Nanofabricated upconversion nanoparticles for photodynamic therapy.

We present a novel process for the production of three-layer Composite Nanoparticles (CNPs) in the size range 100-300 nm with an up-converting phosphor interior, a coating of porphyrin photosensitizer, and a biocompatible PEG outer layer to prevent clearance by the reticuloendothelial system. We show that these CNPs produce millimolar amounts of singlet oxygen at NIR intensities far less than other two-photon techniques.

Assessment of the tolerance dose of the hepatic reticulo-endothelial system (RES) after single fraction HDR-irradiation: an in-vivo study employing SSPIO.

PURPOSE: To prospectively assess a dose-response relationship for the hepatic reticulo-endothelial system (RES) after small volume single fraction irradiation of liver parenchyma in vivo. MATERIALS AND METHODS: Twenty-five liver tumors were treated by computed tomography (CT)-guided interstitial brachytherapy. Magnetic resonance imaging (MRI) was performed 1 day before and 3 days, 6, 12 and 24 weeks after therapy. MR-sequences included T2-w Turbo Spin Echo (TSE) enhanced by hepatic RES targeted Standard Superparamagnetic Iron Oxide (SSPIO). All MRI data sets were merged with three dimensional (3D) dosimetry data and evaluated by two radiologists. We estimated the threshold dose for either edema or function loss as the D90. A match-pair analysis was performed with another 25 liver tumors, which were treated the same but had MRI follow-up using the hepatocyte specific MRI contrast media Gadobenate dimeglumine (Gd-BOPTA). RESULTS: Three days post brachytherapy the D90 for hepatic RES function loss reached the 18.3 Gray (Gy) isosurface (Standard Deviation (SD) 7.7). At 6 weeks, the respective zone had increased significantly to the 12.9 Gy isosurface (SD 4.4). After 12 and 24 weeks, the dysfunction of liver volume decreased significantly to the 15 Gy and 20.4 Gy isosurface respectively (SD 7.1 and 10.0). Comparison to the hepatocyte function loss indicates a higher minimal threshold dose of the hepatic RES. CONCLUSION: Hepatic RES demonstrated a high regenerative capacity and a higher minimal threshold dose than hepatocytes. Temporary function loss was found from the 13 Gy isosurface.

[Bioeffects of chronic exposure to radiofrequency electromagnetic fields of low intensity (standardization strategy)]. / Bioéffekty khronicheskogo vozdeistviia élektromagnitnykh polei radiochastotnogo diapazona malykh intensivnostei (strategiia normirovaniia).

A retrospective analysis of the experimental researches on the effect of radio frequency electromagnetic fields (EMF) on human health, carried out in the USSR, is presented. The results of chronic exposure of laboratory animals to EMF have been considered. Apparently, EMF in the range of 1750-2750 MHz with power density up to 100-500 W/cm2 caused in immune globullin fractions, and a development of autoimmune processes. The changes in parameters of reproductive functions and posterity, the increase in embryo mortality were found. The standartization strategy used in the USSR and currently applied in Russia has been discussed.

[Experimental studies of the value of SPIO for MRI of bone marrow before and after whole body irradiation]. / Experimentelle Untersuchungen zur Wertigkeit von SPIO für die MRT des Knochenmarkes vor und nach Ganzkörperbestrahlung.

PURPOSE: Evaluation of the value of superparamagnetic iron oxides (SPIO; Endorem) for MRI-derived quantifications of the permeability of the blood-bone marrow barrier and the phagocytic activity of reticuloendothelial system (RES) bone marrow cells before and after TBI. METHODS: 12 New Zealand white rabbits underwent MRI of the lumbar spine and os sacrum using T1-weighted spinecho (SE) and T2-weighted Turbo-SE (TSE) sequences before and after injection of SPIO (Endorem). Four animals each were examined without irradiation, after 4 Gy total body irradiation (TBI), and after 12 Gy TBI. Changes in bone marrow signal intensities (SI) after contrast agent injection were quantified as delta SI(%) = SIpost-SIpre)/SIpre) x 100% and these data were correlated with bone marrow histopathology. RESULTS: Histopathology of the bone marrow revealed a radiation-induced decline of all hematopoetic cell lines. SPIO were phagocytosed by bone marrow RES cells and caused a significant bone marrow signal decline on postcontrast T2-weighted images (p < 0.05). delta SI(%) data for T2-weighted images were significantly higher for the irradiated bone marrow as compared to non-irradiated controls (p < 0.05). Dynamic T1-weighted images directly after contrast medium injection were not able to characterize the permeability of the blood-bone marrow barrier. CONCLUSION: Hematopoetic bone marrow can be labelled with SPIO. Irradiation does not impair the phagocytic activity of bone marrow RES cells. However, the bone marrow enhancement with SPIO is smaller as compared to previous results obtained by our group with USPIO.

The reticuloendothelial system and macrophage-monocyte system in thorotrast patients.

To evaluate the function of the reticuloendothelial system and macrophage-monocyte system, blood samples from Thorotrast patients and age-matched healthy controls were used to determine the titer of plasma antibodies to lipid A and the numbers of several lymphocyte subclasses in peripheral blood and for an autoradiographic study of peripheral blood monocytes. The titer of plasma IgM class antibodies to lipid A was significantly elevated in the Thorotrast patients. Counts of CD 11-positive lymphocytes and CD 57-positive lymphocytes, which correspond to monocytes and natural killer cells, respectively, were significantly increased in the Thorotrast patients. Autoradiography showed that alpha-particle tracks were emitted from the monocytes isolated from the peripheral blood of Thorotrast patients. Thus the depressed function of the reticuloendothelial system resulted in the activation of the macrophage-monocyte system in the Thorotrast patients.

Monitoring radiation-induced changes in bone marrow histopathology with ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI.

The purpose of this study was to monitor radiation-induced alterations of the blood-bone marrow barrier (BMB) and the reticuloendothelial system (RES) with AMI-227-enhanced magnetic resonance imaging (MRI). Twenty New Zealand white rabbits (n = 10 following total body irradiation and n = 10 controls) underwent AMI-227-enhanced MRI. Pulse sequences included dynamic fast low-angle shot (FLASH; TR/TE 50/4 msec, flip angle 60 degrees) MRI and static T1- and T2-weighted spin-echo (SE) and turbo-SE sequences of the lumbar spine and sacrum. Bone marrow enhancement was quantified as delta signal intensity (SI) (%) =|[(SIpost - SIpre)/SIpre] x 100%| and compared with histopathology, including iron stains and electron microscopy. Dynamic bone marrow deltaSI (%) data steadily increased up to 10-15 minutes after AMI-227 administration, while blood deltaSI (%) data stayed nearly constant, histologically corresponding to iron oxide leakage into the bone marrow interstitium. This bone marrow contrast enhancement increased significantly following irradiation, corresponding to alterations of the endothelial lining of the bone marrow sinusoids. Late postcontrast images exhibited a significant positive T1 enhancement and negative T2 enhancement of the normal bone marrow, which further increased with irradiation due to increased RES activity. Irradiation-induced changes in bone marrow physiology could be reliably assessed with AMI-227-enhanced MRI.

The effect of X-radiation on reticulo-endothelial system and its treatment with radiodetoxified-endotoxin and trace elements in rats.

A new in vivo method has been developed for the precise observation of RES activity. Both Escherichia coli endotoxin 100 micrograms/100 g i.v. (LPS) and radiodetoxified endotoxin 100 micrograms/100 g body weight i.v. (RD-LPS, TOLERIN) both increased the granulopectic activity of RES. The RD-LPS was more effective. The preparation containing trace elements also increased the activity of RES. The treatment consisting of the use of both trace elements and RD-LPS proved to be the most effective. The activity of RES was inversely proportional to various doses of X-ray irradiation (7, 8, 9 Gy). Trace elements and RD-LPS even improved the immunity system of animals having deteriorated RES.

Evaluation of radiation-induced liver injury with MR imaging: comparison of hepatocellular and reticuloendothelial contrast agents.

Gadolinium (4s)-4-(4-ethoxybenzyl-3,6,9-tris(carboxylato-methyl)-3,6,9- triazaudecandioic acid (EOB) diethylenetriaminepentaacetic acid (DTPA), a hepatocellular-directed magnetic resonance (MR) contrast agent, and coated superparamagnetic iron oxide particles (SPIO), a Kupffer cell-directed contrast agent, were compared for uptake and enhancement in a rodent model of radiation-induced liver injury. A single x-irradiation exposure (50-70 Gy) was delivered to one side of the liver in 18 rats. MR imaging was performed 3 days after x irradiation with sequential injections of the two contrast agents in the same rats. Additionally, biliary excretion of Gd-EOB-DTPA was quantified after whole-liver irradiation in five rats. Electron microscopy of the irradiated liver demonstrated mitochondrial injury in both hepatocyte and Kupffer cell populations. With Gd-EOB-DTPA, however, liver enhancement and biliary excretion were not affected by irradiation. Uptake of SPIO was decreased in the irradiated portion of the liver, with a precise demarcation between irradiated and nonirradiated zones at MR imaging.

Effect of soft x-ray irradiation on immunological functions in mice.

Effect of soft x-ray irradiation on immunological functions in mice was investigated. Soft x-ray irradiation with 100R or more induced a significant reduction in the number of plaque-forming cells (PFC). The reduction in the number of PFC depended on the irradiation doses. Irradiation with 600R or more showed a significant reduction in the delayed reaction of footpad swelling. However, soft x-ray irradiation with doses ranging from 100R to 1000R did not exert significant influence on the K values of carbon clearance test. Irradiation with 100R or more of soft x-ray showed a remarkable reduction of response to concanavalinA (ConA) or lipopolysaccharide (LPS) in spleen cells, and the response to ConA was lower than that to LPS. These results suggest that in the soft x-ray-irradiated mice, antibody-producing ability, delayed type hypersensitivity reaction and mitogenic activity are sensitive to soft x-ray irradiation and furthermore, T cell is more sensitive than B cell, but phagocytic activity of reticulo-endothelial system (RES) is resistant to soft x-ray irradiation.

An increased incidence of tumour bearing Swiss albino mice in Durham after the Chernobyl nuclear accident.

Mice which were alive in Durham at the time of the Chernobyl nuclear accident presented a highly significant increase in the incidence of those which bore tumours. The comparison is based upon mice which were studied over the previous 4 years. In males and females the increase amounted to 19 and 100 per cent respectively. The most frequent neoplasms to increase were malignant tumours of the reticuloendothelial system and of the reticuloses, lymphosarcoma and reticulum cell sarcoma were prevalent in mice kept after Chernobyl. The incidence of reticuloses increased by 24 and 18 per cent in males and females respectively.

Glucan: mechanisms involved in its "radioprotective" effect.

It has generally been accepted that most biologically derived agents that are radioprotective in the hemopoietic-syndrome dose range (eg, endotoxin, Bacillus Calmette Guerin, Corynebacterium parvum, etc) exert their beneficial properties by enhancing hemopoietic recovery and hence, by regenerating the host's ability to resist life-threatening opportunistic infections. However, using glucan as a hemopoietic stimulant/radioprotectant, we have demonstrated that host resistance to opportunistic infection is enhanced in these mice even prior to the detection of significant hemopoietic regeneration. This early enhanced resistance to microbial invasion in glucan-treated irradiated mice could be correlated with enhanced and/or prolonged macrophage (but not granulocyte) function. These results suggest that early after irradiation glucan may mediate its radioprotection by enhancing resistance to microbial invasion via mechanisms not necessarily predicated on hemopoietic recovery. In addition, preliminary evidence suggests that glucan can also function as an effective free-radical scavenger. Because macrophages have been shown to selectively phagocytize and sequester glucan, the possibility that these specific cells may be protected by virtue of glucan's scavenging ability is also suggested.

Hypoxia-induced endotoxemia in primates: role of reticuloendothelial system function and anti-lipopolysaccharide plasma.

Acute hypoxia is known to cause a marked reduction in intestinal and peripheral blood flow, in favor of blood flow to the brain and heart. Complete occlusion of the intestinal circulation is known to damage the gut wall, allowing potentially lethal endotoxins present within the intestines to escape into the circulation. We examined here whether the breathing of a hypoxic gas mixture could lead to sufficient damage of the intestinal wall to cause endotoxemia. Six anesthetized monkeys breathed air for 1 hr, then an hypoxic mixture (FIO2 = 0.13) containing N2O for 1 h and, finally, 100% O2. Plasma endotoxin concentrations were determined by two methods. After approximately 40 min of hypoxia, the plasma endotoxin level rose significantly from 0.39 to 1.60 ng X ml-1 (p less than 0.001) and then subsided to near control levels. Control monkeys breathing air only or 70% N2O in oxygen (FIO2 = 0.3) for 3 h showed no such elevation in plasma endotoxin concentration. We conclude that hypoxia leads to a temporary endotoxemia in primates. Reticuloendothelial system depression by whole body X-irradiation (200 rads) increased both the magnitude and duration of the hypoxia-induced endotoxemia. Prior administration of equine anti-lipopolysaccharide (anti-LPS) hyperimmune plasma greatly reduced the magnitude of the induced endotoxemia. Since endotoxemia may be lethal, the use of anti-LPS as possible prophylaxis should be considered in persons breathing artificial atmospheres or where acute hypoxia may be a danger.

The effect of abdominal radiation on spleen function: a study in children with Wilms' tumor.

Reports of splenic dysfunction in patients with Hodgkin's disease who received radiation therapy to the spleen raise questions concerning impairment of splenic function and the long-term risk of bacterial sepsis in children who receive abdominal radiation for other diseases. Splenic function was studied in 20 children with Wilms' tumor using a quantitative assessment of vacuolated ("pitted") red cells as a measure of reticuloendothelial function. Fourteen children had received abdominal radiation to a field involving the spleen at a median dose of 2000 rads. Their pitted red cells counts were no different from those of 6 children who received therapy without radiation to the spleen or to those of a group of normal children and adults. We conclude that there is no demonstrable long-term impairment of spleen function with radiation doses at or below 2200 rads.

Radioprotective activity of the complex of bivalent copper with 3-mercapto-2-hydroxypropyl ether of dextran (C-79).

The radioprotective activity of C-79 preparation was determined in the course of investigations carried out on mice. The activity was measured by the survival time of lethally irradiated animals and by means of the number of colonies (CFUs) on the spleens of irradiated animals. The endogenous and exogenous CFUs were determined. It was stated that the preparation, when introduced into animals several days before the irradiation with an appropriate dose of X rays, protected the homeopoetic cells of the examined animals against the irradiation effects. It was also revealed that the preparation significantly prolonged the survival time of the lethally irradiated mice. The protection activity of the preparation depended on the dose and the strategy of administration.

The effect of repeated injections of 99mTc-antimony-sulphide colloid on the RES of the rat--histopathologic study.

Experiments on inbred albino rats were performed to test the effect of repeated administrations of 99mTc-antimony sulphide colloid on the integrity of the RES. Experiments were carried out in two batches, one with the preformed colloid given in increasing doses, and the other with the labelled colloid in increasing doses. In all, 9 groups of animals including a control group were tested. Studies included: organ weights of liver, spleen, lungs and kidneys, histopathology, contact macroautoradiography, microautoradiography and 99mTc activity distribution in organs. Results showed no macroscopic or microscopic evidence of tissue damage after repeated injections up to a total dose of 18 mCi 99mTc, 142.2 mg PVP, and 693 microgram Sb, given in 9 equivalent doses at one week intervals. It is concluded that repeated administrations of 99mTc-antimony sulphide colloid for liver scintigraphy are safe.