A novel bi-modal probe based on BaHoF5 and Cu-doped QDs with enhanced CT contrast efficiency and fluorescent brightness for tumor-targeting imaging.

In this work, a novel bi-modal imaging probe with enhanced CT contrast efficiency and FL brightness was constructed, in which the combination of a binary CT contrast agent BaHoF5 and Cu-doped QDs served as a vehicle; hyaluronic acid (HA) was employed as a tumor-targeting ligand. With its CT contrast efficiency about 2.1- and 3.9-fold higher than PEG-BaHoF5 and Iohexol, the CT contrast efficiency and the fluorescent brightness of the bi-modal probe were both enhanced. Likewise, its fluorescent brightness is almost 6-fold brighter after Cu-doped QDs loading. The most important contribution of this work lies on the proposed strategy. The inherent contradiction of the imaging sensitivity of CT and FL imaging is well balanced and a great CT/FL bi-modal imaging performance is simultaneously obtained even at low concentration (400 µg/mL) of the probe, which was superior to the previous CT/FL bi-modal probes. Moreover, since BaHoF5 as a binary CT contrast agent was introduced instead of conventional Au and Bi2S3, the CT/FL bi-modal probe would be more suitable for different patients under different operation voltages. In addition, the in vitro tumor cell imaging also demonstrated a good photo-stability, FL brightness, and tumor-targeting capability of the probe, indicating its great potential in practical bi-modal imaging for further tumor diagnosis and therapy. Graphical abstract A novel bi-modal imaging probe with enhanced CT contrast efficiency and FL brightness was fabricated, in which its CT contrast efficiency was about 2.1- and 3.9-fold higher than PEG-BaHoF5 and Iohexol, respectively, and its fluorescent brightness almost 6-fold brighter after Cu-doped QDs loading.

Phase II study of transarterial holmium-166-chitosan complex treatment in patients with a single, large hepatocellular carcinoma.

PURPOSE: Holmium-166 ((166)Ho) is a neutron-activated radioactive isotope whose effectiveness in hepatocellular carcinoma (HCC) was first reported in a preclinical study in 1991. Chitosan is a polymer of 2-deoxy-2-amino-D-glucose that readily forms a chelate with heavy metals and converts from a solution under acidic conditions into a gel under neutral or basic conditions. We performed a prospective trial of a transarterial administration of a radiopharmaceutical (166)Ho-chitosan complex in patients with single, large HCC. PATIENTS AND METHODS: The study involved 54 patients who had single HCC (>or=3 cm) without a vascular shunt and were either inoperable or refused surgery. The (166)Ho-chitosan complex was administered at a dose of 20 mCi per cm of tumor diameter (capping at 200 mCi) via the artery that directly fed the tumor. RESULTS: The median tumor size was 5.3 cm (range: 3-13 cm). The response rate was 78% (42/54), and 31 patients had a complete response for a median duration of 27 months. The incidence of grade 3 or 4 leukopenia was 18.6%, anemia 7.4%, thrombocytopenia 27.8%, AST/ALT elevation 26%/24%, and total bilirubin elevation 5.6%. There were two treatment-related deaths (3.7%). Subset analysis revealed a substantial difference between the two groups categorized by tumor size (3-5 vs. >5 cm) with respect to response rate (p = 0.004) and overall survival (p = 0.02). CONCLUSION: We found that transarterial administration of the (166)Ho-chitosan complex was highly effective in the treatment of HCC with acceptable toxicities, especially for patients with tumors of 3-5 cm.

Clinical effects of transcatheter hepatic arterial embolization with holmium-166 poly(L-lactic acid) microspheres in healthy pigs.

PURPOSE: The aim of this study is to evaluate the toxicity of holmium-166 poly(L-lactic acid) microspheres administered into the hepatic artery in pigs. METHODS: Healthy pigs (20-30 kg) were injected into the hepatic artery with holmium-165-loaded microspheres ((165)HoMS; n=5) or with holmium-166-loaded microspheres ((166)HoMS; n=13). The microspheres' biodistribution was assessed by single-photon emission computed tomography and/or MRI. The animals were monitored clinically, biochemically, and ((166)HoMS group only) hematologically over a period of 1 month ((165)HoMS group) or over 1 or 2 months ((166)HoMS group). Finally, a pathological examination was undertaken. RESULTS: After microsphere administration, some animals exhibited a slightly diminished level of consciousness and a dip in appetite, both of which were transient. Four lethal adverse events occurred in the (166)HoMS group due either to incorrect administration or comorbidity: inadvertent delivery of microspheres into the gastric wall (n=2), preexisting gastric ulceration (n=1), and endocarditis (n=1). AST levels were transitorily elevated post-(166)HoMS administration. In the other blood parameters, no abnormalities were observed. Nuclear scans were acquired from all animals from the (166)HoMS group, and MRI scans were performed if available. In pigs from the (166)HoMS group, atrophy of one or more liver lobes was frequently observed. The actual radioactivity distribution was assessed through ex vivo (166m)Ho measurements. CONCLUSION: It can be concluded that the toxicity profile of HoMS is low. In pigs, hepatic arterial embolization with (166)HoMS in amounts corresponding with liver-absorbed doses of over 100 Gy, if correctly administered, is not associated with clinically relevant side effects. This result offers a good perspective for upcoming patient trials.

Long-term toxicity of holmium-loaded poly(L-lactic acid) microspheres in rats.

The aim of this study was to get insight into the toxic effects of holmium-166-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) which have very interesting features for treatment of liver malignancies. Acute, mid- and long-term effects were studied in healthy Wistar rats by evaluating clinical, biochemical and tissue response. Rats were divided into four treatment groups: sham, decayed neutron-irradiated Ho-PLLA-MS, non-irradiated Ho-PLLA-MS and PLLA-MS. After implantation of the microspheres into the liver of the rats, the animals were monitored (body weight, temperature and liver enzymes) for a period of 14-18 months. Some of the rats that received previously neutron-irradiated Ho-PLLA-MS were periodically scanned with magnetic resonance imaging (MRI) to see if holmium was released from the microspheres. After sacrifice, the liver tissue was histologically evaluated. Bone tissue was subjected to neutron-activation analysis in order to examine whether accumulation of released holmium in the bone had occurred. No measurable clinical and biochemical toxic effects were observed in any of the treatment groups. Furthermore, histological analyses of liver tissue samples only showed signs of a slight chronic inflammation and no significant differences in the tissue reaction between rats of the different treatment groups could be observed. The non-irradiated PLLA-MS and Ho-PLLA-MS stayed intact during the study. In contrast, 14 months after administration, the neutron-irradiated Ho-PLLA-MS was not completely spherical anymore, indicating that degradation had started. However, the holmium loading had not been released as was illustrated with MRI and affirmed by neutron-activation analysis of bone tissue. In conclusion, neutron-irradiated Ho-PLLA-MS does not provoke any toxic reaction and can be applied safely in vivo.

[Research on the cytotoxic and genotoxic effects of rare-earth element holmium to Vicia faba].

Crystal of nitrate, made by the reaction of holmium trioxide and nitric acid, was dissolved in distilled water, thus diluted into gradient solution. Soaked in the solution for 6 hours (6h), the root tips of Vicia faba were then recovered and cultivated for 22 h and 24 h, respectively. By observing the change of root tips and calculating the frequency of micronucleus (FMN), the frequency of chromosomal aberrations(CAF) and mitosis index (MI),we find that the dosage below 4mg/L (expressed by concentration of holmium trioxide) could accelerate the growth of root tips of Vicia faba. CAF and FMN increased while MI decreased with the rise of concentrations. From it a dosage effect relationship is clearly seen. And it indicated that the rare earth element holmium has certain cytotoxic and genotoxic effects. Furthermore, the different recovery groups have different FMN, CAF and MI, and the difference lies in the fact that FMN of 22 h recovery group was lower than that of 24 h recovery group, while CAF and MI were higher than those of 24 h recovery group. The results suggest that the statistics of FMN should be made after that of CAF.

Toxicities of 166Holmium-chitosan in mice.

166Holmium (166Ho) is a radionuclide of rare earth chemical and is known to have antitumor activity. Several chemicals were complexed with 166Ho to facilitate the transport of this radionuclide to the site of action. In this study, 166Ho was complexed to chitosan (Chit) which decreases the distribution of Ho into other tissues when applied intrahepatically. To investigate the single dose toxicity, mice were administered intravenously with 1 mCi/kg body weight of 166Ho-Chit (DW-166HC), Chit or nothing. Organ weights, hematological and histopathological studies were performed in 6 animals per group at 1, 3 and 14 days after administration. In 166Ho-Chit treated animals, a slight decrease of erythrocyte number was observed at day 14 and increases of relative liver and lung weights were found at day 3. Although marked multiple necrotic foci in the white pulp and depletion of marginal zone in the spleen were noted at day 1, these findings were decreased in severity and fully recovered at day 3 and day 14, respectively. Slightly decreased kidney weights were observed both in Chit and in 166Ho-Chit treated groups without histological alterations. Thus it is suggested that most effects of 166Ho-Chit observed at an early stage after administration are limited to rapidly dividing cells and reversible within 14 days.