaging of the canine hepatic arteries by CT angiography. After completion of arterial phase scanning, venous structures of the liver were well visualized as seen on the venous phase.

Successful Surgical Treatment of Aortoenteric Fistula

In order to establish optimal management for aortoenteric fistula (AEF) the records of five patients treated for AEF (four aortoduodenal and one aortogastric fistula) were retrospectively reviewed. The arterial reconstruction procedures were selected according to the surgical findings, underlying cause, and patient status. In situ aortic reconstructions with prosthetic grafts were performed on three patients who had no gross findings of periaortic infection, whereas axillo-bifemoral bypass was carried out in the other two patients with periaortic purulence. In all patients, after retroperitoneal irrigation a pedicled omentum was used to cover the aortic graft or aortic stump. In the preoperative abdominal computed tomography (CT) scan there was a periaortic air shadow in four out of five patients. There was no surgical mortality or graft infection observed during a mean follow-up period of 40 months (range, 24-68 months). Therefore, the treatment results of an AEF can be improved using intravenous contrast-enhanced abdominal CT for rapid diagnosis and selection of an appropriate surgical procedure based on the surgical findings and underlying cause.

A Case of Successful Treatment of Stomal Variceal Bleeding with Transjugular Intrahepatic Portosystemic Shunt and Coil Embolization

Variceal bleeding from enterostomy site is an unusual complication of portal hypertension. The bleeding, however, is often recurrent and may be fatal. The hemorrhage can be managed with local measures in most patients, but when these fail, surgical interventions or portosystemic shunt may be required. Herein, we report a case in which recurrent bleeding from stomal varices, developed after a colectomy for rectal cancer, was successfully treated by placement of transjugular intrahepatic portosystemic shunt (TIPS) with coil embolization. Although several treatment options are available for this entity, we consider that TIPS with coil embolization offers minimally invasive and definitive treatment.