A Pilot First-in-Human Study of Embrace,a Polyethylene Glycol-Based Liquid Embolic Agent,in the Embolization of Malignant and Benign Hypervascular Tumors

PurposeTo investigate the safety and efficacy of an aqueous polyethylene glycol-based liquid embolic agent, Embrace Hydrogel Embolic System (HES), in the treatment of benign and malignant hypervascular tumors.Materials and MethodsA prospective, single-arm, multicenter study included 8 patients, 5 males and 3 females, with a median age of 58.5 years (30–85 years), who underwent embolization in 8 tumors between October 2019 and May 2020. Technical success was defined as successful delivery of HES to the index vessel, with disappearance of >90% of the targeted vascular enhancement or, for portal vein embolization, occlusion of the portal branches to the liver segments for future resection. The volume of HES administered, ease of use (5 point Likert scale), administration time, and adverse events (AEs) were recorded. Evaluation was performed at 7, 30, and 90 days via clinical assessment and blood testing, and follow-up imaging was performed at 30 days.ResultsEight patients were enrolled, and 10 embolizations were performed in 8 lesions. Tumors included hepatocellular carcinoma (n = 4), renal angiomyolipoma (n = 3), and intrahepatic cholangiocarcinoma (n = 1). Technical success was 100%, and the average ease of use was 3.3 ± 1.0 SD. The HES delivery time was 1–28 minutes (median, 16.5 minutes), and the HES volume injected was 0.4–4.0 mL (median, 1.3 mL). All patients reached 30-day follow-up with imaging, and 6 patients reached 90-day follow-up. There were 3 serious AEs in 2 patients that were unrelated to the embolic agent.ConclusionHES resulted in a 100% embolization technical success rate. The product ease of use was acceptable, and no target vessel recanalization was noted on follow-up imaging at 30 days.     

尿酸性肾病中医分型与氧化应激指标的相关性研究

目的：探讨尿酸性肾病中医分型与氧化应激相关性。方法：采用回顾性分析方法对2017年12月至2019年9月北京中医药大学第三附属医院收治的尿酸性肾病患者105例进行研究，选择同时期正常健康者105例作为对照，参考《中药新药临床研究指导原则》将105例尿酸性肾病和临床常见证型相结合，分成脾肾气虚18例、气阴两虚证19例、肝肾阴虚16例、阴阳两虚12例、湿热蕴结19例、瘀血阻滞17例、痰浊内阻13例，均在入院次日清晨空腹抽取静脉血，检测氧化应激氧化应激、肾功能损害指标，比较不同组别在氧化应激指标含量水平变化情况，比较中医分型和氧化应激、肾功能损害指标水平变化。结果：1）尿酸性肾病组总抗氧化能力（T-ACO）、晚期蛋白氧化物（AOPP）、血清丙二醇（MDA）、超氧化物歧化酶（SOD）含量水平分别为（19.45±3.42）U/mL、（42.45±3.53）μmol/L、（4.52±1.23）nmol/L、（76.78±5.64）U/mL，正常对照组则分别为（10.76±1.31）U/mL、（20.84±1.28）μmol/L、（2.13±0.76）nmol/L、（130.85±16.75）U/mL，尿酸性肾病组T-ACO、AOPP、MDA较正常对照组显著偏高，SOD显著偏低（P<0.05）。2）虚证中阴阳两虚证SOD含量上较其他证型均偏低，而MDA、T-AOC、AOPP、胱抑素C（CysC）、β2微球蛋白、尿微量白蛋白（UMALB）、蛋白尿发生率则较其他证型均偏高，差异均有统计学意义（P<0.05），实证中瘀血阻滞证SOD含量较其他证型均偏低，而MDA、T-AOC、AOPP则较其他证型均偏高，差异均有统计学意义（P<0.05）。结论：尿酸性肾病中医分型的阴阳两虚证、瘀血阻滞证氧化应激水平、肾损害指标均显著升高，可结合该实验室检查进行临床干预。     

Effectiveness of the Biophysical Barriers to the Peridural Fibrosis in Rat Laminectomy Model

Purpose: Peridural fibrosis which could occur after the spinal surgery could adhere neural tissue closely and may cause to neural entrapment symptoms and require surgical reintervention. Aim of the study: Present study was designed to reduce occurrence of peridural fibrosis in rat laminectomy model by using biophysical barriers called hyaluronic acid (HAS) dural barrier, activated polyethylene glycol and polyethylene imine (PEG) dural barrier, and platelet-rich plasma (PRP). Materials and methods: In this study, 2 of 26 male Wistar albino rats (325–350 g body weight), which were not included into study groups were sacrificed by removing their total blood and their blood was used for preparation of PRP, and remaining rats were randomly delivered into four groups called SHAM, HAS, PEG, and PRP groups. Then L3-4-5 laminectomy was performed to all animals and experimental agents were administered to the selected groups mentioned above. Spinal colons of all animals were removed gross total after 6-week period and investigated histopathologically. Additionally, real-time-polymerase chain reaction was used to obtain collagen type I and type III, transforming growth factor-1β, and tumor necrosis factor-α gene expressions. Results: All results demonstrated that polyethylene glycol and polyethylene imine dural barrier and PRP could decrease peridural fibrosis formation efficiently in rat. Conclusion: Present study results suggested that to reduce or block formation of peridural fibrosis, either polyethylene glycol and polyethylene imine dural barrier or PRP could be used effectively in human subjects after they will be closely investigated in future studies.     

番泻叶、聚乙二醇和二甲基硅油联合应用对胶囊内镜检查可见度及检出率的影响

目的探讨番泻叶、聚乙二醇和二甲基硅油联合应用对于胶囊内镜(CE)检查可见度及检出率的影响。方法选取该院2016年6月-2018年9月拟行CE检查的患者126例,采用随机数表法分为对照组(n=62)与观察组(n=64),两组检查前禁食3 d,对照组予以聚乙二醇和二甲基硅油作为肠道准备,观察组在此基础上给予口服番泻叶。比较两组胃排空时间、小肠转运时间、胃和小肠的染色节段长度、绿色条带长度、肠道清洁程度、两组病变检出情况及不良反应发生情况。结果两组患者胃排空时间、小肠转运时间、胃和小肠的染色节段无明显差异(P0.05);观察组全小肠和远端小肠绿色条带长度短于对照组,差异均有统计学意义[(5.53±2.93) vs (6.74±2.76)cm;t=2.39,P=0.019;(3.37±2.04) vs (5.56±2.13)cm;t=5.90,P=0.000];两组近端小肠清洁程度差异无统计学意义(P0.05),观察组远端小肠(89.06%vs59.68%,χ2=14.35,P=0.000)和全小肠(87.50%vs 48.39%,χ2=22.23,P=0.000)清洁率明显高于对照组,差异有统计学意义;观察组病变总检出率明显高于对照组(92.18%vs 72.58%,χ2=8.40,P=0.004);两组不良反应发生率差异无统计学意义(17.74%vs 18.75%,P0.05)。结论添加番泻叶可有效提高聚乙二醇和二甲基硅油对于CE的检查可见度和检出率。     

载紫杉醇的大黄酸偶联物纳米胶束的制备及初步评价

目的制备载紫杉醇的D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopheryl polyethylene glycol 1000 succinate,TPGS)修饰的羧甲基壳聚糖-大黄酸偶联物(PTX/TPGS-CR)纳米胶束,并对其进行初步评价。方法采用透析法,以载药量、包封率及粒径为指标,通过单因素考察优化PTX/TPGS-CR纳米胶束的制备工艺并进行验证。以溶血实验及血管刺激性实验初步考察PTX/TPGS-CR纳米胶束的安全性。四甲基偶氮唑盐微量酶反应比色法(MTT)法考察PTX/TPGS-CR纳米胶束对Hela细胞的毒性。通过激光扫描共聚焦显微镜定性和流式细胞仪定量考察Hela细胞对PTX/TPGS-CR纳米胶束的摄取情况。结果制备工艺优化后制得的PTX/TPGS-CR纳米胶束粒径为(197.3±4.4)nm,PDI为(0.131±0.021),电位为(-31.8±0.5)mV,载药量为(48.20±3.03)%,包封率为(87.26±4.91)%。溶血实验结果表明,其溶血率低于1.71%;血管静脉注射无明显刺激性。其对Hela细胞的杀伤作用具有浓度和时间依赖性,能被Hela细胞高效摄取。结论PTX/TPGS-CR纳米胶束载药量和包封率高,安全性好,其体外抗肿瘤活性稍优于Taxol?。     

Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

Screening of Polymer-Based Drug Delivery Vehicles Targeting Folate Receptors in Triple-Negative Breast Cancer

PurposeTo compare cellular uptake and cytotoxicity of fluorescein (FL)-labeled polyethylene glycols (PEGs) carrying 2 folate groups (targeted delivery vehicles [TDVs]) to non-PEGylated molecules with 1 or 2 folate groups.Materials and MethodsThree PEGylated TDVs and 2 non-PEGylated folic acid (FA)–fluorescein (FL) conjugates (FA-FL and FA-FL-FA) were synthesized. Two triple-negative breast cancer cell lines (MDA-MB-231and MDA-MB-468) were cultured to 70% confluency and incubated for 2 h in a folate-depleted medium. Folate receptor (FR) expression was confirmed by immunocytochemistry. Cellular uptake and cytotoxicity of compounds were measured by flow cytometry. Intracellular localization was confirmed using confocal microscopy.ResultsMDA-MB-231 demonstrated 40% more FR staining than MD-MB-468. Intracellular localization of the 2 non-PEGylated molecules (FA-FL and FA-FL-FA) and the 3 PEGylated TDVs was confirmed with confocal microscopy. Cellular uptake was independent of concentration for FA-FL, but there was 26.8% more cytotoxicity at 30 μg/mL compared with no treatment (P ≤ .05). Uptake was > 90% for FA-FL-FA at 10 μg/mL and 30 μg/mL without significant cytotoxicity (P ≤ .005). Cellular uptake was > 80% for all TDVs. The molecule containing monodispersed PEG with M_n = 1,000 g/mol had the highest uptake in both cell lines without cytotoxicity. Maximum toxicity was demonstrated by the molecule containing PEG_2,000 only at the highest dose of 30 μg/mL (8.66% ± 3.94% cytotoxicity; cut-off was 20%).ConclusionsThe molecule containing monodispersed PEG with M_n = 1,000 g/mol and 2 FA targeting groups demonstrated better targetability and cellular uptake as a TDV.