Nano-sized therapeutic agents have several advantages over low molecular weight agents such as a larger loading capacity, the ability to protect the payload until delivery, more specific targeting due to multivalency and the opportunity for controlled/sustained release. However, the delivery of nano-sized agents into cancer tissue is problematic because it mostly relies on the enhanced permeability and retention (EPR) effect that depends on the leaky nature of the tumor vasculature and the prolonged circulation of nano-sized agents, allowing slow but uneven accumulation in the tumor bed. Delivery of nano-sized agents is dependent on several factors that influence the EPR effect; 1. Regional blood flow to the tumor, 2. Permeability of the tumor vasculature, 3. Structural barriers imposed by perivascular tumor cells and extracellular matrix, 4. Intratumoral pressure. In this review, these factors will be described and methods to enhance nano-agent delivery will be reviewed.

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Improving conventional enhanced permeability and retention (EPR) effects; what is the appropriate target?

Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?

A semiconductor light emitting device comprising a light emitting layer disposed between an n-type region and a p-type region is combined with a ceramic layer which is disposed in a path of light emitted by the light emitting layer. The ceramic layer is composed of or includes a wavelength converting material such as a phosphor. Luminescent ceramic layers according to embodiments of the invention may be more robust and less sensitive to temperature than prior art phosphor layers. In addition, luminescent ceramics may exhibit less scattering and may therefore increase the conversion efficiency over prior art phosphor layers.

Luminescent ceramic for a light emitting device

Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages

Cadmium (Cd) is unique among metals because of its diverse toxic effects, extremely protracted biological half-life (approximately 20–30 years in humans), low rate of excretion from the body, and predominant storage in soft tissues (primarily liver and kidney) rather than bone. The health hazards associated with cadmium exposure became known in the 1940s when FRiberg (1948) reported the occurrence of emphysema and proteinuria in workers exposed to cadmium dust. In the 1960s, cadmium was catapulted into the mainstream of metal toxicology research when cadmium was identified as the major etiological factor in itai-itai disease, a condition that afflicted Japanese women exposed to cadmium via their diet which contained cadmium-contaminated rice and water. Cadmium is an extremely toxic element of continuing concern because environmental levels have risen steadily due to continued worldwide anthropogenic mobilization. The mobilization has derived from past and current industrial and agricultural practices.

Toxicology of cadmium

The effects of the vasoconstrictor phenylephrine and the vasodilator hydralazine on blood flow to tumor were studied and compared to those on blood flow to normal tissues in vivo. Regional blood flow and cardiac output were measured with the use of radioactive microspheres in 150- to 250-g inbred Harlan F344 rats bearing subcutaneous nodules of two types of transplantable carcinoma ("hard" and "soft") with microscopically different vascular patterns. Three groups of rats were treated with hydralazine, saline, or phenylephrine, and regional blood flow was determined at the time of maximum blood pressure response. Results were correlated with quantitative morphometric analysis of arteriolar and capillary wall thickness in tumor and normal tissue. Phenylephrine decreased and hydralazine increased normal tissue perfusion as indicated by cardiac output. Tumor blood flow remained low and was not significantly influenced by drug treatment, except for the phenylephrine effect on hard tumors. Histologic study of tumor vessel walls revealed an absence of smooth muscle capable of responding to the vasoactive drugs by constriction or dilation. Evidently, by their selective action on normal vessels, vasoactive drugs can change the ratio of tumor:normal tissue perfusion. In particular, the increase of normal tissue: tumor blood flow by vasodilator drugs may enhance the selectivity of local heat therapy.

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Abnormal Response of Tumor Vasculature to Vasoactive Drugs

This investigation has shown that not only the extent of fetal resorption and malformation but also the types of malformation seen in rats depend upon the strain used and day of gestation. Furthermore, the effects of zinc deficiency and cadmium administration on the fetus can be at least additive, as was seen for malformations. For fetal resorption, zinc deficiency potentiated the action of cadmium.

Fetal effects of cadmium in pregnant rats on normal and zinc deficient diets.

The three-ridge clamAmblema perplicata was used to monitor two streams for the presence of zinc (Zn) and cadmium (Cd) derived from an industrial source. Clams were collected from a relatively uncontaminated area in one river and transported to four study sites in the two contaminated streams. The clams were placed into polyethylene cages and left in these streams for one week. Control clams were treated in a similar manner and left in the uncontaminated river.

The use of the three-ridge clam (Amblema perplicata) to monitor trace metal contamination

Levels of cadmium and zinc in various components of Williamson Ditch (an industrially contaminated stream flowing into Palestine Lake), Trimble Creek (a stream draining Palestine Lake) and the Tippecance River (a river receiving Trimble Creek) were determined. Water, sediment, plant, fish and clam samples were analyzed for cadmium and zinc content by atomic absorption spectrophotometry. Unweighted mean metal concentrations in Trimble Creek were the following: water, 51 µg Zn/1 and 4.2 µg Cd/1; sediment, 592 µg Zn/g and 48.8,µg Cd/g; plants, 375 µm Zn/g and 7.91 µg Cd/g; fish, 145 µg Zn/g and 6.02 µg Cd/g. These concentrations were generally lower than those found in Williamson Ditch and higher than those found in the Tippecanoe River or background levels previously reported for other aquatic ecosystems.

The impact of an industrially contaminated lake on heavy metal levels in its effluent stream

Concentration factors (CF) of 54Mn for three aquatic species: green algae (Protococcoidal chlorella), Daphnia magna, and fathead minnows (Pimephales promelas) were determined following direct exposure to the isotope in solution. The maximum accumulation (CF = 911) in P. chlorella was reached at 48 hours of exposure; the maximum uptake (CF = 65) in Daphnia was reached at 8 hours of exposure; and the maximum accumulation (CF = 22.6) in fathead minnows was at 128 hours of exposure. The data indicate that 54Mn accumulation decreases with ascent up a theoretical aquatic food chain when water is the only source of contamination.

Richard J. Vetter

Papers

Abnormal Response of Tumor Vasculature to Vasoactive Drugs

Fetal effects of cadmium in pregnant rats on normal and zinc deficient diets.

The use of the three-ridge clam (Amblema perplicata) to monitor trace metal contamination

The impact of an industrially contaminated lake on heavy metal levels in its effluent stream

The uptake of Manganese-54 by green algae (Protococcoidal chlorella), Daphnia magna, and fathead minnows (Pimephales promelas)