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1.  188Re radiopharmaceuticals for radiosynovectomy: evaluation and comparison of tin colloid, hydroxyapatite and tin-ferric hydroxide macroaggregates 
Radiosynovectomy is a therapy used to relieve pain and inflammation from rheumatoid arthritis and related diseases. In this study three 188Re particulate compounds were characterized according to their physico-chemical properties and their biological behavior in rabbits. The results were compared in order to establish which was the radiopharmaceutical that better fits the requirements of this kind of radiotherapy.
Three radiopharmaceutical formulations, tin colloid, hydroxyapatite particles (HA) and ferric hydroxide macroaggregates coated with tin colloid (FHMA), were physically characterized (number, volume and surface of the particles). For this purpose laser diffraction methodology was used. To evaluate cavity leakage of activity the following studies in New Zealand rabbits were performed: scintigraphic images for 48 hr after intraarticular injection of each radiopharmaceutical, biodistribution at 48 hr and urine samples collection during the first 24 hr post-radiopharmaceutical administration.
Labeling procedures for 188Re-HA and 188Re-Sn-FHMA were labour intensive while 188Re-Sn was easily prepared. Furthermore, 188Re-Sn colloid offered the greatest surface area in the 2–10 microm range and was obtained with a radiochemical purity over 95%, while percentage of bound activity for 188Re-HA and 188Re-Sn-FHMA were 55% and 92% respectively. Stability was verified for the three radiopharmaceuticals for 24 hr. Scintigraphic studies and biodistribution in rabbits after intraarticular administration of the radiopharmaceuticals showed relevant activity only in the knee, this being over 90% of the residual activity in the whole body at 48 hr in every case. Renal elimination of 188Re-Sn colloid and 188Re-Sn-FHMA was detected by activity measurements in urine samples, during the first 12 hr post-radiopharmaceutical injection.
The percentage of activity retained in the knee was 69.1% for 188Re-Sn colloid, 55.1% for 188Re-Sn-FHMA and 33.6% for 188Re-HA.
The 188Re-Sn colloid was easy to prepare, minimum facilities were required, was stable for 24 hr and showed minimal leakage from the joint after intraarticular injection into the rabbit's knee. Furthermore, 188Re-Sn colloid has greater retention in the knee when it is compared with the other radiopharmaceuticals, so it could provide the best therapeutic effect/absorbed dose ratio for the patient.
PMCID: PMC373254  PMID: 15040807
2.  The Efficacy of Magnetic Resonance Imaging and X-Ray in the Evaluation of Response to Radiosynovectomy in Patients with Hemophilic Arthropathy 
Objective: We aimed to assess the role of Magnetic Resonance Imaging (MRI) and X-Ray in the evaluation of response to radiosynovectomy (RS) in patients with hemophilic arthropathy.
Material and Methods: Eleven patients who suffered from hemophilic arthropathy with a mean age of 11.7 (range between 7-15) were included in this study. 148-185 MBq Yttrium 90 silicate (Y-90) was administered intraarticularly to ten knee joints and one patient was treated with intraarticular 74 MBq Rhenium 186 (Re-186) injection into his ankle. Before radiosynovectomy, plain anteroposterior and lateral X-rays of the target joints were obtained by standard technique. The follow-up MRI and X-ray studies of the patients were done 6 months after RS. Pettersson hemophilic arthropathy scales were utilized to stage the condition of the joints on plain X-ray and classification of the investigated joints on MRI were done according to Denver score. The clinical assessment of the efficacy of the RS was made with the comparison of the average bleedings before and after the intervention.
Results: During the 6-month follow-up period after RS, an improvement in number of hemarthrosis 75% or greater compared with the prior six months occurred in six joints (54.5%). The Pettersson scores worsened in 1/11 (9%), remained unchanged in 9/11 (81.8%), and improved in 1/11 (9%) joints. At the 6-month follow-up, the MRI score worsened in one (9%) and was unchanged in 10/11 joints (90.9%).
Conclusion: MRI is a more sensitive tool than plain radiography for evaluating and follow-up of joint disease in persons with hemophilia, but both methods don’t show correlation with the therapeutic response
Conflict of interest:None declared.
PMCID: PMC3590945  PMID: 23487524
Radiosynovectomy; hemophilic arthropathy; magnetic resonance imaging; therapy response
3.  Consecutive radiosynovectomy procedures at 6-monthly intervals behave independently in haemophilic synovitis 
Blood Transfusion  2013;11(2):254-259.
Previous studies on the same group of patients investigated here demonstrated the effectiveness of radiosynovectomy in the treatment of chronic haemophilic synovitis even if one, two or three radiosynovectomy procedures (RS-1, RS-2, RS-3) may be necessary. The purpose of this study was to determine whether the joints’ response to each radiosynovectomy procedure behaved independently or not.
Materials and methods
One hundred and fifty-six radiosynovectomies were performed in 104 joints of 78 people diagnosed with chronic haemophilic synovitis. The patient’s mean age was 18 years. Fifty-eight patients required radiosynovectomy in a single joint, whereas 20 received treatment in more than one joint. Of the 104 joints subjected to radiosynovectomy, 33 were elbows, 47 knees and 24 ankles. Radiosynovectomy was carried out with either yttrium-90 or rhenium-186 (1–3 injections with 6-month intervals between them). Of the 104 joints, 68 required a single injection of the radioisotope (RS-1), 20 required two injections (RS-2) and 16 required three injections (RS-3). In eight cases (7.6%), the affected joints eventually required surgery.
An analysis of seven variables (number of bleeding episodes, articular pain, range of motion in flexion and extension, muscle strength in flexion and extension, and synovial thickness by imaging) demonstrated that each consecutive radiosynovectomy behaves independently in haemophilic synovitis.
Each consecutive radiosynovectomy behaves independently in haemophilic synovitis. This finding had not been documented in the literature before the present study.
PMCID: PMC3626478  PMID: 23245712
haemophilia; synovitis; radiosynovectomy
4.  Application of Rhenium-186 Radiosynovectomy in Elbow Diffuse Pigmented Villonodular Synovitis. - A Case Report with Multiple Joint Involvement 
After surgical therapy of diffuse pigmented villonodular synovitis (DPVNS), recurrence is seen in almost half of the patients. The effectiveness of radiosynovectomy (RSV) in preventing recurrence and complaints of DPVNS is well known. Elbow involvement in DPVNS is a very rare condition; therefore, RSV in elbow hasn’t been experienced widely. The aim of this case report is to show the effectiveness of RSV with rhenium-186 (Re-186) sulfide colloid. We applied Re-186 sulfide colloid to the elbow joint of DPVNS patients six weeks after arthroscopic synovectomy. As a result, the patient did not have any complaints, and our findings are compatible with residue or recurrence on magnetic resonance imaging (MRI) in sixth and twentieth month controls after administration. We concluded that Re-186 is an effective adjuvant therapy for the prevention of recurrence and complaints.
PMCID: PMC4043031  PMID: 24900063
Rhenium-186 (Re-186); Radiosynovectomy; Elbow; Diffuse Pigmented Villonodular Synovitis (DPVNS)
5.  Treatment of Diffuse Pigmented Villonodular Synovitis of the Knee with Combined Surgical and Radiosynovectomy 
HSS Journal  2008;5(1):19-23.
Treatment of extensive diffuse pigmented villonodular synovitis (PVNS) of large joints by isolated surgical resection is unsatisfactory, with high rates of local recurrence. Post-synovectomy adjuvant treatment with external beam radiation therapy or intra-articular injection of radioactive material as yttrium-90 (90Y) yielded better results. Between January 2005 and January 2007, 12 patients (eight men and four women aged 19–49 years) with extensive diffuse PVNS of the knee were treated. All patients had an adjuvant post-operative external beam radiation therapy (2,600–3,000 cGy) conventionally fractionated 200 cGy/fraction, five fractions/week, 6–8 weeks after surgery. Mean follow-up time was 27 months (range from 20 to 36 months). All patients were followed up using clinical assessment, magnetic resonance imaging, and plain X-ray. In all patients, neither evidence of disease recurrence nor progression of bone or articular destruction was noted. No complications were noticed after surgery or after post-operative external beam radiation therapy. A combination of debulking surgery using anterior and posterior approach with adjuvant post-operative external beam radiation therapy for extensive diffuse PVNS of the knee joint is a reliable treatment method, with good results in regard to the incidence of local recurrence and functional outcome.
PMCID: PMC2642543  PMID: 19096892
PVN; synovitis; radiosynovectomy; synovectomy
6.  Role of radiosynovectomy in the treatment of rheumatoid arthritis and hemophilic arthropathies 
Radiosynovectomy is a novel method of treatment for several acute and chronic inflammatory joint disorders. A small amount of a beta-emitting radionuclide is injected into the affected joint delivering a radiation dose of 70 to 100 Gy to the synovia. The proliferative tissue is destroyed, secretion of fluid and accumulation of inflammation causing cellular compounds stops and the joint surfaces become fibrosed, providing long term symptom relief. The radionuclides are injected in colloidal form so that they remain in the synovium and are not transported by lymphatic vessels causing radiation exposure to other organs. Complete reduction of knee joint swelling has been seen in above 40% and pain relief in 88% of patients. Wrist, elbow, shoulder, ankle and hip joints showed significant improvement in 50-60% and restoration of normal function and long term pain relief has been achieved in about 70% of small finger joints. In hemophilic arthropathies complete cessation of bleeding in about 60% and improved mobility in 75% of patients has been reported.
PMCID: PMC3097689  PMID: 21614297
Radiosynovectomy; treatment of hemophilic arthropathies; radionuclides in rheumatoid arthritis
7.  Development of 177Lu-phytate Complex for Radiosynovectomy 
Objective(s): In this work a new possible agent for radiosynovectomy has been targeted for articular pain palliation.
Materials and Methods: Lu-177 of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu2O3 sample with thermal neutron flux of 4 × 1013 The product was converted into chloride form which was further used for labeling of 177Lu-phytate complex and checked using ITLC (MeOH: H2O: acetic acid, 4: 4: 2, as mobile phase). The complex stability and viscosity were checked in the final solution up to seven days. The prepared complex solution (100 µCi/100 µl) was injected intra-articularly to male rat knee joint. Leakage of radioactivity from injection site and its distribution in organs were investigated up to seven days.
Results: The complex was successfully prepared with high radiochemical purity (>99.9 %). Approximately, the whole injected dose has remained in injection site seven days after injection.
Conclusion: The complex was proved to be a feasible agent for cavital radiotherapy in oncology and rheumatology.
PMCID: PMC3700046  PMID: 23826493
Biodistribution; Lutetium-177; Phytate Radiosynovectomy
8.  Development of 166Ho-phytate Complex for Radiosynovectomy 
66Ho-chloride was obtained by bombardment of natural Ho(NO3)3 dissolved in acidic media using thermal neutron flux (4-5 × 1013
166Ho-holmium chloride (185 MBq) was used successfully for preparation of 166Ho-phytate complex with high radiochemical purity (>99.9 %, ITLC, MeOH: H2O: acetic acid, 4: 4: 2, as mobile phase). The complex stability and viscosity were checked in the final solution up to 2 days. The prepared complex solution (60 μCi/100 μl) was injected intraarticularly to male rat knee joints. Leakage of radioactivity from the injection site and its distribution in organs were investigated up to 2 days.
Approximately all of the injected dose had remained in the injection site 2 days after injection.
The complex was proved to be a feasible agent for cavital radiotherapy in oncology and rheumatology.
PMCID: PMC4043017  PMID: 24899986
Phytate; Radiosynovectomy; Holmium-166; Biodistribution; SPECT
9.  Preparation and evaluation of Lu-177 phytate Complex for Radiosynovectomy 
Lu-177 of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu2O3 sample with thermal neutron flux of 4 × 1013 n/cm/s. The product was converted into chloride form which was further used for labeling of Lu-177 phytate complex successfully with high radiochemical purity (>99.9%, instant thin layer chromatography, MeOH: H2O: Acetic acid, 4:4:2, as mobile phase). The complex stability and viscosity were checked in the final solution up to 7 days. The prepared complex solution (100 μCi/100 μl) was injected intra-articularly to the male rat knee joint. Leakage of radioactivity from the injection site and its distribution in organs were investigated up to 7 days. Approximately, all injected dose has remained in injection site 7 days after injection. The complex was proved to be a feasible agent for cavital radiotherapy in oncology and rheumatology.
PMCID: PMC4149764  PMID: 25191108
Biodistribution; lutetium-177; phytate; radiosynovectomy
10.  Influence of Formulation and Processing Variables on Properties of Itraconazole Nanoparticles Made by Advanced Evaporative Precipitation into Aqueous Solution 
AAPS PharmSciTech  2012;13(3):949-960.
Nanoparticles, of the poorly water-soluble drug, itraconazole (ITZ), were produced by the Advanced Evaporative Precipitation into Aqueous Solution process (Advanced EPAS). This process combines emulsion templating and EPAS processing to provide improved control over the size distribution of precipitated particles. Specifically, oil-in-water emulsions containing the drug and suitable stabilizers are sprayed into a heated aqueous solution to induce precipitation of the drug in form of nanoparticles. The influence of processing parameters (temperature and volume of the heated aqueous solution; type of nozzle) and formulation aspects (stabilizer concentrations; total solid concentrations) on the size of suspended ITZ particles, as determined by laser diffraction, was investigated. Furthermore, freeze-dried ITZ nanoparticles were evaluated regarding their morphology, crystallinity, redispersibility, and dissolution behavior. Results indicate that a robust precipitation process was developed such that size distribution of dispersed nanoparticles was shown to be largely independent across the different processing and formulation parameters. Freeze-drying of colloidal dispersions resulted in micron-sized agglomerates composed of spherical, sub-300-nm particles characterized by reduced crystallinity and high ITZ potencies of up to 94% (w/w). The use of sucrose prevented particle agglomeration and resulted in powders that were readily reconstituted and reached high and sustained supersaturation levels upon dissolution in aqueous media.
PMCID: PMC3429681  PMID: 22752680
colloidal dispersion; emulsion; evaporative precipitation into aqueous solution; itraconazole; nanoparticles; poorly water-soluble drug
11.  Preparation and therapeutic evaluation of 188Re-thermogelling emulsion in rat model of hepatocellular carcinoma 
Radiolabeled Lipiodol® (Guerbet, Villepinte, France) is routinely used in hepatoma therapy. The temperature-sensitive hydrogel polyethylene glycol-b-poly-DL-lactic acid-co-glycolic acid-b-polyethylene glycol triblock copolymer is used as an embolic agent and sustained drug release system. This study attempted to combine the polyethylene glycol-b-poly-DL-lactic acid-co-glycolic acid-b-polyethylene glycol hydrogel and radio-labeled Lipiodol to form a new radio-thermogelling emulsion, rhenium-188–N,N’-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride–Lipiodol/hydrogel (188Re-ELH). The therapeutic potential of 188Re-ELH was evaluated in a rodent hepatoma model. Rhenium-188 chelated with N,N’-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride was extracted with Lipiodol to obtain rhenium-188–N,N’-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride–Lipiodol (188Re-EL), which was blended with the hydrogel in equal volumes to develop 188Re-ELH. The 188Re-ELH phase stability was evaluated at different temperatures. Biodistribution patterns and micro-single-photon emission computed tomography/computed tomography images in Sprague Dawley rats implanted with the rat hepatoma cell line N1-S1 were observed after in situ tumoral injection of ~3.7 MBq 188Re-ELH. The therapeutic potential of 188Re-EL (48.58±3.86 MBq/0.1 mL, n=12) was evaluated in a 2-month survival study using the same animal model. The therapeutic effects of 188Re-ELH (25.52±4.64 MBq/0.1 mL, n=12) were evaluated and compared with those of 188Re-EL. The responses were assessed by changes in tumor size and survival rates. The 188Re-ELH emulsion was stable in the gel form at 25°C–35°C for >52 hours. Biodistribution data and micro-single-photon emission computed tomography/computed tomography images of the 188Re-ELH group indicated that most activity was selectively observed in hepatomas. Long-term 188Re-ELH studies have demonstrated protracted reductions in tumor volumes and positive effects on the survival rates (75%) of N1-S1 hepatoma-bearing rats. Conversely, the 2-month survival rate was 13% in the control sham group. Therapeutic responses differed significantly between the two groups (P<0.005). Thus, the hydrogel enhanced the injection stability of 188Re-EL in an animal hepatoma model. Given the synergistic results, direct 188Re-ELH intratumoral injection is a potential therapeutic alternative for hepatoma treatment.
PMCID: PMC4159399  PMID: 25214783
188Re-ECD-Lipiodol; hydrogel; hepatoma; thermogelling emulsion
12.  Combined therapeutic efficacy of 188Re-liposomes and sorafenib in an experimental colorectal cancer liver metastasis model by intrasplenic injection of C26-luc murine colon cancer cells 
Molecular and Clinical Oncology  2014;2(3):380-384.
Rhenium-188 (188Re) displays abundant intermediate energy β emission and possesses a physical half-life of 16.9 h. Sorafenib is an orally available multikinase inhibitor that targets Raf kinases and vascular endothelial growth factor receptors (VEGFRs). Sorafenib has demonstrated preclinical and clinical activity against several types of tumors, such as renal cell and colorectal carcinoma. In this study, we investigated the efficacy of radiotherapeutics of 188Re-liposomes combined with sorafenib in a C26-luc metastatic colorectal liver tumour mouse model. Liver metastases were established by intrasplenic injection of C26-luc murine colon cancer cells. Based on the results of the toxicity assessment, an administration dose of 80% the maximum tolerated dose was selected. 188Re-liposomes were administered on day 1, when metastases of several hundred micrometers in diameter were observed. In the combination therapy group, 10 mg/kg sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar) was administered every other day for 1 week and the survival of mice was assessed. The tumor growth was more significantly inhibited in the 188Re-liposome plus sorafenib group compared with the 188Re-liposome alone, sorafenib alone and untreated normal saline groups (P=0.0000). Furthermore, 188Re-liposomes combined with sorafenib achieved higher survival rates compared with the 188Re-liposome alone, sorafenib alone and untreated normal saline groups (P=0.0000). These results support the use of combined radio-chemotherapy with 188Re-liposomes plus sorafenib as a viable treatment option in the adjuvant setting for liver metastases of colorectal cancer.
PMCID: PMC3999117  PMID: 24772304
liver metastasis; liposomes; rhenium-188; colon cancer; radiotherapy
13.  Preparation of Colloidal Gold Immunochromatographic Strip for Detection of Paragonimiasis skrjabini 
PLoS ONE  2014;9(3):e92034.
Paragonimiasis is a food-borne trematodiasis, a serious public health issue and a neglected tropical disease. Paragonimus skrjabini is a unique species found in China. Unlike paragonimiasis westermani, it is nearly impossible to make a definitive diagnosis for paragonimiasis skrjabini by finding eggs in sputum or feces. Immunodiagnosis is the best choice to detect paragonimiasis skrjabini. There is an urgent need to develop a novel, rapid and simple immunoassay for large-scale screening patients in endemic areas.
Methodology/Principal Findings
To develop a rapid, simple immunodiagnostic assay for paragonimiasis, rabbit anti-human IgG was conjugated to colloidal gold particles and used to detect antibodies in the sera of paragonimiasis patients. The synthesis and identification of colloidal gold particles and antibody-colloidal gold conjugates were performed. The size of colloidal gold particles was examined using a transmission electron microscope (TEM). The average diameter of colloidal gold particles was 17.46 nm with a range of 14.32–21.80 nm according to the TEM images. The formation of antibody-colloidal gold conjugates was monitored by UV/Vis spectroscopy. Excretory-secretory (ES) antigen of Paragonimus skrjabini was coated on nitrocellulose membrane as the capture line. Recombinant Staphylococcus protein A was used to prepare the control line. This rapid gold immunochromatographic strip was assembled in regular sequence through different accessories sticked on PVC board. The relative sensitivity and specificity of the strip was 94.4% (51/54) and 94.1% (32/34) respectively using ELISA as the standard method. Its stability and reproducibility were quite excellent after storage of the strip at 4°C for 6 months.
Immunochromatographic strip prepared in this study can be used in a rapid one-step immunochromatographic assay, which is instantaneous and convenient.
PMCID: PMC3958401  PMID: 24643068
14.  Analysis of lapine cartilage matrix after radiosynovectomy with holmium-166 ferric hydroxide macroaggregate 
Objective: To study the short and long term effects of radiosynovectomy on articular cartilage in growing and mature rabbits.
Methods: The articular cartilage of the distal femurs of rabbits was examined four days, two months, and one year after radiosynovectomy with holmium-166 ferric hydroxide macroaggregate ([166Ho]FHMA). Arthritic changes were evaluated from histological sections by conventional and polarised light microscopy, and glycosaminoglycan measurements using safranin O staining, digital densitometry, and uronic acid determination. Proteoglycan synthesis was studied by metabolic [35]sulphate labelling followed by autoradiography, and electrophoretic analysis of extracted proteoglycans. Northern analyses were performed to determine the mRNA levels of type II collagen, aggrecan, and Sox9 in cartilage samples.
Results: Radiosynovectomy had no major effect on the histological appearance of articular cartilage in mature rabbits, whereas more fibrillation was seen in [166Ho]FHMA radiosynovectomised knee joints of growing rabbits two months after treatment, but not after one year. Radiosynovectomy did not cause changes in the glycosaminoglycan content of cartilage or in the synthesis or chemical structure of proteoglycans. No radiosynovectomy related changes were seen in the mRNA levels of type II collagen, whereas a transient down regulation of aggrecan and Sox9 mRNA levels was seen in young rabbits two months after [166Ho]FHMA radiosynovectomy.
Conclusions: [166Ho]FHMA radiosynovectomy caused no obvious chondrocyte damage or osteoarthritic changes in mature rabbits, but in growing rabbits some transient radiation induced effects were seen—for example, mild cartilage fibrillation and down regulation of cartilage-specific genes.
PMCID: PMC1754287  PMID: 12480668
15.  Radiosynovectomy in Hemophilic Synovitis 
Radisosynovectomy (RS) is a local form of radionuclide therapy used in various forms of arthritis characterized by synovitis. In hemophilic arthropathy, RS provides removal of inflamed synovium and prevents further joint damage. This review focuses on the practical aspects of radionuclide synovectomy in hemophilic patients and describes the issues both related to the methodology and post-therapeutic follow-up.
Conflict of interest:None declared.
PMCID: PMC3957964  PMID: 24653927
radioisotope therapy; Hemophilia; synovitis
16.  Long term follow up of radiosynovectomy with yttrium-90 silicate in haemophilic haemarthrosis. 
Annals of the Rheumatic Diseases  1993;52(7):548-550.
OBJECTIVES--The aim of this study was to evaluate the long term effect of radiation synovectomy with yttrium-90 silicate in haemophiliac patients with recurrent haemarthrosis. METHODS--The bleeding frequency and the mobility of the joint were recorded in 16 joints of 14 patients 1 year before radiosynovectomy and during follow up, which ranged from 3 to 6 years. Patients evaluated the effect of their own treatment by completing a questionnaire. Radiographs of the joints were scored by an independent radiologist before treatment. RESULTS--A satisfactory reduction of the frequency of haemorrhage was achieved in 94% of joints during the first year after treatment and was maintained in 63% until the end of the follow up period. In general there was no decrease in mobility attributable to radiosynovectomy, and the patients' own evaluations agreed with the evaluations based on the frequencies of haemarthrosis in 75%. Patients who had only minor, or no, radiological abnormalities of the joints before treatment showed the best results. One patient developed synovitis as a complication of the radiosynovectomy. CONCLUSION--Radiosynovectomy is an effective and safe treatment for recurrent haemarthrosis in haemophiliac patients, especially in those who have joints with no or minor radiological damage.
PMCID: PMC1005098  PMID: 8346985
17.  Lipid Nanocapsules Loaded with Rhenium-188 Reduce Tumor Progression in a Rat Hepatocellular Carcinoma Model 
PLoS ONE  2011;6(3):e16926.
Due to their nanometric scale (50 nm) along with their biomimetic properties, lipid nanocapsules loaded with Rhenium-188 (LNC188Re-SSS) constitute a promising radiopharmaceutical carrier for hepatocellular carcinoma treatment as its size may improve tumor penetration in comparison with microspheres devices. This study was conducted to confirm the feasibility and to assess the efficacy of internal radiation with LNC188Re-SSS in a chemically induced hepatocellular carcinoma rat model.
Methodology/Principal Findings
Animals were treated with an injection of LNC188Re-SSS (80 MBq or 120 MBq). The treated animals (80 MBq, n = 12; 120 MBq, n = 11) were compared with sham (n = 12), blank LNC (n = 7) and 188Re-perrhenate (n = 4) animals. The evaluation criteria included rat survival, tumor volume assessment, and vascular endothelial growth factor quantification. Following treatment with LNC188Re-SSS (80 MBq) therapeutic efficiency was demonstrated by an increase in the median survival from 54 to 107% compared with control groups with up to 7 long-term survivors in the LNC188Re-SSS group. Decreased vascular endothelial growth factor expression in the treated rats could indicate alterations in the angiogenesis process.
Overall, these results demonstrate that internal radiation with LNC188Re-SSS is a promising new strategy for hepatocellular carcinoma treatment.
PMCID: PMC3049769  PMID: 21408224
18.  Duloxetine HCl Lipid Nanoparticles: Preparation, Characterization, and Dosage Form Design 
AAPS PharmSciTech  2011;13(1):125-133.
Solid lipid nanoparticles (SLNs) of duloxetine hydrochloride (DLX) were prepared to circumvent the problems of DLX, which include acid labile nature, high first-pass metabolism, and high-dosing frequency. The DLX-SLNs were prepared by using two different techniques, viz. solvent diffusion method and ultrasound dispersion method, and evaluated for particle size, zeta potential, entrapment efficiency, physical characteristics, and chemical stability. Best results were obtained when SLNs were prepared by ultrasound dispersion method using glyceryl mono stearate as solid lipid and DLX in ratio of 1:20 and mixture of polysorbate 80 and poloxamer 188 as surfactant in concentration of 3%. The mean particle size of formulation and entrapment efficiency was 91.7 nm and 87%, respectively, and had excellent stability in acidic medium. Differential scanning calorimetry and X-ray diffraction data showed complete amorphization of DLX in lipid. In vitro drug release from SLNs was observed for 48 h and was in accordance with Higuchi kinetics. In vivo antidepressant activity was evaluated in mice by forced swim test. DLX-SLNs showed significant enhancement in antidepressant activity at 24 h when administered orally in comparison to drug solution. These results confirm the potential of SLNs in enhancing chemical stability and improving the efficacy of DLX via oral route. The SLN dispersion was converted into solid granules by adsorbing on colloidal silicon dioxide and characterized for particle size after redispersion, morphology, and flow properties. Results indicated that nanoparticles were successfully adsorbed on the carrier and released SLNs when dispersed in water.
PMCID: PMC3299448  PMID: 22167415
acid labile; adsorption; duloxetine HCl; lymphatic absorption; solid lipid nanoparticles
19.  Effect of Hydrofracking Fluid on Colloid Transport in the Unsaturated Zone 
Environmental Science & Technology  2014;48(14):8266-8274.
Hydraulic fracturing is expanding rapidly in the US to meet increasing energy demand and requires high volumes of hydrofracking fluid to displace natural gas from shale. Accidental spills and deliberate land application of hydrofracking fluids, which return to the surface during hydrofracking, are common causes of environmental contamination. Since the chemistry of hydrofracking fluids favors transport of colloids and mineral particles through rock cracks, it may also facilitate transport of in situ colloids and associated pollutants in unsaturated soils. We investigated this by subsequently injecting deionized water and flowback fluid at increasing flow rates into unsaturated sand columns containing colloids. Colloid retention and mobilization was measured in the column effluent and visualized in situ with bright field microscopy. While <5% of initial colloids were released by flushing with deionized water, 32–36% were released by flushing with flowback fluid in two distinct breakthrough peaks. These peaks resulted from 1) surface tension reduction and steric repulsion and 2) slow kinetic disaggregation of colloid flocs. Increasing the flow rate of the flowback fluid mobilized an additional 36% of colloids, due to the expansion of water filled pore space. This study suggests that hydrofracking fluid may also indirectly contaminate groundwater by remobilizing existing colloidal pollutants.
PMCID: PMC4102097  PMID: 24905470
20.  Distribution of yttrium 90 ferric hydroxide colloid and gold 198 colloid after injection into knee. 
Annals of the Rheumatic Diseases  1976;35(6):516-520.
Thirteen knees were injected with yttrium 90(90Y) ferric hydroxide colloid, and 12 with gold 198(198Au) colloid for treatment of persistent synovitis. Retention in the knee and uptake in lymph nodes and liver were measured by a quantitative scanning technique. There was no significant difference in the retention in the knee of the two different colloids. A tendency towards higher lymph node uptake was observed with 198Au compared with 90y. The inflammatory activity of the knee at the time of treatment may have influenced the subsequent lymph node uptake of 198Au, but not that of the 90Y, nor the overall leakage of either from the knee. 90Yferric hydroxide colloid was retained in the treated knee at least as well as other colloids which have been used for this purpose.
PMCID: PMC1006595  PMID: 1008619
21.  Evaluation of 188Re-labeled PEGylated nanoliposome as a radionuclide therapeutic agent in an orthotopic glioma-bearing rat model 
In this study, the 188Re-labeled PEGylated nanoliposome (188Re-liposome) was prepared and evaluated as a therapeutic agent for glioma.
Materials and methods
The reporter cell line, F98luc was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of 188Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered 188Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the 188Re-liposome-treated rats.
By using bioluminescent imaging, the well-established reporter cell line (F98luc) showed a high relationship between cell number and its bioluminescent intensity (R2=0.99) in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of 188Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the 188Re-liposome-treated group than the control group (P<0.05). As a result, the lifespan of glioma-bearing rats treated with 188Re-liposome was prolonged 10.67% compared to the control group.
The radiotherapeutic evaluation by dosimetry and survival studies have demonstrated that passive targeting 188Re-liposome via systemic administration can significantly prolong the lifespan of orthotopic glioma-bearing rats while maintaining reasonable systemic radiation safety. Therefore, 188Re-liposome could be a potential therapeutic agent for glioblastoma multiforme treatment.
PMCID: PMC4296959  PMID: 25624760
188Re; liposome; radionuclide therapy; bioluminescent imaging; glioma
22.  Targeted Killing of Virally Infected Cells by Radiolabeled Antibodies to Viral Proteins 
PLoS Medicine  2006;3(11):e427.
The HIV epidemic is a major threat to health in the developing and western worlds. A modality that targets and kills HIV-1-infected cells could have a major impact on the treatment of acute exposure and the elimination of persistent reservoirs of infected cells. The aim of this proof-of-principle study was to demonstrate the efficacy of a therapeutic strategy of targeting and eliminating HIV-1-infected cells with radiolabeled antibodies specific to viral proteins in vitro and in vivo.
Methods and Findings
Antibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 (213Bi) and rhenium 188 (188Re) selectively killed chronically HIV-1-infected human T cells and acutely HIV-1-infected human peripheral blood mononuclear cells (hPBMCs) in vitro. Treatment of severe combined immunodeficiency (SCID) mice harboring HIV-1-infected hPBMCs in their spleens with a 213Bi- or 188Re-labeled monoclonal antibody (mAb) to gp41 resulted in a 57% injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99% elimination of HIV-1-infected cells in a dose-dependent manner. The number of HIV-1-infected thymocytes decreased 2.5-fold in the human thymic implant grafts of SCID mice treated with the 188Re-labeled antibody to gp41 compared with those treated with the 188Re-control mAb. The treatment did not cause acute hematologic toxicity in the treated mice.
The current study demonstrates the effectiveness of HIV-targeted radioimmunotherapy and may provide a novel treatment option in combination with highly active antiretroviral therapy for the eradication of HIV.
In vitro data and results in mice suggest that HIV-targeted radioimmunotherapy is potentially safe and effective and may provide a strategy toward eradication of HIV in infected patients.
Editors' Summary
In a person infected with HIV, the symptoms of AIDS can be delayed or controlled with drug combinations such as highly active antiretroviral therapy (HAART). However, at the moment there is no cure for HIV infection or AIDS; HAART has to be taken for life and has unpleasant side effects, and the HIV virus can become resistant to some of the drugs. Even in people for whom HAART is successfully controlling disease, HIV remains at very low levels in white blood cells, and is capable of infecting more cells if treatment is stopped for some reason or becomes ineffective because the virus has developed resistance. One possible approach that could potentially eradicate HIV in an infected person is to inject antibodies, targeted against elements of the HIV particle, joined to a radioactive “tag.” The idea is that the antibodies would bind to HIV particles at the surface of infected white blood cells, and the radioactivity would then kill the infected cell. This strategy, called “radioimmunotherapy,” has been successfully used to develop treatments for certain cancers.
Why Was This Study Done?
The researchers wanted to find out whether radioimmunotherapy had any potential for treating HIV infection. As the first step, they needed to find out whether radioactive antibodies targeted against HIV proteins could kill HIV infected cells in animals, and also whether the animals suffered any serious side effects as a result. This is an early step in developing new treatments that would need to show promising results before the approach would be tried in humans.
What Did the Researchers Do and Find?
The researchers first did some experiments on HIV-infected white blood cells in vitro (i.e., test tube experiments), and second in vivo on HIV-infected PBMCs in the spleens of mice. They found that in vitro, HIV-infected white blood cells were successfully killed by radioactive antibodies that had been developed against specific proteins in the HIV particle that are routinely displayed at the surface of infected cells. Two different types of antibody, and two different types of radioactive tag, were tried. Both antibodies were very effective in targeting HIV infected cells, but one type of radioactive tag (bismuth 213) was better than the other (rhenium 188). Then, SCID mice were infected intrasplenically with HIV-infected PBMCs and treated with the radioactively tagged antibodies (these particular mice had a deficient immune system, which means that they tolerate transplanted HIV-infected human PBMCs that serve as in vivo targets for the radioactive antibodies. The number of HIV-infected human PBMCs was reduced in the treated mice compared with control animals, which were treated with antibodies not joined to a radioactive tag. The greater the antibody dose, the greater the proportion of HIV-infected human PBMC that were killed. Finally, the researchers also looked at whether the antibody treatment damaged platelets in the infected mice, and they saw a drop in platelet numbers only for the mice receiving the highest dose of antibodies.
What Do These Findings Mean?
These results provide preliminary support for the idea that radioimmunotherapy might be an approach for treatment of HIV. They argue that additional experiments in animals are warranted. If those continue to be promising, it will be critical to find out whether the radioactively labeled antibodies are safe in humans, and whether they are effective. The researchers who did this study feel that the strategy, if eventually shown to be safe and effective, would likely be of most value in preventing HIV infection very shortly after someone is exposed to the virus or treating HIV-infected patients not responsive to anti-retroviral therapy.
Additional Information.
Please access these Web sites via the online version of this summary at
The Medline Plus (provided by the US National Library of Medicine) encyclopedia has an entry on HIV/AIDS
The AIDSMap provides patient information on HIV/AIDS treatment and care
The US Centers for Disease Control and Prevention has resources on HIV/AIDS treatment, including current treatment guidelines
PMCID: PMC1630718  PMID: 17090209
23.  Albumin and artificial colloids in fluid management: where does the clinical evidence of their utility stand? 
Critical Care  2000;4(Suppl 2):S16-S20.
Key questions remain unresolved regarding the advantages and limitations of colloids for fluid resuscitation despite extensive investigation. Elucidation of these questions has been slowed, in part, by uncertainty as to the optimal endpoints that should be monitored in assessing patient response to administered fluid. Colloids and crystalloids do not appear to differ notably in their effects on preload recruitable stroke volume or oxygen delivery. Limited evidence nevertheless suggests that colloids might promote greater oxygen consumption than crystalloids. It remains unclear, in any case, to what extent such physiological parameters might be related to clinically relevant outcomes such as morbidity and mortality. Recent randomized controlled trial results indicate that, at least in certain forms of fluid imbalance, albumin is effective in significantly reducing morbidity and mortality. Much further investigation is needed, however, to determine the effects of colloid administration on clinically relevant outcomes in a broad range of critically ill patients. The ability of administered colloids to increase colloid osmotic pressure (COP) constitutes one mechanism by which colloids might reduce interstitial oedema and promote favourable patient outcomes. However, the applicability of this mechanism may be limited, due to the operation of compensatory mechanisms such as increased lymphatic drainage. Attempts to increase COP might also be less useful in states of increased vascular permeability such as acute respiratory distress syndrome, although this issue has by no means been settled by empirical data. Colloids are clearly more efficient than crystalloids in attaining resuscitation endpoints as judged by the need for administration of far smaller fluid volumes. Among the colloids, albumin offers several advantages compared with artificial colloids, including less restrictive dose limitations, lower risk of impaired haemostasis, absence of tissue deposition leading to severe prolonged pruritus, reduced incidence of anaphylactoid reactions, and ease of monitoring to prevent fluid overload. The cost of albumin, nevertheless, limits its usage. Crystalloids currently serve as the first-line fluids in hypovolaemic patients. Colloids can be considered in patients with severe or acute shock or hypovolaemia resulting from sudden plasma loss. Colloids may be combined with crystalloids to obviate administration of large crystalloid volumes. Further clinical trials are needed to define the optimal role for colloids in critically ill patients.
PMCID: PMC3226170  PMID: 11255594
colloids; critical care; osmotic pressure; serum albumin; shock
24.  The effect of colloid formulation on colloid osmotic pressure in horses with naturally occurring gastrointestinal disease 
BMC Veterinary Research  2014;10(Suppl 1):S8.
Naturally occurring gastrointestinal disease is an important cause of acute hypoproteinemia in adult horses and hydroxyethyl starch colloid fluid treatment is a component of supportive care in these cases to improve plasma volume and maintain colloid osmotic pressure (COP). The objectives of the present study were to compare 2 formulations of high molecular weight hydroxyethyl starch and their relative effect on COP, acid-base status, and survival of horses with acute hypoproteinemia secondary to gastrointestinal disease.
Twenty adult horses, ≥ 1 year of age, were prospectively enrolled, with informed client consent, if they developed acute hypoproteinemia, defined as a plasma total protein <5.0 g/dL or albumin <2.2 g/dL during hospitalization while undergoing treatment for gastrointestinal disease. Horses were randomly assigned to receive a rapid infusion of either 6% hydroxyethyl starch in 0.9% saline or 6% hydroxyethyl starch in lactated ringers solution at a dose of 10ml/kg. Venous blood gas analysis, COP, and PCV were evaluated before and after colloid administration.
For both groups, average COP prior to treatment was 11.0 mmHg (9.7 – 12.2 mmHg) and post colloid treatment was 13.2 mmHg (12.0 -14.7 mmHg) [Normal range 18 – 22 mmHg]. COP was significantly increased with colloid treatment (p<0.001) but this increase was not significantly different between treatment groups. Venous pH did not change significantly with treatment. Twelve horses survived to hospital discharge and survival did not differ significantly between treatment groups.
Post-treatment COP improved approximately 20% regardless of the formulation used, however, values did not reach the normal range of COP observed in healthy horses. Acid-base parameters were not significantly impacted by either treatment. Further study is needed to determine how these two products compare with regards to other outcome measures. Evaluation of the relative effects of colloid formulation in horses with clinical disease is a future area of interest.
PMCID: PMC4123155  PMID: 25237987
25.  How Effective is a Saline Arthrogram for Wounds Around the Knee? 
Traumatic arthrotomies may predispose patients to subsequent septic arthritis and therefore are regarded as serious injuries requiring emergent treatment. The saline arthrogram is a commonly used test to determine if a patient has a traumatic arthrotomy. We determined the sensitivity of the saline arthrogram to identify known intraarticular wounds in 78 patients (80 knees) undergoing elective arthroscopic procedures. There were 66 infrapatellar and 14 suprapatellar incisions. The average length of the incision was 7.5 mm. Intraarticular position was confirmed with a blunt probe. A saline arthrogram then was performed using 60 mL normal saline. The known arthrotomy (operative wound) was observed during the injection for evidence of saline leakage (positive static test). If no leakage was observed, the knee was brought through a range of motion with continued observation for leakage from the arthrotomy (positive dynamic test). Twenty-two of 80 knees had a positive test without passive range of motion of the knee (static sensitivity, 36%). Eight additional knees had a positive test with subsequent passive motion (dynamic sensitivity, 43%). Our data suggest a saline arthrogram has low sensitivity for detecting known small traumatic arthrotomy wounds of the knee.
Level of Evidence: Level I, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2505139  PMID: 18196428

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