title: Preparation and therapeutic evaluation of (188)Re-thermogelling emulsion in rat model of hepatocellular carcinoma.
abstract: 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 ((188)Re-ELH). The therapeutic potential of (188)Re-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 ((188)Re-EL), which was blended with the hydrogel in equal volumes to develop (188)Re-ELH. The (188)Re-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 (188)Re-ELH. The therapeutic potential of (188)Re-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 (188)Re-ELH (25.52±4.64 MBq/0.1 mL, n=12) were evaluated and compared with those of (188)Re-EL. The responses were assessed by changes in tumor size and survival rates. The (188)Re-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 (188)Re-ELH group indicated that most activity was selectively observed in hepatomas. Long-term (188)Re-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 (188)Re-EL in an animal hepatoma model. Given the synergistic results, direct (188)Re-ELH intratumoral injection is a potential therapeutic alternative for hepatoma treatment.
authors.affiliation: Isotope Application Division, Institute of Nuclear Energy Research, Longtan, Taiwan ; Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Ying-Hsia
authors.initials: YH
authors.lastname: Shih
authors.affiliation: Department of Internal Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Xi-Zhang
authors.initials: XZ
authors.lastname: Lin
authors.affiliation: Isotope Application Division, Institute of Nuclear Energy Research, Longtan, Taiwan.
authors.forename: Chung-Hsin
authors.initials: CH
authors.lastname: Yeh
authors.affiliation: Isotope Application Division, Institute of Nuclear Energy Research, Longtan, Taiwan ; Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Liang
authors.initials: CL
authors.lastname: Peng
authors.affiliation: Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan ; Department of Oncology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Ming-Jium
authors.initials: MJ
authors.lastname: Shieh
authors.affiliation: Isotope Application Division, Institute of Nuclear Energy Research, Longtan, Taiwan.
authors.forename: Wuu-Jyh
authors.initials: WJ
authors.lastname: Lin
authors.affiliation: Isotope Application Division, Institute of Nuclear Energy Research, Longtan, Taiwan ; Institute of Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan.
authors.forename: Tsai-Yueh
authors.initials: TY
authors.lastname: Luo
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000532:radiotherapy*; D004338:Drug Combinations; D004655:Emulsions / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D020100:Hydrogels / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D007459:Iodized Oil / Q000737:chemistry; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D009942:Organometallic Compounds / Q000737:chemistry; D011092:Polyethylene Glycols; D011098:Polyglactin 910; D011868:Radioisotopes / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012211:Rhenium / Q000737:chemistry / Q000627:therapeutic use*; D016019:Survival Analysis; D014018:Tissue Distribution
chemical_list: D004338:Drug Combinations; D004655:Emulsions; D020100:Hydrogels; D009942:Organometallic Compounds; D011868:Radioisotopes; C520330:polyethylene glycol-poly(lactic-co-glycolic acid)-polyethylene glycol; C493916:rhenium-188 ethyl cysteinate dimer lipiodol; D011098:Polyglactin 910; D011092:Polyethylene Glycols; D012211:Rhenium; D007459:Iodized Oil
keywords: 188Re-ECD-Lipiodol; hepatoma; hydrogel; thermogelling emulsion