Search

1. Introduction Prostate cancer is estimated to rank first in number of cancer cases and second in number of deaths due to cancer among men in the Western world [1]. [...], Molecular imaging with promise of personalized medicine can provide patient-specific information noninvasively, thus enabling treatment to be tailored to the specific biological attributes of both the disease and the patient. This study was to investigate the characterization of DO3A-C[H.sub.2]CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-N[H.sub.2] (AMBA) in vitro, MicroSPECT/CT imaging, and biological activities of [sup.111]In-AMBA in PC-3 prostate tumor-bearing SCID mice. The uptake of [sup.111]In-AMBA reached highest with 3.87 ± 0.65% ID/g at 8h. MicroSPECT/CT imaging studies suggested that the uptake of [sup.111]In-AMBA was clearly visualized between 8 and 48 h postinjection. The distribution half-life ([t.sub.1/2a]) and the elimination half-life ([t.sub.1/2])of [sup.111]In-AMBA in mice were 1.53 h and 30.7 h, respectively. The [C.sub.m]ax and AUC of [sup.111]In-AMBA were 7.57% ID/g and 66.39 h* % ID/g, respectively. The effective dose appeared to be 0.11 mSv/[MBq.sup.-1]. We demonstrated a good uptake of [sup.111]In-AMBA in the GRPR-overexpressed PC-3 tumor-bearing SCID mice. [sup.111]In-AMBA is a safe, potential molecular image-guided diagnostic agent for human GRPR-positive tumors, ranging from simple and straightforward biodistribution studies to improve the efficacy of combined modality anti- cancer therapy.

Summary: Background Cetuximab is a fully humanized IgG1 subclass monoclonal that binds specifically to the human epidermal growth factor receptor (EGFR). Although EGFR is expressed in normal cells, the overexpression of EGFR is detected in many human cancers, such as colon, rectum and lung tumors. In this study, cetuximab with a combination of radiotherapy nuclear 188Re achieved better therapeutic effect on lung cancer. Methods188Re-cetuximab administered by the i.v. route in human NCI-H292 lung tumor-bearing mice was investigated. NanoSPECT/CT images were taken to evaluate the distribution and tumor targeting of 188Re-cetuximab in mice. The anti-tumor effect of 188Re-cetuximab was assessed by the tumor growth inhibition, survival ratio. Results For nanoSPECT/CT imaging, a significant uptake in tumor was observed at 24 and 48 h following the injection of 188Re-cetuximab. The anti-tumor effect of 188Re-cetuximab was assessed by tumor growth inhibition and the survival ratio. The tumor-bearing mice treated with 188Re-cetuximab showed a better mean tumor growth inhibition rate (MGI = 0.049) and longer median survival time and lifespan (62.50 d; 70.07%) than those treated with 188Re-perrhenate and cetuximab only by single injection. A synergistic effect of tumor growth inhibition was observed with the combination index exceeding one for 188Re-cetuximab (CI = 6.135 and 9.276). Conclusion The tumor targeting and localization of 188Re-cetuximab were confirmed in this study. Synergistic therapeutic efficacy was demonstrated for the radioimmunotherapy of 188Re-cetuximab. The results of this study reveal the potential advantage and benefit obtained from 188Re-cetuximab for diagnosis and therapy of oncology applications in the future. [ABSTRACT FROM AUTHOR]

Molecular imaging with promise of personalized medicine can provide patient-specific information noninvasively, thus enabling treatment to be tailored to the specific biological attributes of both the disease and the patient. This study was to investigate the characterization of DO3A-CH(2)CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH(2) (AMBA) in vitro, MicroSPECT/CT imaging, and biological activities of (111)In-AMBA in PC-3 prostate tumor-bearing SCID mice. The uptake of (111)In-AMBA reached highest with 3.87 ± 0.65% ID/g at 8 h. MicroSPECT/CT imaging studies suggested that the uptake of (111)In-AMBA was clearly visualized between 8 and 48 h postinjection. The distribution half-life (t(1/2[alpha])) and the elimination half-life (t(1/2[beta])) of (111)In-AMBA in mice were 1.53 h and 30.7 h, respectively. The C(max) and AUC of (111)In-AMBA were 7.57% ID/g and 66.39 h % ID/g, respectively. The effective dose appeared to be 0.11 mSv/MBq(-1). We demonstrated a good uptake of (111)In-AMBA in the GRPR-overexpressed PC-3 tumor-bearing SCID mice. (111)In-AMBA is a safe, potential molecular image-guided diagnostic agent for human GRPR-positive tumors, ranging from simple and straightforward biodistribution studies to improve the efficacy of combined modality anticancer therapy. [ABSTRACT FROM AUTHOR]

Abstract: The biodistribution, pharmacokinetics, dosimetry and comparative therapeutic efficacy of intravenously administrated 188Re-N,N-bis(2-mercaptoethyl)-N′,N′-diethylethylenediamine (BMEDA)-labeled pegylated liposome (188Re-liposome) and 5-FU were investigated in a CT26-luc lung-metastatic model. After intravenous administration of 188Re-liposome, tumor accumulation from the radioactivity was observed. Levels of radioactivity in tumors were maintained at steady levels (from 5.40 to 5.67 %ID/g) after 4 to 24 h. In pharmacokinetics, the AUC(0→∞), MRT(0→∞) and Cl of 188Re-liposome in blood via intravenous route were 998 h %ID/ml, 28.7 h and 0.1 ml/h, respectively. The total excreted fractions of feces and urine were 0.61 and 0.26, respectively. Absorbed doses for 188Re-liposome in the liver and red marrow were 0.31 and 0.08 mSv/MBq, respectively. Tumor-absorbed doses for 188Re-liposome ranged from 48.4 to 1.73 mGy/MBq at 10 to 300 g tumor spheres. In therapeutic efficacy, the survival times of mice after 188Re-liposome [80% maximum tolerated dose (MTD); 29.6 MBq], 5-FU (80% MTD; 144 mg/kg), liposome or normal saline treatments were evaluated. Consequently, radiotherapeutics of 188Re-liposome attained a longer lifespan (increase of 34.9%; P=.005) in mice than in the normal saline group. The increase in lifespan of the 188Re-liposome group was 2.5-fold greater than that of the 5-FU group. Therefore, intravenous administration of 188Re-liposome could provide a benefit and it is a promising strategy for delivery of passive nanotargeted radiotherapeutics in oncology applications. [Copyright &y& Elsevier]

Abstract: Nanoliposomes are important carriers capable of packaging drugs for various delivery applications through passive targeting tumor sites by enhanced permeability and retention effect. Radiolabeled liposomes have potential applications in radiotherapy and diagnostic imaging. The purpose of this study was to investigate the biodistribution, pharmacokinetics and imaging of nanotargeted 188Re-N,N-bis (2-mercaptoethyl)-N′,N′-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (RBLPL) and unencapsulated 188Re-BMEDA after intraperitoneal (ip) injection in a C26 colon carcinoma ascites mouse model. The nanopegylated liposomes were labeled with 188Re-BMEDA. The labeling efficiency of RBLPL was 82.3±4.5%. In vitro stability of RBLPL in normal saline at room temperature and in rat plasma at 37°C for 72 h was 92.01±1.31% and 82.4±1.64%, respectively. The biodistribution studies indicated that the radioactivity in ascites was 69.96±14.08 percentage injected dose per gram (% ID/g) at 1h to 5.99±1.97% ID/g at 48 h after ip administration of RBLPL. The levels of radioactivity in tumor were progressive accumulation to a maximum of 6.57±1.7% ID/g at 24 h. The radioactivity of 188Re-BMEDA in ascites reached the maximum level of 54.89±5.91% ID/g at 1 h and declined rapidly with time. Pharmacokinetic studies revealed that the terminal half-life, total body clearance and area under the curve of RBLPL were 5.3-, 9.5- and 9.4-fold higher than that of 188Re-BMEDA in blood, respectively. These results suggested that the long circulation, bioavailability and localization of RBLPL in tumor and ascites sites, which also demonstrate that the ip administration of RBLPL is a potential multifunctional nanoradiotherapeutics and imaging agents on a C26 colon carcinoma ascites mouse model. [Copyright &y& Elsevier]

Background/aim: The biodistribution, pharmacokinetics and therapeutic evaluation of 188 Re-human serum albumin microspheres ( 188 Re-HSAM) by labeling with 188 Re(I)-tricarbonyl ion ( 188 Re(OH 2 ) 3 (CO) 3 )+) were investigated in a GP7TB orthotopic hepatoma rat model., Materials and Methods: Male F344 rats received intrahepatic inoculations with GP7TB 1 mm3 cubes. The efficacy of 188 Re-HSAM was examined following a single-dose treatment via the intraarterial route. Rats were monitored for survival until death., Results: The labeling efficiency of the 188 Re-HSAM was about 80%. After intraarterial administration of 188 Re-HSAM, radioactivity in tumors accumulated from 18.41±3.48 %ID/g at 1 h to 12.43±4.70 %ID/g at 24 h. The tumor/liver ratios ranged from 3.03 at 1 h to 1.89 at 72 h. The major uptake organs of 188 Re-HSAM were liver (73.35%ID to 48.92%ID), tumor (10.54%ID to 3.51%ID) and kidney (7.48 %ID to 0.14%ID). The T 1/2λz of 188 Re-HSAM was 259.34 h after intraarterial injection. The AUC (0→96 h) of 188 Re-HSAM was 0.69 h*% ID/g. In the efficacy study, the median survival time for the rat (n=6), that received normal saline was 80 d. The median survival times for the mice treated with 10 mCi (n=4), 5.2 mCi (n=6) and 2.9 mCi (n=3) of 188 Re-HSAM were 130 d (p=0.003), 106 d (p=0.002) and 83.5 d (p=0.617), respectively. The increase in life span of 10 mCi, 5.2 mCi and 2.9 mCi of 188 Re-HSAM were 62.5%, 32.5% and 4.4%, respectively., Conclusion: Administration of 188 Re-HSAM demonstrated better survival time and therapeutic efficacy at the higher dose in the GP7TB hepatoma model. These results suggested that intraarterial administration of 188 Re-HSAM could provide a benefit and promising strategy for delivery of radiotherapeutics in oncology applications., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The combination of a radioisotope with a chemotherapeutic agent in a liposomal carrier (ie, Indium-111-labeled polyethylene glycol pegylated liposomal vinorelbine, [(111)In-VNB-liposome]) has been reported to show better therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this therapeutic effect is attributable to the combination of a radioisotope with chemotherapeutics. The goal of this study was to investigate the pharmacokinetics, biodistribution, and correlation of Indium-111 radioactivity and vinorelbine concentration in the (111)In-VNB-liposome., Methods: The VNB-liposome and (111)In-VNB-liposome were administered to rats. Blood, liver, and spleen tissue were collected to determine the distribution profile of the (111)In-VNB-liposome. A liquid chromatography tandem mass spectrometry system and gamma counter were used to analyze the concentration of vinorelbine and radioactivity of Indium-111., Results: High uptake of the (111)In-VNB-liposome in the liver and spleen demonstrated the properties of a nanosized drug delivery system. Linear regression showed a good correlation (r = 0.97) between Indium-111 radioactivity and vinorelbine concentration in the plasma of rats administered the (111)In-VNB-liposome., Conclusion: A significant positive correlation between the pharmacokinetics and biodistribution of (111)Indium radioactivity and vinorelbine in blood, spleen, and liver was found following administration of the (111)In-VNB-liposome. The liposome efficiently encapsulated both vinorelbine and Indium-111, and showed a similar concentration-radioactivity time profile, indicating the correlation between chemotherapy and radiotherapy could be identical in the liposomal formulation.

Background: Nanoliposomes are designed as carriers capable of packaging drugs through passive targeting tumor sites by enhanced permeability and retention (EPR) effects. In the present study the biodistribution, pharmacokinetics, micro single-photon emission computed tomography (micro-SPECT/CT) image, dosimetry, and therapeutic efficacy of (188)Re-labeled nanoliposomes ((188)Re-liposomes) in a C26 colonic peritoneal carcinomatosis mouse model were evaluated., Methods: Colon carcinoma peritoneal metastatic BALB/c mice were intravenously administered (188)Re-liposomes. Biodistribution and micro-SPECT/CT imaging were performed to determine the drug profile and targeting efficiency of (188)Re-liposomes. Pharmacokinetics study was described by a noncompartmental model. The OLINDA|EXM computer program was used for the dosimetry evaluation. For therapeutic efficacy, the survival, tumor, and ascites inhibition of mice after treatment with (188)Re-liposomes and 5-fluorouracil (5-FU), respectively, were evaluated and compared., Results: In biodistribution, the highest uptake of (188)Re-liposomes in tumor tissues (7.91% ± 2.02% of the injected dose per gram of tissue [%ID/g]) and a high tumor to muscle ratio (25.8 ± 6.1) were observed at 24 hours after intravenous administration. The pharmacokinetics of (188)Re-liposomes showed high circulation time and high bioavailability (mean residence time [MRT] = 19.2 hours, area under the curve [AUC] = 820.4%ID/g*h). Micro-SPECT/CT imaging of (188)Re-liposomes showed a high uptake and targeting in ascites, liver, spleen, and tumor. The results were correlated with images from autoradiography and biodistribution data. Dosimetry study revealed that the (188)Re-liposomes did not cause high absorbed doses in normal tissue but did in small tumors. Radiotherapeutics with (188)Re-liposomes provided better survival time (increased by 34.6% of life span; P < 0.05), tumor and ascites inhibition (decreased by 63.4% and 83.3% at 7 days after treatment; P < 0.05) in mice compared with chemotherapeutics of 5-fluorouracil (5-FU)., Conclusion: The use of (188)Re-liposomes for passively targeted tumor therapy had greater therapeutic effect than the currently clinically applied chemotherapeutics drug 5-FU in a colonic peritoneal carcinomatosis mouse model. This result suggests that (188)Re-liposomes have potential benefit and are safe in treating peritoneal carcinomatasis of colon cancer.

AMBA (DO3A-CH(2)CO-G-(4-aminobenzoyl)-QWAVGHLM-NH(2)) is a bombesin (BN)-like peptide having high affinity with gastrin-releasing peptide receptors (GRPr).(177)Lu-AMBA is currently undergoing clinical trial as a systemic radiotherapy for hormone refractory prostate cancer (HRPC) patients. This study evaluated the biodistribution, pharmacokinetics, bioluminescent imaging (BLI) and microSPECT/CT imaging of (177)Lu-AMBA in PC-3M-luc-C6 luciferase-expressing human prostate tumour-bearing mice. Plasma stability of (177)Lu-AMBA could be maintained up to 55.67±6.07% at 24 h in a protection buffer. High positive correlations of PC-3M luc-C6 tumour growth in SCID mice between caliper measurement and BLI were observed (R(2)=0.999). Both the biodistribution and microSPECT/CT imaging in PC-3M-luc-C6 bearing-tumour mice showed that (177)Lu-AMBA in tumour uptake could be retained for 24 h. The distribution half-life (t(1/2α)) and the elimination half-life (t(1/2β)) of (177) Lu-AMBA in mice were 0.52 h and 26.6 h, respectively. These results indicated that BLI could be used to monitor the growth of tumour. High uptake of (177)Lu-AMBA in PC-3M-luc-C6 tumour-bearing mice by microSPECT/CT imaging can further evaluate the potential of (177)Lu-AMBA therapy for PC-3M-luc-C6 tumours.

Liposomes can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness and reducing toxicity. To evaluate therapeutic strategies, it is essential to use animal models reflecting important safety aspects before clinical application. The objective of this study was to investigate acute radiotoxicity of ¹⁸⁸Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (¹⁸⁸Re-BMEDA-liposome) in Sprague-Dawley rats. Rats were administered with ¹⁸⁸Re-BMEDA-liposome, normal saline as blank or non-radioactive liposome as vehicle control via intravenous injection and observed for 14 days. Examinations were conducted with respect to mortality, clinical signs, food consumption, body weight and hematological and biochemical analyses. In addition, gross necropsy, histopathological examinations and cytogenetic analyses were also performed. None of the rats died and no clinical sign was observed during the 14-day study period. Rats administered with ¹⁸⁸Re-BMEDA-liposome at dosage of 185 MBq displayed a significant weight loss compared with the control from study day (SD) 1 to SD 4, and the white blood cell count reduced to 5-10% of initial value (female: 18.55 ± 6.58 to 0.73 ± 0.26 x 10³  µl⁻¹; male: 14.52 ± 5.12 to 1.43 ± 0.54 x 10³  µl⁻¹) 7 days-post injection, but were found to have recovered on SD 15. There were no significant differences in biochemical parameters and histopathological assessments between the ¹⁸⁸Re-BMEDA-liposome-treated and control groups. The frequencies of dicentric chromosomes were associated with dosage of ¹⁸⁸Re-BMEDA-liposome. The information generated from this study on acute toxicity will serve as a safety reference for further subacute toxicity study in rats and human clinical trials., (Copyright © 2010 John Wiley & Sons, Ltd.)