A novel gold-polymer-antibody conjugate for targeted (radio-photothermal) treatment of HepG2 cells.

Localization of the near-infrared (NIR) plasmonic nanoparticles at the tumor sites is essential for safe and efficient photothermal therapy of cancer. In this work, two biocompatible polymers: modified poly(ethylene glycol) (PEG) and branched polyethyleneimine (bPEI) were used to bind plasmonic hollow gold nanospheres (HAuNS) to the tumor-specific antibody, atezolizumab (ATZ). The photo-immunoconjugate (HAuNS-PEI-PEG-ATZ) was prepared via a simple and cost-effective procedure. The conjugate was also prepared with the radioiodinated antibody (ATZ-131I) to combine the targeted radio- and photothermal cytotoxic actions against human hepatoma (HepG2) cells. In vitro study revealed that attachment to the antibody and the use of cellular internalizing polymers enhanced the cellular localization of both gold and the radiotherapeutic Iodine-131. Compared to bare gold nanoparticles, (HAuNS-PEI-PEG-ATZ) conjugate exhibited a significantly enhanced photothermal ablation of HepG2 cells after laser irradiation (0.4 W cm-2, 5 min). Laser irradiation of the cells treated with the radiolabeled conjugate (HAuNS-PEI-PEG-ATZ-131I) exhibited the highest cytotoxicity against HepG2 cells due to the combinatorial cytotoxic effects.

Biocompatible mucoadhesive nanoparticles for brain targeting of ropinirole hydrochloride: Formulations, radiolabeling and biodistribution.

Two nanoformulations with mucoadhesive properties and brain-targeting mechanisms were designed to deliver the anti-Parkinson's drug, ropinirole hydrochloride (RH). In the first formulation, RH and the amphiphilic block copolymer methoxy poly(ethylene glycol)-b-poly(caprolactone) were assembled in a core-shell morphology followed by coating with a mucoadhesive chitosan outer layer producing a multilayer vehicle (MLV). In the second formulation, RH was encapsulated during the polyelectrolyte complexation of two natural polymers, chitosan and alginate producing RH-loaded chitosan-alginate polyelectrolyte (PEC) nanocomplex. Conditions of each formulation were adopted for optimal drug loading. Physico-chemical characterization of the prepared formulations (particle size, polydispersity index and zeta-potential) exhibited stable monodispersed nanoparticles. RH was radiolabeled by I-131 radiotracer in a high-radiochemical yield. Biodistribution and brain targeting of RH from the prepared formulations were studied after administration of 131 I-RH-loaded nanoparticles to albino mice via intranasal and intravenous routs. Elevated brain radioactivity was detected post IN administration of (131 I-RH/PCL-PEG/CS) nanoparticles and (131 I-RH/CS-ALG) nanoparticles comparing with the IN administrated RH solutions (Cmax  = 2.8 ± 0.3, 2 ± 0.3, 0.93 ± 0.03% radioactivity/g, 1 h post administration, respectively). This demonstrated that a relatively high-brain targeting could be achieved via intranasal route of administration of RH-loaded nanoparticles. The proposed models are further potential for application to deliver many other brain-targeting therapeutics.

Targeted photoimmunotherapy based on photosensitizer-antibody conjugates for multiple myeloma treatment.

Despite the high in vitro efficacy of photodynamic therapeutics, lack of tumor targeting significantly reduces their in vivo efficacy and thus limits their clinical use. Photoimmunotherapy (PIT) is a new synthetic strategy to target and treat cancer by photodynamic therapy (PDT). In this study, we describe design and synthesis of a third-generation photosensitizer comprising a PEGylated-phthalocyanine star-polymer photosensitizer that covalently bound to a myeloma tumor-selective antibody (MAb) via the carbodiimide chemistry. The free photosensitizer demonstrated a minimum dark toxicity when tested in mammalian myeloma cell line (SP2/OR); and a moderate phototoxicity after irradiation with non thermal laser red light as a result of light-induced production of cytotoxic singlet oxygen species. Covalent attachment of the photosensitizer (Pc) to the MAb resulted in a significantly enhanced phototoxicity. This is mainly ascribed to the fact that internalization enhances phototoxicity of Pc-MAb bioconjugates. The radioactivated photoimmuno-conjugates 131I(PcMAb) demonstrated the highest phototoxicity to myeloma cells. The suggested bioconjugates are promising candidates as multiple therapeutic models for in vivo treatment of myeloma.

Modified technique for thermal radiofrequency ablation of Thoracic dorsal root ganglia under combined fluoroscopy and CT guidance: a randomized clinical trial.

BACKGROUND: This study is comparing thermal radiofrequency ablation (TRFA) of the thoracic dorsal root ganglia (TDRG) guided by Xper CT and fluoroscopy with the standard fluoroscopy. METHODS: This randomized clinical trial included 78 patients suffering from chronic refractory pain due to chest malignancies randomly allocated into one of two groups according to guidance of TRFA of TDRG. In CT guided group (n = 40) TRFA was done under integrated Xper CT-scan and fluoroscopy guidance, while it was done under fluoroscopy guidance only in standard group (n = 38). The primary outcome was pain intensity measured by visual analog scale (VAS) score, functional improvement and consumption of analgesics. The secondary outcome measures were patient global impression of changes (PGIC) and adverse effects. RESULTS: VAS scores decreased in the two groups compared to baseline values (p < 0.001) and were lower in CT guided group up to 12 weeks. Pregabalin and oxycodone consumption was higher in the standard group at 1, 4 and 12 weeks (p < 0.001). Functional improvement showed near significant difference between the two groups (P = 0.06 at week 1, 0.07 at week 4 respectively) while the difference was statistically significant at week 12 (P = 0.04). PGIC showed near significant difference only at week 1 (P = 0.07) while the per-patient adverse events were lower in CT guided group (p = 0.027). CONCLUSIONS: Integrated modality guidance with Xper CT-scan and fluoroscopy together with suprapedicular inferior transforaminal approach may improve efficacy and safety of TRFA of TDRG for the treatment of intractable chest pain in cancer patients. TRIAL REGISTRATION: The study was retrospectively registered at clinicaltrials.gov on 04/22/2018 (Registration No.: NCT03533413).

Laser-responsive liposome for selective tumor targeting of nitazoxanide nanoparticles.

Nitazoxanide [2-(Acetyloxy)-N-(5-nitro-2-thiazolyl)benzamide], usually referred as NTZ, is an antiparasites drug with a potential anti-cancer reactivity. However, the bioavailability of nitazoxanide is limited due to its poor water solubility. In this study, nitazoxanide could be successfully incorporated in a stable biocompatible liposome (NTZ-LP) using a modified thin film hydration technique. Further, a novel lipophilic phthalocyanine star polymer R4PcZn was prepared as photosensitizer and in situ incorporated with NTZ in the liposome formulation affording a laser-responsive liposome (NTZ-ZnPc-LP). Both (NTZ-LP) and (NTZ-ZnPc-LP) showed high entrapment efficiency (EE) and high in vitro drug release rates. Transmission electron microscope (TEM) images and dynamic light scattering (DLS) measurements of (NTZ-LP) and (NTZ-ZnPc-LP) showed unilamellar vesicles of mean diameter 192.2 and 87.4nm, respectively. In addition, NTZ nanoparticles (NTZ NPs) were prepared via membrane extrusion method using DMF and water as solvents. All formulations were similarly prepared using radiolabeled nitazoxanide 125I-NTZ. After induction of solid tumor in mices using Ehrlich Ascites Carcinoma, the prepared formulations were injected in the tail vein of the mices. Tumor sites of the animal injected with (125I-NTZ-ZnPc-LP) were illuminated with a HeNe laser (λ=630nm). Afterwards, the biodistriburtion of 125I-NTZ was tagged using γ counter. Results showed that the light-responsive formulation (125I-NTZ-ZnPc-LP) affords a higher accumulation of 125I NTZ in the tumor sites after illumination. This can be attributed to the rupture of liposome lipid bilayer as a result of the photosensitization process and the singlet oxygen species resulted thereof. Despite (NTZ NPs) formulation showed a rapid accumulation of NTZ in tumor, it showed unfavoured rapid blood clearance rate.

Accelerated balloon-occluded retrograde transvenous obliteration without indwelling balloon occlusion for gastric varices with small gastrorenal shunts using a terminal gelfoam plug.

OBJECTIVE: We performed balloon-occluded retrograde transvenous obliteration in three consecutive patients with small gastric varices without indwelling balloon catheter occlusion. Foam of 3% sodium tetradecyl sulfate mixed with iodized oil and room air was injected retrograde through the gastrorenal shunt, followed by a thick absorbable gelatin sponge (Gelfoam, Pfizer) plug under only 10-minute balloon occlusion. CONCLUSION: Because complete obliteration of gastric varices was achieved in all patients without any complications, our technique is considered to be safe and effective for small gastric varices.

Transjugular intrahepatic portosystemic shunts in liver transplant recipients: technical analysis and clinical outcome.

OBJECTIVE: The purpose of this study is to compare the technical success of transjugular intrahepatic portosystemic shunt (TIPS) in transplanted versus nontransplanted livers and to assess the clinical outcome of TIPS in liver transplant recipients. MATERIALS AND METHODS: A retrospective audit of patients receiving a TIPS was performed in two institutions during 1996-2009. The technical success of the TIPS was compared for transplanted versus nontransplanted livers. Clinical success was defined as graft survival longer than 1 month with improvement in symptoms. The cohort was divided into grafts that survived less than 3 months versus 3 months or more. The model for end-stage liver disease (MELD) scores and portosystemic gradients before and after TIPS creation were evaluated for predictive value for graft survival. The TIPS stent type, MELD scores and portosystemic gradients before and after TIPS creation, and causes of liver disease were evaluated for their predictive value for ascites response after TIPS creation. RESULTS: Thirty-nine TIPS in transplanted livers were found, representing 5.5% (39/715) of all TIPS procedures performed and 2.0% (39/1992) of all liver transplant recipients. Ninety percent of TIPS in transplanted livers had ascites. The median time from transplant to creation of the TIPS was 29 months (2-127 months). The median MELD score was 16 before and 22 after the TIPS procedure. The technical success rates for TIPS were 97% (38/39) in transplanted livers versus 97% (657/676) in nontransplanted livers (p = 1.00). Intent-to-treat clinical success rates were 36% for all indications versus 31% for ascites only. There were no predictors for ascites response. Six-, 12-, and 24-month graft survival rates were 43%, 32%, and 22%, respectively. One-year graft survival for a MELD score less than 17 versus a score of 17 or higher was 54% versus 8%, respectively (p < 0.05). CONCLUSION: Transplantation does not pose a technical challenge to TIPS creation. One third of patients have a favorable outcome. MELD score is the only predictor of graft survival.

Stent-grafts for transjugular intrahepatic portosystemic shunt creation: specialized TIPS stent-graft versus generic stent-graft/bare stent combination.

PURPOSE: To compare functional and anatomic outcomes of transjugular intrahepatic portosystemic shunts (TIPSs) created with the specialized Viatorr stent versus a Wallstent/Fluency stent combination. MATERIALS AND METHODS: Retrospective review of patients who underwent TIPS creation with stent-grafts was conducted over a 54-month period ending in June 2008. Patients were divided into three groups: Viatorr only, Fluency only, and combined Viatorr/Fluency, the latter of which was included in the overall evaluation but excluded from the comparative analysis between the Viatorr and Fluency groups. Patient demographics, Child-Pugh scores, and portosystemic gradient (PSG) reduction were compared. Patencies were calculated using the Kaplan-Meier method and compared. RESULTS: A total of 126 TIPSs created with stent-grafts were found: 28 with Fluency stents, 93 with Viatorr devices, and five combined. No significance in demographic factors or PSGs was found among groups (P > .05). Major encephalopathy rates were 3.6% and 4.3% in the Fluency and Viatorr groups, respectively (P = 1.000). Hemodynamic success rates were 93% and 98% in the Fluency and Viatorr groups, respectively (P = .099). The primary unassisted patency rates at 6, 9, and 12 months were 87%, 81%, and 81%, respectively, in the Fluency group and 95%, 93%, and 89%, respectively, in the Viatorr group (P = .03). Portal and hepatic end stenoses were the causes of TIPS narrowing in the Fluency and Viatorr groups, respectively. CONCLUSIONS: The Wallstent/Fluency stent combination is associated with a 1-year patency rate greater than 80%, with no significant difference versus the Viatorr stent regarding technical and hemodynamic success and encephalopathy rate. However, the Viatorr stent is associated with improved patency (89%) versus this bare stent/stent-graft combination.

Transjugular intrahepatic portosystemic shunts in liver transplant recipients for management of refractory ascites: clinical outcome.

PURPOSE: To determine the effectiveness of transjugular intrahepatic portosystemic shunt (TIPS) creation in liver transplant recipients with recurrent portal hypertension presenting with refractory ascites. MATERIALS AND METHODS: A retrospective review of transplant recipients undergoing TIPS creation was performed over a 6-year period. Recipients were noted for age, sex, TIPS indication, Model for End-stage Liver Disease (MELD) score, cause of initial liver disease, and time between first transplantation and TIPS creation. Clinical success was defined as graft survival of longer than 1 month with improvement in ascites. New-onset or worsening encephalopathy was noted. Graft survival and patency were calculated according to the Kaplan-Meier method. MELD score and portosystemic gradient (PSG) before and after TIPS creation were evaluated for prediction of graft loss less than 3 months after TIPS creation. RESULTS: Nineteen liver transplant recipients underwent TIPS creation for ascites. Mean time from transplantation was 3.5 years (range, 3.7-112.2 months). Mean MELD score before TIPS creation was 17 (range, 7-24). The technical, hemodynamic, and clinical success rates were 100%, 95%, and 16%, respectively. Encephalopathy developed in five patients (26%). Thirty- and 90-day mortality rates were 16% (n = 3) and 21% (n = 4), respectively. Primary unassisted patency and graft survival rates at 1, 3, and 6 months were 100%, 90%, and 90% and 79%, 58%, and 47%, respectively. MELD score parameters were significant indicators (P < .05) for graft survival beyond 3 months, but PSG parameters were not. CONCLUSIONS: TIPS for the management of ascites in liver transplant recipients is not as clinically effective as it is in patients with native livers (16% vs 50%-80% in the literature). MELD score is a predictor of graft survival; PSG parameters are not.

Dual-tract transhepatic U-shaped hemodialysis inferior vena cava catheter: a feasibility study in a swine model.

PURPOSE: To evaluate the feasibility of establishing a U-shaped inferior vena cava (IVC) catheter entirely from a transhepatic approach and to determine the catheter caliber that would provide adequate flow for hemodialysis. MATERIALS AND METHODS: Three pigs (weight, 45-50 kg) were used. A peripheral right hepatic vein was accessed transhepatically by using a 22-gauge needle, and a 0.018-inch wire was passed into the hepatic veins and IVC. An accessory right hepatic vein was accessed from the IVC. A snare was deployed in the accessory vein and used as a target for a second transhepatic 22-gauge needle pass. A wire was snared through the second transhepatic tract, around into the IVC, and through the first transhepatic tract. The 0.018-inch wire was upsized to a 0.035-inch platform. Measurements where made to tailor a U-shaped catheter from simple 10.2- and 12-F tubes by cutting them longitudinally (single long side hole) along the length of the IVC segment. The U-shaped hemodialysis catheter was placed over the wire and positioned so that the catheter opening lay in the IVC. With use of a dialysis machine, pressures and flow tolerance at set flow rates (100, 200, 300, 350, and 400 mL/min) were tested. RESULTS: All pigs underwent and survived successful catheter placements. All 10.2- and 12-F catheters tolerated flow rates up to 350 and 400 mL/min, respectively. CONCLUSIONS: Establishing a U-shaped hemodialysis catheter with an entirely transhepatic approach is technically feasible. The 10.2-F U-shaped dialysis catheters provided a flow rate (>350 mL/min) that is appropriate for hemodialysis in human clinical settings.

Intravenous morphine for augmentation of postoperative T-tube cholangiograms in liver transplant recipients with choledocho-choledochal anastomoses.

PURPOSE: To determine the effectiveness of augmenting T-tube cholangiography by using intravenous morphine in orthotopic liver transplant recipients with choledocho-choledochostomies and poor filling of intrahepatic biliary ducts and to determine factors that may increase the likelihood of nonfilling of intrahepatic ducts. MATERIALS AND METHODS: A retrospective review of T-tube cholangiograms obtained in orthotopic liver transplant recipients was performed. Intravenous morphine had been given by two of five operators to augment T-tube cholangiograms with poor filling of bile ducts. Patients with malpositioned tubes and decompressive bile leaks were excluded from morphine diagnostic efficacy evaluation but were included in the overall cholangiogram diagnostic yield. Anastomotic narrowing, if present, was graded as follows: >50%, 20%-50%, and <20% diameter reduction. Patients with intrahepatic bile duct filling were compared to those without filling with regard to age, sex, time from transplantation, and clinically significant (>50%) stenoses. RESULTS: One hundred sixty-eight cholangiograms were obtained in 127 recipients. Twenty-three of the 168 cholangiograms (13.7%) had malpositioned/blocked T-tubes and five (3%) had decompressive leaks; 140 cholangiograms had well-positioned tubes and no leaks. Twenty-two of the 140 cholangiograms with well-positioned tubes and no leaks (15.7%) had nonfilling of peripheral bile ducts. Morphine (range, 2-6 mg; mean, 4 mg) had been used in 13 cases. Adequate filling after morphine was noted in 12 of the 13 cases (92%), and no complications occurred. Morphine improved adequate diagnostic examination of well-positioned patent T-tubes from 85% (123/145) to 93% (135/145). No parameters helped predict inadequate filling in well-positioned tubes (P > .05). CONCLUSIONS: In 92% of cases, intravenous morphine was successful in opacifying the biliary tract without complications. In well-positioned T-tubes, the use of morphine increased diagnostic yield from 85% to 93%. No predictors for inadequate filling were found.