A Simple Method for Estimating Dose Delivered to Hepatocellular Carcinoma after Yttrium-90 Glass-Based Radioembolization Therapy: Preliminary Results of a Proof of Concept Study

PurposeTo investigate a simple semiquantitative method to estimate yttrium-90 (⁹⁰Y) dose delivered with radioembolization to infiltrative hepatocellular carcinoma (HCC).Materials and MethodsIn a prospective study, patients with infiltrative HCC and portal vein thrombosis (PVT) underwent glass-based ⁹⁰Y radioembolization including technetium-99m macroaggregated albumin (^99mTc-MAA) hepatopulmonary shunt study before therapy and bremsstrahlung single photon emission computed tomography (SPECT)/computed tomography (CT) after ⁹⁰Y radioembolization. Baseline magnetic resonance imaging was coregistered with ^99mTc-MAA and bremsstrahlung SPECT/CT imaging separately. Unit tumor activity (⁹⁰Y radioactivity delivered to each cubic centimeter of tumor) was estimated based on a lobar infusion approach. Correlation between proportions of ^99mTc-MAA and ⁹⁰Y delivered to the tumor was investigated. Survival analysis was performed using Kaplan-Meier estimations.Results⁹⁰Y therapy was administered in 18 consecutive patients (median age, 55.3 y; mean tumor volume, 588 cm³). Higher intratumoral ⁹⁰Y dose predicted prolonged survival, with 13.2-month median survival in patients with HCC and mean ⁹⁰Y dose of ≥ 100 Gy versus 4.6-month median survival for other patients (P < .001). Of administered ⁹⁰Y dose, 51.9% was delivered to the targeted tumors compared with 74.1% of ^99mTc-MAA with linear correlation between biodistribution of ^99mTc-MAA and ⁹⁰Y observed (Pearson r = 0.774, P < .001).ConclusionsThe findings in this study suggest that approximately 50% of administered ⁹⁰Y dose is taken up by targeted infiltrative HCC with PVT. Intratumoral ⁹⁰Y dose ≥ 100 Gy in unresectable infiltrative HCC via a lobar intraarterial approach is a positive prognostic factor for survival.     

Influence of whole-body vibration on biodistribution of the radiopharmaceutical [99mTc]methylene diphosphonate in Wistar rats

Abstract

Purpose: The radionuclide bone scan is the basis of skeletal nuclear medicine imaging. Bone scintigraphy is a highly sensitive method for indicating disease in bone. Mechanical stimulation in the manner of whole-body vibration (WBV) appears beneficial to the maintenance and/or enhancement of skeletal mass in individuals. The aim of this work was to evaluate the effect of WBV on the biodistribution of the radiopharmaceutical [^99mTc]methylene diphosphonate (^99mTc-MDP ) in Wistar rats.

Materials and methods: In the biodistribution analysis, animals were anesthetized with sodium thiopental, the radiopharmaceutical ^99mTc-MDP was administered via ocular plexus and after 10 min the animals were submitted to vibration of 20 Hz (1 min) in an oscillatory platform. Following, the animals were sacrificed, the organs were isolated, the radioactivity determined in a well counter, and the percentages of radioactivity per gram (%ATI/g) in the organs were calculated. An unpaired t-test following Welch test (p < 0.05) was done for statistical analysis of the results.

Results: The biodistribution was significantly (p < 0.05) decreased in kidney, bone, lung, stomach, prostate and bowel.

Conclusion: The analysis of the results indicates that the vibration could produce metabolic alterations with influence in the uptake of the radiopharmaceutical ^99mTc-MDP in bone, stomach, bowel, prostate, kidney and bladder.     

Correlation of Technetium-99m Macroaggregated Albumin and Yttrium-90 Glass Microsphere Biodistribution in Hepatocellular Carcinoma: A Retrospective Review of Pretreatment Single Photon Emission CT and Posttreatment Positron Emission Tomography/CT

Purpose

To evaluate whether technetium-99 (^99mTc)-labeled macroaggregated albumin (MAA) can predict subsequent yttrium-90 (⁹⁰Y) distribution and imaging response in patients with hepatocellular carcinoma (HCC).

Safety and Efficacy Assessment of Flow Redistribution by Occlusion of Intrahepatic Vessels Prior to Radioembolization in the Treatment of Liver Tumors

We evaluated the feasibility, safety, and efficacy of radioembolization (administered from one or two vascular points) after the redistribution of arterial blood flow in the liver in patients with hepatic neoplasms and arterial anatomic peculiarities (AAP). Twenty-four patients with liver neoplasms and AAP (graded according to Michel’s classification) were included in the study. During pretreatment angiographic planning, all extrahepatic vessels that could feed the tumor were embolized and the intrahepatic vessels occluded in order to redistribute blood flow. The distribution of microspheres was initially assessed by using technetium-99m-labeled macroaggregated albumin (^99mTc-MAA) from one of two vascular points before the administration of yttrium-90 (⁹⁰Y)-radiolabeled resin microspheres. Perfusion of lesions situated in the redistributed segments (L-RS) and nonredistributed segments (L-NRS) were compared by assessing the distribution of ^99mTc-MAA by SPECT/CT. Perfusion was graded as normal, reduced, or absent. ⁹⁰Y resin microspheres were then injected from the same arterial sites as ^99mTc-MAA and the tumor response recorded 3 months later. The tumor response in L-RS was compared with that in L-NRS and graded as better, similar, or worse. Among 11 patients with type I AAP in whom mainly vessels in segments I–III or IV were occluded, perfusion of L-RS was graded as similar (n = 7) or reduced (n = 4). Among the remaining 13 patients with AAP types III (n = 3), V (n = 4), VIII (n = 3), and others (n = 3) in which aberrant arteries were occluded, perfusion of L-RS was graded as similar (n = 9), reduced (n = 3), or absent (n = 1). Overall, ^99mTc-MAA was present in the L-RS of 95.8% patients and the distribution of ^99mTc-MAA in L-RS and L-NRS were graded as similar in 66.6% of patients. Compared with lesions in the L-NRS, tumor response in L-RS was similar in 23 cases and worse in 1 case. No complications were recorded after the administration of ⁹⁰Y resin microspheres. Redistribution of flow in L-RS is feasible and enables a safe and effective delivery of ⁹⁰Y resin microspheres that are able to be distributed via intrahepatic collaterals and access the microvasculature of L-RS.     

Intra-arterial infusion of N-isopropyl-p[123I]iodoamphetamine for assessing effective blood supply to pulmonary and hepatic neoplasms

The biodistribution and pharmacokinetics of intra-arterially administered N-isopropyl-p[¹²³I] iodoamphetamine (¹²³I-IMP) were prospectively evaluated in 38 patients with histologically proven pulmonary or hepatic tumors. Intra-arterially infused¹²³I-IMP was distributed initially in peripheral tissues in which the blood supply was maintained. Its concentration in malignant neoplasms was demonstrated to be higher than in normal tissues. In pulmonary cancer, the tumor uptake of the administered dose without a tissue attenuation correction (% uptake) of¹²³I-IMP at 1–2 min after injection was 14.7 ± 5.7% (s.d.). The tumor to normal tissue ratio was 2.1 ± 0.7 in hepatocellular carcinoma and 1.4 ± 0.7 in metastatic tumors. The biodistribution of¹²³I-IMP was also compared to that of^99mTc-macroaggregated albumin (^99mTc-MAA) in 9 cases of hepatic cancer. The distribution of¹²³I-IMP resembled that of^99mTc-MAA in 5 cases and was different in 4 cases.¹²³I-IMP was more concentrated in the tumor than^99mTc-MAA. Intra-arterial infusion scintigraphy with¹²³I-IMP seems to provide information on effective blood supply to neoplasms which are targeted in interventional radiology.     

Evaluation of 99mTc(CO)5I as a potential lung perfusion agent

IntroductionThe use of ^99mTc-macroggregated albumin for lung perfusion imaging is well established in nuclear medicine. However, there have been safety concerns over the use of blood-derived products because of potential contamination by infective agents, for example, Variant Creutzfeldt Jakob Disease. Preliminary work has indicated that Tc(CO)₅I is primarily taken up in the lungs following intravenous administration. The aim of this study was to evaluate the biodistribution and pharmacokinetics of ^99mTc(CO)₅I and its potential as a lung perfusion agent.Methods^99mTc(CO)₅I was synthesized by carbonylation of ^99mTcO_4? at 160 atm of CO at 170°C in the presence of HI for 40 min. Radiochemical purity was determined by HPLC using ⁹⁹Tc(CO)₅I as a reference. ^99mTc(CO)₅I was administered by ear-vein injection to three chinchilla rabbits, and dynamic images were acquired using a gamma camera (Siemens E-cam) over 20 min. Imaging studies were also performed with ^99mTc-labeled macroaggregated albumin (^99mTc-MAA) and ^99mTcO_4? for comparison. ^99mTc(CO)₅I was administered intravenously to Sprague–Dawley rats, and tissue distribution studies were obtained at 15 min and 1 h postinjection. Comparative studies were performed using ^99mTc-MAA.ResultsRadiochemical purity, assessed by HPLC, was 98%. The retention time was similar to that of ⁹⁹Tc(CO)₅I. The dynamic images showed that 70% of ^99mTc(CO)₅I appeared promptly in the lungs and remained constant for at least 20 min. In contrast, ^99mTcO_4? rapidly washed out of the lungs after administration. As expected ^99mTc-MAA showed 90% lung accumulation. The percentage of injected dose per gram of organ ±S.D. at 1 h for ^99mTc(CO)₅I was as follows: blood, 0.22±0.02; lung, 12.8±2.87; liver, 0.8±0.15; heart, 0.15±0.01; kidney, 0.47±0.08. The percentage of injected dose per organ ±S.D. at 1 h was as follows: lung, 22.47±2.31; liver, 10.53±1.8; heart, 0.18±0.01; kidney, 1.2±0.17. Tissue distribution studies with ^99mTc-MAA showed 100% lung uptake.Conclusion^99mTc(CO)₅I was synthesized with a high radiochemical purity and showed a high accumulation in the lungs. Further work on the mechanism and optimization of lung uptake of ^99mTc-pentacarbonyl complexes is warranted.     

Same-Day Repeat Hepatopulmonary Shunt Measurement during Planning Angiography for Hepatic Radioembolization

This report describes a technique for measuring lung shunt fraction (LSF) twice in a single session during planning arteriography for radioembolization using low and standard dose technetium-99m macroaggregated albumin (^99mTc-MAA). A patient with a 16.0 cm hepatocellular carcinoma and LSF of 70% was treated with lenvatinib for 4 weeks. Planning arteriography with administration of 0.5 millicuries of ^99mTc-MAA was then performed. Arterial access was maintained while the LSF was calculated, which was persistently elevated at 54%. Embolization of arteriovenous shunts was performed during the same session and 5.0 millicuries of ^99mTc-MAA were administered. The repeat LSF was 29%. Successful radioembolization was subsequently performed.     

Intravenous Vasopressin for the Prevention of Nontarget Gastrointestinal Embolization during Liver-directed Cancer Treatment: Experimental Study in a Porcine Model

PurposeThe aim of this study was to evaluate the potential for intravenous vasopressin to reduce the risk of nontarget gastrointestinal embolization during transcatheter liver-directed cancer therapies in a porcine model.Materials and MethodsAn angiographic catheter was used to select the celiac or common hepatic artery under fluoroscopic guidance in six anesthetized pigs. After angiography of the hepatic and splanchnic territories was performed, technetium-99m macroaggregated albumin (^99mTc-MAA) was injected through the catheter. Serial arteriograms were obtained before, every 5 minutes during, and after peripheral intravenous vasopressin infusion at 0.4 U/min for a minimum of 20 minutes. After 10 minutes of infusion, indium-111 (¹¹¹In)-MAA was injected through the arterial catheter. Quantitative comparisons of liver and gastrointestinal activity using dual-isotope single-photon emission computed tomography (SPECT)/CT imaging were performed.ResultsCatheter angiography demonstrated reduced blood flow to the splanchnic vasculature while maintaining blood flow through the hepatic arteries during vasopressin infusion. Angiographic findings correlated with the relative distribution of ^99mTc-MAA (before the vasopressin infusion) and ¹¹¹In-MAA (after the vasopressin infusion) on SPECT/CT. The increased ratio of liver to gastrointestinal tract activity during the vasopressin infusion was statistically significant (6.2:11.4, respectively; P = .018).ConclusionsIntravenous vasopressin reduces arterial blood flow to the splanchnic vasculature while preserving hepatic arterial blood flow in a healthy porcine model. Intraprocedural vasopressin administration has the potential to benefit liver-directed cancer therapies by enhancing tumor targeting as well as preventing the unintended delivery of bland embolic, chemoembolic, or radioembolic agents into the gastrointestinal vascular territories.     

Chlorin e6 conjugated silica nanoparticles for targeted and effective photodynamic therapy

Photodynamic therapy (PDT) using photosensitizer drug has become an important therapeutic modality. However, the stability and targeted delivery of photosensitizer remain a critical challenge for efficient PDT treatment. In the present study, we developed chlorin e6 (Ce6)-conjugated and folic acid (FA)-decorated silica nanoparticles (silica-Ce6-FA) for targeted delivery of photosensitizer to the cancer cells. The synthesized NPs exhibited excellent stability and biocompatibility with MDA-MB-231 cells. The formulated particles were efficiently taken up by folate receptor-positive MDA-MB-231 cells, which were confirmed by comparative analysis with folate receptor-negative HepG2 cells. The folate receptor-targeted silica-Ce6-FA was highly accumulated inside the MDA-MB-231 cells than free Ce6. The obtained NPs produced singlet oxygen efficiently under 670-nm laser exposure. The cell-killing effect of silica-Ce6-FA was higher when compared with free Ce6 under PDT treatment. The PDT-induced mitochondrial damage and apoptotic cell death were detected in silica-Ce6-FA-treated cells.     

Photodynamic therapy using a cytotoxic photosensitizer porphyrus envelope that targets the cell membrane

BackgroundSubcellular localization of a photosensitizer is known to determine the therapeutic efficacy of photodynamic therapy (PDT). Cell membrane is an optimal target that promises an effective treatment outcome.ObjectivesWe previously developed a novel photosensitizer named porphyrus envelope (PE) by combining hemagglutinating virus of Japan envelope (HVJ-E) with lipidated protoporphyrin IX (PpIX lipid). In the current study, the cellular localization of PE and its ability to induce multiple anti-tumor effect were characterized.Materials and MethodsThe localization and uptake of PpIX lipid in cells were evaluated with confocal laser scanning microscopy and a cell-based fluorescent assay, respectively. The ability of PE to suppress the migration and proliferation of cancer cells was assessed using a scratch-wound assay. The synergistic effect of PDT and HVJ-E treatment was evaluated using an in vitro experiment with PC-3 cells.ResultsPE localized along the cell membrane and PpIX lipid accumulated selectively in the prostate cancer cells within 10 min. Also, PE maintained the ability to undergo fusion and induce cancer cell death even after light irradiation at the dose for PDT. Incubation with PE resulted in delayed migratory and proliferative activity of PC-3 cells. PE-mediated PDT was twice as effective when cells were further incubated with PE following PDT.ConclusionsPE allows rapid drug delivery targeting the cell membrane. Because the cytotoxicity of HVJ-E was maintained, synergistic effect of HVJ-E and the photochemical reactions resulted in highly effective killing of prostate cancer cells in vitro and thus represents a promising treatment for prostate cancer.     

Alteration of the organ uptake of the (99m)Tc-radiopharmaceuticals, (99m)Tc-DPD, (99m)Tc-DMSA, (99m)Tc-tin colloid and (99m)Tc-MAA, induced by the applied cytotoxic drugs methotrexate sodium and cyclophosphamide

AIM: To investigate the influence of certain cytotoxic drugs on the organ uptake of the following (99m)Tc-radiopharmaceuticals: (99m)Tc-2,3-dicarboxypropane-1,1-diphosphonic acid ((99m)Tc-DPD), (99m)Tc-meso-2,3-dimercaptosuccinic acid ((99m)Tc-DMSA), (99m)Tc-tin colloid and (99m)Tc-macroaggregated albumin ((99m)Tc-MAA). Methotrexate sodium and cyclophosphamide were used as models to evaluate these effects. METHODS: Two groups of healthy male Wistar rats were treated separately by oral application of the drugs for 7 days. On the eighth day, each of the (99m)Tc-radiopharmaceuticals was applied in a separate group of treated animals. They were sacrificed at different time intervals and the radioactivity in the organs of interest was measured. The organ uptake of the (99m)Tc-radiopharmaceuticals in an additional control group of animals was also studied. RESULTS: The results obtained showed an alteration in the organ uptake of (99m)Tc-radiopharmaceuticals in animals treated with cytotoxic drugs. In rats treated with methotrexate sodium, there was a higher uptake of (99m)Tc-DMSA in the bones, stomach and intestine, a higher uptake of (99m)Tc-DPD in the bones, intestine, blood and muscle, a lower uptake of (99m)Tc-tin colloid in the liver and a lower accumulation of (99m)Tc-MAA in the lungs. Cyclophosphamide-treated animals showed enhanced uptake of (99m)Tc-DMSA in the kidneys, a twofold enhanced uptake of (99m)Tc-DPD in all organs except the stomach, a decreased uptake of (99m)Tc-tin colloid in the lungs, spleen and kidneys and a significantly decreased uptake of (99m)Tc-MAA in the lungs. CONCLUSION: These results confirm that both methotrexate sodium and cyclophosphamide may alter the organ uptake of (99m)Tc-radiopharmaceuticals in experimental animals.     

Technical solutions to ensure safe yttrium-90 radioembolization in patients with initial extrahepatic deposition of (99m)technetium-albumin macroaggregates

Purpose  

To evaluate the incidence of extrahepatic deposition of technetium-99m–labeled albumin macroaggregates (^99mTc-MAA) after pretreatment angiography, before yttrium-90 radioembolizaton (⁹⁰Y-RE), and to report on technical solutions that can be used to ensure safe delivery of ⁹⁰Y-microspheres in patients with initial extrahepatic deposition.     

<Superscript>18</Superscript>F-labelled annexin V: a PET tracer for apoptosis imaging

Annexin V can be used to detect apoptotic cells in vitro and in vivo, based on its ability to identify extracellular phosphatidylserine, which arises during apoptosis. In the present study, we examined the synthesis of fluorine-18 labelled annexin V as a positron emission tomography tracer for apoptosis imaging. The distribution of [¹⁸F]annexin V and technetium-99m labelled annexin V, a well-characterised SPET tracer for apoptosis imaging, was compared. [¹⁸F]annexin V was synthesised using N-succinimidyl 4-[¹⁸F]fluorobenzoate as an ¹⁸F labelling reagent. Synthesised and purified [¹⁸F]annexin V was confirmed by SDS-PAGE. In an ex vivo imaging experiment, [¹⁸F]annexin V was intravenously injected into rats 24 h after the induction of myocardial ischaemia, and accumulation in the left ventricle was examined. [¹⁸F]annexin V accumulated in the infarct area of the left ventricle, where apoptotic cells were observed. In separate experiments, [¹⁸F]annexin V or [^99mTc]annexin V was intravenously injected into ischaemic or normal animals, and the distribution of the tracers was compared. In ischaemic animals, accumulation of [¹⁸F]annexin V and [^99mTc]annexin V in the infarct area was about threefold higher than in the non-infarct area. Furthermore, the ratio of accumulation in the normal heart to the blood radioactivity was not significantly different between the tracers. In normal animals, however, the uptake of [¹⁸F]annexin V in the liver, spleen and kidney was much lower than that of [^99mTc]annexin V. The low uptake of [¹⁸F]annexin V in these organs might represent an advantage over [^99mTc]annexin V.     

<Superscript>99m</Superscript>Tc-MAA/<Superscript>90</Superscript>Y-Bremsstrahlung SPECT/CT after simultaneous Tc-MAA/<Superscript>90</Superscript>Y-microsphere injection for immediate treatment monitoring and further therapy planning for radioembolization

Purpose  

An angiographic evaluation combined with ^99mTc-macroaggregated albumin (Tc-MAA) scanning should precede the treatment of any selected candidates for radioembolization (RE) of the liver. If the tumours in one liver lobe have not been targeted in the test angiogram, it should be repeated. However, in a few cases treatment of one liver lobe or at least some segments is safe and feasible and performing a repeated test angiogram with Tc-MAA (Re-MAA) in a separate session leads to more radiation exposure and could be time consuming. Our aim was to evaluate the feasibility of concurrent RE of a part of the liver and therapy planning for another region by simultaneous injection of the Tc-MAA and ⁹⁰Y-microspheres in two different locations in the therapy session. Tc-MAA and bremsstrahlung (BS) single photon emission computed tomography (SPECT)/CT were performed separately in an effort to distinguish between the distributions of these two different radiopharmaceuticals.     

Preclinical characterization of (18)F-MAA, a novel PET surrogate of (99m)Tc-MAA

Introduction^99mTc-labeled macroaggregated albumin (^99mTc-MAA) scintigraphy scan is routinely performed for lung perfusion imaging and for the assessment of in vivo distribution of ⁹⁰Y-labeled SIR-Spheres prior to selective internal radiation treatment for hepatocellular carcinoma. Positron emission tomography (PET) imaging is superior to gamma scintigraphy in terms of sensitivity, spatial resolution and accuracy of quantification. This study reported that ¹⁸ F-labeled macroaggregated albumin (¹⁸ F-MAA) is an ideal PET imaging surrogate for ^99mTc-MAA.Methods¹⁸ F-MAA was prepared from the commercial MAA kit via a one-step conjugation with N-succinimidyl 4-¹⁸ F-fluorobenzoate (¹⁸ F-SFB). The biodistribution study and microPET/microSPECT imaging were conducted in normal SD rats after intravenous injection of ¹⁸ F-MAA/^99mTc-MAA. A comparison study of these two radiotracers was performed after co-injection via the intrahepatic arterial in a N1S1 hepatoma-bearing SD rat model.ResultsThe optimal condition for ¹⁸ F-MAA preparation is coupling MAA (0.5 mg) with ¹⁸ F-SFB at 45 °C for 5 min in a phosphate buffer of pH 8.5. ¹⁸ F-MAA was prepared in 60 min with high radiochemical yield (30%–35%) and high radiochemical purity (> 95%). The in vivo distribution of ¹⁸ F-MAA after intravenous injection meets the specifications of MAA depicted in European Pharmacopeia. Our study demonstrated excellent correlation between ¹⁸ F-MAA and ^99mTc-MAA in the regional distribution of tumor, liver and lungs (R² = 0.965, 0.886 and 0.991, respectively), and also in the tumor-to-liver and tumor-to-lungs ratio (R² = 0.965 and 0.987, respectively) in a N1S1 hepatoma-bearing SD rat model. The organ uptakes derived from animal PET/CT and SPECT/CT imaging after administration of these two tracers were in accordance with those obtained in the distribution studies.ConclusionsStarting from commercial MAA kit, an efficient preparation of ¹⁸ F-MAA was successfully established. Highly correlated, almost parallel, regional distribution of ¹⁸ F-MAA and ^99mTc-MAA in both normal rats and hepatoma-bearing rats was observed. The findings, taken together, demonstrate that ¹⁸ F-MAA is an ideal surrogate for ^99mTc-MAA for clinical PET applications.     

Mismatch between99mTc-DTPA aerosol and81mKr lung ventilation scintigraphy: a pitfall of radionuclide imaging

Pulmonary ventilation and perfusion scintigraphies were performed using^99mTc-MAA,^81mKr, and^99mTc-DTPA aerosol in a patient with asthma. Lung perfusion scintigraphy and^99mTc-DTPA aerosol scintigraphy showed multiple matching defects, however,^81mKr ventilation scintigraphy showed mismatch with lung perfusion scintigraphy. A pitfall of this examination was discussed.     

Development of Functional Polymers Targeting Tumor-Associated Amino Acid Transporters for Photosensitizer Delivery

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality that has been clinically approved for various cancer treatment [1]. To extend the potential of PDT to various types of cancers, it is important to develop new photosensitizers or drug delivery systems that can accumulate selectively within target tumors. Up to now, tremendous efforts have been devoted to the development of photosensitizers, some of which are already clinically used [2]. In addition to these efforts, recent studies have reported photosensitizers and drug delivery systems targeting specific molecules and environment in malignant tumors [3,4]. For example, we developed functional polymers possessing multiple cyclic RGD peptides in the side chains for photosensitizer delivery to target α_vβ₃ integrins, and this polymer-photosensitizer conjugate selectively accumulate within subcutaneous tumors in mice upon intravenous injection and accomplished appreciable PDT effects [4]. Such studies indicate that active targeting of tumor-associated molecules or environment should be a promising approach to achieve efficient PDT effects without giving unfavorable photochemical damage to normal tissues. In this context, we recently developed functional polymers targeting tumor-associated amino acid transporters [5]. The polymer had multiple amino acid moieties in the side chains and provided multivalent interaction with target amino acid transporters, exerting efficient tumor accumulation after systemic administration. In this study, based on this strategy, we fine-tuned the chemical structure of the polymers targeting tumor-associated amino acid transporters for PDT. In in vitro study, the fine-tuned polymer-photosensitizer conjugate exhibited strong phototoxicity without substantial dark toxicity to cultured cancer cells in an amino acid transporter-selective manner. Even in in vivo study, the polymer-photosensitizer conjugate demonstrated significantly enhanced PDT effect. Our polymers may be promising drug delivery systems for PDT.     

HER-2受体放射性配体99Tcm-TP1623的制备及其在正常动物体内的分布

目的 探讨HER-2受体放射性配体 ⁹⁹Tc^m-B2-S22-AFA(⁹⁹Tc^m-TP1623)在健康小鼠体内的生物分布和健康家兔体内的动态显像分布.方法 采用氯化亚锡间接法 ⁹⁹Tc^m标记TP1623,3MM色谱纸层析测定 ⁹⁹Tc^m-TP1623标记率,计算其比活度;通过体外稳定性实验、血清蛋白结合实验和油/水分配实验,鉴定标记产品理化性质;研究 ⁹⁹Tc^m-TP1623于1、5、10、30、60和120 min在健康小鼠体内的生物分布特性;通过SPECT显像,结合感兴趣区(ROI)时间-放射性曲线分析,观察 ⁹⁹Tc^m-TP1623在健康家兔体内的动态分布变化.结果 ⁹⁹Tc^m-TP1623标记率为(96.4±0.1)%,比活度为(24.35±0.06)TBq/mmol,室温下放置6 h后放化纯度为(95.03±0.97)%.油/水分配系数P为－(2.51±0.15).小鼠血液放射性清除快,通过肾脏排泄较快,心、肺、肝、肌肉、骨骼等放射性随时间延长逐渐减低,60 min后放射性呈明显低水平,肠道放射性则随时间缓慢增加.脑放射性始终呈最低水平.健康家兔体内 ⁹⁹Tc^m-TP1623血池影消退迅速,主要通过肾脏排泄,见胆囊、肠道排泄影,胃区和颈部未见放射性浓聚,脑组织始终呈低本底.结论 ⁹⁹Tc^m-TP1623制备方法简便,标记率及产品比活度高,体内、外稳定性好,具有优良的动物体内动力学特性.     

Is prophylactic embolization of the hepatic falciform artery needed before radioembolization in patients with <Superscript>99m</Superscript>Tc-MAA accumulation in the anterior abdominal wall?

Purpose  

While influx of chemoembolic agents into the hepatic falciform artery (HFA) from the hepatic artery can cause supraumbilical skin rash, epigastric pain and even skin necrosis, the significance of a patent HFA in patients undergoing radioembolization is not completely clear. Furthermore, the presence of tracer in the anterior abdominal wall seen in ^99mTc-macroaggregated albumin (^99mTc-MAA) images, which is generally performed prior to radioembolization, has been described as a sign of a patent HFA. The aim of this retrospective study was to evaluate the incidence and consequences of ^99mTc-MAA accumulation in the anterior abdominal wall, indicating a patent HFA, in patients undergoing radioembolization of liver tumours.     

The synthesis of 64Cu-chelated porphyrin photosensitizers and their tumor-targeting peptide conjugates for the evaluation of target cell uptake and PET image-based pharmacokinetics of targeted photodynamic therapy agents

Objective

Targeted photodynamic therapy (PDT) is necessary for preventing the side effects associated with PDT, such as photosensitivity caused by the distribution of photosensitizers into normal tissues. In the development of targeted PDT agents, a simple evaluation system of in vivo pharmacokinetics, as well as target cell uptake, is absolutely imperative. We hypothesized that ⁶⁴Cu chelation with porphyrin photosensitizer-biomacromolecule conjugates may become a simple and versatile labeling strategy for this purpose.

Methods

Protoporphyrin IX (PPIX) and a bombesin (BBN) analog, that interacts with the gastrin-released peptide (GRP) receptor, were used as a photosensitizer and tumor-targeting peptide, respectively. Then, a conjugate of PPIX and BBN analog linked via short polyethylene glycol (PPIX-PEG6-BBN analog) was synthesized and used as a targeted PDT agent. In addition, a ⁶⁴Cu-chelated PPIX-PEG6-BBN analog was synthesized under optimized reaction conditions. Lastly, cell uptake study and PET image-based pharmacokinetic analyses of the PPIX-PEG6-BBN analog were carried out in a human prostate cancer cell line, PC-3, which highly expresses the GRP receptor, and PC-3 tumor-bearing mice.

Results

It was confirmed that degradation (thought to be based on radiolysis) occurs, and large amounts of ⁶⁴Cu-labeling compounds are wasted in the reaction mixture. Interestingly, the addition of ethanol into the reaction mixture provides an effective solution for this problem. As for cell uptake study, the [⁶⁴Cu]PPIX-PEG6-BBN analog demonstrated significantly higher uptake for PC-3 cells than [⁶⁴Cu]PPIX and, in addition, the uptake of [⁶⁴Cu]PPIX-PEG6-BBN analog was significantly inhibited by adding excess cold BBN analog peptide. PET image-based pharmacokinetic evaluation revealed that [⁶⁴Cu]PPIX-PEG6-BBN analog and [⁶⁴Cu]PPIX rapidly accumulate into the liver and kidney, circulate in blood for a long time compared with normal peptides, and distribute at a low level in the tumor. This result suggested that in vivo biodistribution of PPIX-PEG6-BBN analog is mainly dependent on the lipophilicity of PPIX. Ex vivo measurements of radioactivity distribution after PET studies showed that although there was no remarkable difference in the tumor/skin ratio of radioactivity between [⁶⁴Cu]PPIX-PEG6-BBN analog and [⁶⁴Cu]PPIX, the pancreas (an organ that also expresses GRP receptors)/skin ratio was significantly higher in the case of [⁶⁴Cu]PPIX-PEG6-BBN analog.

Conclusion

We report on the successful synthesis of ⁶⁴Cu-chelated porphyrin photosensitizers and their tumor-targeting peptide conjugates under conditions in which radiolysis is suppressed. This labeling strategy with porphyrin photosensitizers may be of value for the rapid development of ideal targeted PDT agents.