Rationally designed upconversion nanoparticles for NIR light-controlled lysosomal escape and nucleus-based photodynamic therapy.

Cell nucleus-based photodynamic therapy is a highly effective method for cancer therapy, but it is still challenging to design nucleus-targeting photosensitizers. Here, we propose the "one treatment, multiple irradiations" strategy to achieve nucleus-based photodynamic therapy using the photosensitizer rose bengal (RB)-loaded and mesoporous silica-coated upconversion nanoparticles with the surface modification of amine group (UCNP/RB@mSiO2-NH2 NPs). After implementation into cancer cells, the rationally designed UCNP/RB@mSiO2-NH2 NPs could be specifically accumulated in the acidic lysosomes due to their amino group-decorated surface. Upon a short-term (3 min) irradiation of 980 nm near-infrared light, the reactive oxygen species produced by RB through the Förster resonance energy transfer between the upconversion nanoparticles and RB molecules could effectively destroy lysosomes, followed by the release of the UCNP/RB@mSiO2-NH2 NPs from the lysosomes. Subsequently, these released UCNP/RB@mSiO2-NH2 NPs could be transferred into the cell nucleus, where a second 980 nm light irradiation was conducted to achieve the nucleus-based photodynamic therapy. The rationally designed UCNP/RB@mSiO2-NH2 NPs showed excellent anticancer performance in both two-dimensional and three-dimensional cell models using the "one treatment, multiple irradiations" strategy.

Effect of the dose on the toxicokinetics of a quaternary mixture of rare earth elements administered to rats.

Large human biomonitoring studies are starting to assess exposure to rare earth elements (REEs). Yet, there is a paucity of data on the toxicokinetics of these substances to help interpret biomonitoring data. The objective of the study was to document the effect of the administered dose on the toxicokinetics of REEs. Male Sprague-Dawley rats were injected intravenously with 0.3, 1 or 10 mg/kg body weight (bw) of praseodynium chloride (PrCl3), cerium chloride (CeCl3), neodymium chloride (NdCl3) and yttrium chloride (YCl3) administered together as a mixture. Serial blood samples were withdrawn up to 72 h following injection, and urine and feces were collected at predefined time intervals up to 7 days post-dosing. The REEs were measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). For a given REE dose, the time courses in blood, urine and feces were similar for all four REEs. However, the REE dose administered significantly impacted their kinetics, as lower cumulative excretion in urine and feces was associated with higher REE doses. The fraction of REE remaining in rat tissues at the terminal necropsy on post-dosing day 7 also increased with the dose administered, most notably in the lungs and spleen at the 10 mg/kg bw dose. The toxicokinetic parameters calculated from the blood concentration-time profiles further showed significant increases in the mean residence time (MRTIV) for all four REEs at the 10 mg/kg bw dose. The shift in the REE kinetics at high dose may be explained by a higher retention in lysosomes, the main organelle responsible for accumulation of these REEs in different tissues.

Polypyrrole-based double rare earth hybrid nanoparticles for multimodal imaging and photothermal therapy.

Nanotheranostic agents that can simultaneously provide real-time tracking and accurate treatment at tumor sites are playing an increasingly important role in medicine. Herein, a novel polypyrrole (PPy)-based theranostic agent containing double rare-earth elements (PPy@BSA-Gd/Dy NPs) was successfully synthesized via an integrated strategy combining biomineralization and oxidation polymerization. The obtained PPy@BSA-Gd/Dy NPs with a diameter of approximately 59.48 ± 6.12 nm exhibited excellent solubility, long-term stability, superior biocompatibility, and negligible toxicity. Importantly, due to its intrinsic paramagnetic and strong X-ray attenuation ability, this agent demonstrated brilliant imaging performance in both T1/T2-weighted magnetic resonance imaging (MRI) and X-ray computed tomography (CT) imaging in vitro and vivo. Additionally, with an excellent photothermal conversion efficiency (26.61%) upon irradiation by an 808 nm laser, this theranostic agent showed significant photothermal cytotoxicity against HeLa cells and 4T1 cells in vitro and antitumor efficacy through intravenous injection in vivo. Meanwhile, biodistribution and blood circulation were also used to explore its fate in vivo. In summary, this study highlighted the versatility and practicability of PPy@BSA-Gd/Dy NPs and also suggested that the agent may be a promising candidate for T1/T2-weighted MRI/CT tri-modal imaging guided photothermal cancer therapy.

Lifetime-Encoded Infrared-Emitting Nanoparticles for in Vivo Multiplexed Imaging.

Advanced diagnostic procedures are required to satisfy the continuously increasing demands of modern biomedicine while also addressing the need for cost reduction in public health systems. The development of infrared luminescence-based techniques for in vivo imaging as reliable alternatives to traditional imaging enables applications with simpler and more cost-effective apparatus. To further improve the information provided by in vivo luminescence images, the design and fabrication of enhanced infrared-luminescent contrast agents is required. In this work, we demonstrate how simple dopant engineering can lead to infrared-emitting rare-earth-doped nanoparticles with tunable (0.1-1.5 ms) and medium-independent luminescence lifetimes. The combination of these tunable nanostructures with time-gated infrared imaging and time domain analysis is employed to obtain multiplexed in vivo images that are used for complex biodistribution studies.

Synthesis of a rare-earth doped hafnia hydrosol: Towards injectable luminescent nanocolloids.

A major obstacle in the introduction of luminescent nanoparticles (NPs) for medical applications is that quantum dots, the most widely studied luminescent materials, despite being biologically safe after coating with a bioshell, still contain a toxic core mostly consisting of semi-conductor NPs, which are not approved by regulatory agencies. Here we point to a potential solution of this problem by using rare-earth (RE) doped hafnia NPs. Hafnia is approved for medical injections as an effective means for the treatment of radiosensitive and radioresistant tumors and can significantly decrease potential toxicity of RE ions. As a step towards the achievement of this goal we describe the development of a bio-friendly method for the preparation of a stable doped hafnia hydrosol with an isoelectric point (IEP) of 8.2, which shows high fluorescence and biocompatibility in regular coagulant tests and cytotoxic assays.

Cancer-targeted near infrared imaging using rare earth ion-doped ceramic nanoparticles.

The use of near-infrared (NIR) light over 1000 nm (OTN-NIR or second NIR) is advantageous for bioimaging because it enables deep tissue penetration due to low scattering and autofluorescence. In this report, we describe the application of rare earth ion-doped ceramic nanoparticles to cancer-targeted NIR imaging using erbium and ytterbium ion-doped yttrium oxide nanoparticles (YNP) functionalized with streptavidin via bi-functional PEG (SA-YNP). YNP has NIR emission at 1550 nm, with NIR excitation at 980 nm (NIR-NIR imaging). Cancer-specific NIR-NIR imaging was demonstrated using SA-YNP and biotinylated antibodies on cancer cells and human colon cancer tissues. NIR-NIR imaging through porcine meat of 1 cm thickness was also demonstrated, supporting the possible application of deep tissue NIR-NIR bioimaging using YNP as a probe. Our results suggest that non-invasive imaging using YNP has great potential for general application in cancer imaging in living subjects.

Effect of graded levels of rare earth elements in diets of fattening bulls on growing and slaughtering performance, and on nutrient digestibility of wethers.

The aim of the present dose response study was to examine the long-term effects of increasing the amounts of rare earth elements (REE) in the diet on growth and slaughtering performance of fattening bulls. A total of 48 bulls of German Holstein with an average initial live weight (LW) of 119 + 13 kg were divided into four dietary treatment groups (n = 12): a control group and three REE-treated groups, which were fed a supplement of 100, 200 and 300 mg REE-citrate per kg dry matter (DM) containing mainly cerium (57.9%), lanthanum (34.0%) and praseodymium (6.5%). The feeding trial was divided into a growing period for 8 weeks and a fattening period for 39 weeks. The growing diet consisted of concentrate, grass silage and grass hay, while the fattening diet consisted of concentrate and maize silage. The animals were slaughtered at approximately 556 kg LW. The intake of grass hay and maize silage (0.55-0.31 kg/d and 6.09-5.44 kg/d, respectively) decreased linearly (p < 0.05) with increasing REE-citrate supplementation, while LW gain showed only a numerical decrease during the growing (2-4%) and the fattening period (4-5%). The feed-to-gain ratio and ME-to-gain ratio were not significantly affected by REE treatment during the whole feeding trial. The most striking effect of REE on carcass characteristics was a significantly higher dressing percentage in Group C (200 mg REE citrate kg/DM) compared to the other groups, while no effects were found on liver, kidneys, heart, thymus, pancreas, spleen and thyroid gland weights. The digestibility trials with wethers indicate that a supplementation of 300 mg REE-citrate per kg DM to a ration consisting of concentrate and straw does not enhance the digestibility of nutrients. These results suggest that, under the conditions of the present study, the supplementation of fattening bull diets with REE cannot be recommended.

Nano rare-earth oxides induced size-dependent vacuolization: an independent pathway from autophagy.

Four rare earth oxides have been shown to induce autophagy. Interestingly, we often noticed plentiful vacuolization, which was not always involved in this autophagic process. In this study, we investigated three other rare-earth elements, including Yttrium (Y), Ytterbium (Yb), and Lanthanum (La). Autophagic effect could be induced by all of them but only Y(2)O(3) and Yb(2)O(3) could cause massive vacuolization. Y(2)O(3) and Yb(2)O(3) treated by sonication or centrifugation to reduce particle size were used to test vacuolization level in HeLa cell lines. The results showed that rare earth oxides-induced vacuolization is size-dependent and differs from autophagic pathway. To further clarify the characteristics of this autophagic process, we used MEF Atg-5 (autophagy associated gene 5) knockout cell line, and the result showed that the autophagic process induced by rare earth oxides is Atg-5-dependent and the observed vacuolization was independent from autophagy. Similar results could also be observed in our tests on 3-methyladenine(3-MA), a well-known autophagy inhibitor. In conclusion, for the first time, we clarified the relationship between massive vacuolization and autophagic process induced by rare earth oxides and pointed out the size effect of rare earth oxides on the formation of vacuoles, which give clues to further investigation on the mechanisms underlying their biological effects.

Weaning pig performance and faecal microbiota with and without in-feed addition of rare earth elements.

Two 6-week feeding trials were conducted on a total of 112 newly weaned piglets to examine the recently reported growth promoting effects of dietary rare earth elements (REE) in European pig production. Rare earth element-diets were supplemented with a REE-citrate premix of lanthanum and the light lanthanoides cerium, praseodymium and neodymium at 200 mg/kg for 6 weeks after weaning. Overall for both trials, growth performance of REE-citrate and control fed piglets did not differ significantly (p > 0.05). An early enhancive tendency for REE-citrate in trial 1 (feed conversion ratio, FCR -3%, p = 0.15) proved irreproducible in trial 2. In the late period of trial 1, in-feed addition of REE-citrate significantly impaired piglet performance (FCR + 8%, p = 0.01). A cultivation-independent molecular approach, polymerase chain reaction-denaturing gradient gel electrophoresis was further applied to assess REE induced alterations in the predominant faecal microbiota from weaning pigs. Calculation of various ecological characteristics does not indicate (p > 0.05) an often discussed selective effect on local microbial composition of dietary REE.

Effect of dietary rare earth elements on growth performance and blood parameters of rats.

Rare earth elements (REE) have been shown to influence growth performance in animal production, especially in pigs. In the present study, the effect of oral administration of rare earth elements on growing rats was investigated. Pure LaCl3 or an REE mixture containing 38% of LaCl3, 52% of CeCl3, 3% of PrCl3 and 7% of chlorides of other REE were used at two different concentrations as supplements to the diets. Fifty male Wistar rats at 4 weeks of age were allotted to five experimental groups: a control group; a La-low group and a La-high group with 75 and 150 mg/kg LaCl3.6H2O, respectively; a REE-low and an REE-high group with 75 and 150 mg/kg REE mixture, respectively. The animals were housed in individual pens. Feed and water were provided ad libitum. After 18 days the oral supplementation of LaCl3.6H2O or of the REE mixture improved daily body weight gain (BWG) by up to 5 or 9% (p > 0.05), respectively. LaCl3.6H2O as well as the REE mixture had positive effects (p < 0.05) on feed conversion ratio (FCR) with a decreased ratio by up to 8 and 11%, respectively. Supplementation of REE also had clear effects on blood serum parameters. The activities of alkaline phosphatase (AP) and alanine amino transferase (ALT) increased significantly (p < 0.05). At the same time, blood glucose level decreased and blood creatine level increased significantly (p < 0.05). There was no significant difference in cholesterol, total protein, albumin and urea nitrogen among the groups. There was no significant difference in triglyceride level between the control and those REE groups, however, a significantly lower (p < 0.01) triglyceride level was found in the 150 mg/kg REE mixture group compared with that in 75 mg/kg REE mixture group and the 150 mg/kg LaCl3.6H2O group. The results suggest that oral supplementation of REE improves growth performance in rats as in pigs. In this respect, concentration and type of REE supplemented to the diets are two important factors herein.

Preparation of microcapsules containing rare-earth metal elements.

Microcapsules for internal radiation therapies containing the rare-earth metal elements Dy, Ho and Cu with a diameter of 5-10 microm were successfully obtained by an interfacial polymerization method and a successive sedimentation technique was employed to fractionate the microcapsules. A triisocyanate monomer and tricresylphosphate were used for a wall forming material and a core solvent for the metals, respectively. The amount of the metal elements loaded was measured using a high frequency plasma photoemission apparatus. The beta-ray radioactivity of 1 mg of microcapsules irradiated with a common neutron source is estimated as 370 microCi, which is satisfactorily strong for usual radiotherapy, when microcapsules containing Dy are used. Differential interference microscopy indicated narrow size distribution of the fractionated microcapulses.

[Arthroscopic shoulder stabilization. Differentiated treatment strategy with Suretac, Fastak, Holmium: YAG-laser and electrosurgery]. / Arthroskopische Schulterstabilisierung. Differenzierte Behandlungsstrategie mit Suretac, Fastak, Holmium: YAG-Laser und Elektrochirurgie.

The goal for arthroscopic stabilization of anterior glenohumeral instability is to achieve an outcome equivalent to or better than open procedures. A number of arthroscopic procedures have been advocated to reestablish continuity of the inferior glenohumeral ligament complex (IGHLC) with the glenoid. Implantable suture anchors were developed to avoid the problems associated with arthroscopic staple capsulorrhaphy like iatrogenic injury of the glenoid or humeral surface, loosening and migration of the staple. Several transosseous techniques include the need for an accessory posterior incision, the possibility of neurovascular injury (Suprascapular or axillary nerve), and the loosening of the repair after typing over the fascia of the infraspinatus posteriorly. The preferred techniques are cannulated, absorbable fixation device (Suretac) and easy implantable suture anchors made of titanium (Fastak). Even in the hands of experienced arthroscopists, unacceptably high recurrence rates for arthroscopic shoulder stabilization have been reported, due to the steep learning curve for both technical performance and patient selection. Our experience suggests, that if proper selection criteria are employed, normal patients and overhead-athletes may benefit from the advantages of an arthroscopic repair without accepting an increased risk for recurrence. We performed a prospective analysis of 105 shoulders, who underwent arthroscopic stabilization with Suretac or Fastak between 4/96 and 7/98. 48 shoulders were available for followup at least one year. The redislocation rate was 6.25% (3 shoulders) and the rate of subluxation without dislocation also was 6.25%, but none of the shoulders required a second open stabilization. The reason for redislocation or subluxation were 5/6 traumatic injuries, participating in contact sports or in one case a generalized ligamentous laxity. In combination with the LACS-Procedure or the Electro thermally assisted capsular shift (ETACS) not only the capsular detachment but also the capsular redundancy may be adressed and a lower failure rate can be expected.

Differences in behavior among the chlorides of seven rare earth elements administered intravenously to rats.

Differences in behavior among the chlorides of seven rare earth elements (REEs)-yttrium (Y), cerium (Ce), and praseodymium (Pr) (light REEs); europium (Eu) and dysprosium (Dy) (medium REEs); ytterbium (Yb) and lutetium (Lu) (heavy REEs)-were investigated through intravenous administration of the REEs to rats. (1) Distributions of REEs and mineral concentrations in the organs on Day 1 were investigated at low and high doses (9-10 and 18-20 mg REE/kg, or 56-66 and 112-132 mumol REE/kg). More than 78% of the REEs administered was distributed into liver, bone, and spleen. High doses of Y, Eu, and Dy markedly increased the accumulation of REEs in spleen and lungs as well as the concentration of Ca in liver, spleen, and lungs. (2) The distribution patterns of REEs and changes in Ca concentrations in major organs over time were investigated by the administration of Pr, Eu, Dy, Yb (low dose), and Y (high dose). REEs disappeared from the blood within 1 day but were retained in the organs for a long time. The percentages of the doses of Y, Eu, Dy, and Yb found in the liver were highest at 8 hr to 2 days, then decreased gradually; hepatic Pr levels, however, remained high. Changes in Ca concentrations in liver, spleen, and lungs were in accordance with those of REEs. (3) Severe hepatotoxicity was observed after administration of Ce and Pr; fatty liver, jaundice, and elevated serum GOT and GPT levels were most prominent on Day 3. Therefore, we hypothesized that REE chlorides might be categorized into three groups according to their ionic radii (light REEs, Y and medium REEs, and heavy REEs) and from their behavior, i.e., distribution pattern, Ca-accumulating action, and hepatotoxicity.

Evaluation of gadobutrol in a rabbit model as a new lanthanide contrast agent for computed tomography.

RATIONALE AND OBJECTIVES: The efficacy of the neutral lanthanide contrast agent gadobutrol was compared to that of the iodinated contrast agent iopromide in rabbits. METHODS: The computed tomography (CT) attenuation of increasing concentrations of gadolinium (Gd) (gadobutrol) and iodine (I) (iopromide) was measured in Hounsfield units (HU) in aqueous solution at 80, 120, and 137 kV. The peak enhancement (net increase in CT attenuation compared with baseline) and the time-enhancement product in the aorta and in the renal parenchyma of the outer and inner cortex were measured in rabbits over a 5-minute period after the animals were given single intravenous injections of 0.7, 1.0, and 1.5 mmol Gd/kg of gadobutrol and 1.0 and 2.4 mmol I/kg of iopromide. RESULTS: In vitro, the CT attenuation of gadolinium was 40% higher than that of iodine at equivalent mass concentrations (120 kV). The mean peak enhancements in the aorta after the injections of 0.7, 1.0, and 1.5 mmol Gd/kg and 1.0 and 2.4 mmol I/kg were 216, 313, 591, 224, and 498 HU, respectively. In addition, a 30-second injection of the high dose of gadobutrol resulted in an attenuation profile that was suitable for a three-dimensional reconstruction of the aorta and the renal vasculature. CONCLUSIONS: Because of the higher CT attenuation of gadolinium compared with that of iodine, the neutral macrocyclic chelate gadobutrol is a more effective contrast agent than iopromide for CT at lower doses of the imaging atom.

Pulmonary toxicity of stable and radioactive lanthanides.

The pulmonary toxicity of inhaled lanthanides has been the subject of debate. In question have been the relative contributions of radioactive vs. stable elements in the development of lanthanide-associated progressive pulmonary interstitial fibrosis. The central question of this debate is: Are lanthanide dusts that are devoid of radioactive contaminants capable of producing progressive pulmonary disease, or are lanthanide-induced lesions more appropriately termed "benign pneumoconioses"? This paper examines the epidemiologic and experimental record in order to answer the above question. It is clear from the available data that significant pathogenic potential of inhaled lanthanides exists and is related to the type and physicochemical form of the material inhaled and to the dose and duration of exposure. Contamination of the dust with radioactive materials may accelerate and enhance the pathologic response, depending on the form and dose of radioactivity encountered. Nevertheless, there is little evidence to suggest that the level of radioactive contamination of occupationally encountered lanthanide dusts is sufficient to be included as a risk factor for pulmonary disease. Thus, the pulmonary syndrome induced by stable rare earths includes progressive pulmonary fibrosis and should not be referred to as "benign pneumoconiosis."

Toxicological studies on safety of rare earths used in agriculture.

Studies on the toxicity and safety of a mixture of rare earth metal nitrates (Ce, La, Nd, Pr, and Sm) used in agricultural operations are reported. In mice, rats, and guinea pigs, the oral LD50 ranged from 1397 to 1876 mg/kg; absorption in the gastrointestinal tract was low. The accumulation coefficient was greater than 5. In rabbits, a topical application of a suspension of 500 mg/ml produced mild irritation of the skin and eye mucosa. Subchronic and chronic toxicity studies were done at different dose levels in monkeys (100 mg/kg) and rats (200 and 1800 mg/kg); biochemical and histopathological examination of tissues showed no abnormal or specific pathological changes. In chronic feeding studies with rats, the incidence of tumors and malignant tumors in test groups was lower than that in the control. Rat fetuses did not show any teratogenicity when the dams were orally fed up to 330 mg/kg of this nitrate mixture. Ames mutagenicity tests were negative at a 50 mg/kg level. The results indicate that an oral dose of 60 mg/kg should be considered as a no-effect level with an ADI of 0.6 mg/kg and that the level of rare earth nitrates used in Chinese agriculture is within acceptable risk or safety limits.