| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||
Correspondence |
The short communication paper by Hainfield et al in the British Journal of Radiology is a very interesting paper [1]. It demonstrates that nanoparticles could be used as contrast media in radiology. However, the following points need further clarification:
The tests were conducted on animals with higher concentration of gold nanoparticles for imaging purposes to show the effects of gold nanoparticles as contrast media than those performed for toxicity studies. For imaging, a concentration of around 270 mg Au cm–3 was used. If we assume that mouse tissue density is close to that of water, i.e. 1 g cm–3, then the above concentration is 270 mg Au per gram of tissue, while for toxicity studies maximum concentration was tested at 700 mg kg–1, i.e. 0.7 mg g–1 (270/0.7). This means the concentration of the Au particles is around 300 times less in toxicity studies compared with imaging studies.
To clarify further:
Imaging study:
0.001 ml g–1 of 270 mg Au ml–1 is equal to a whole body dose of 2.7 mg g–1 body weight ( = 2700 mg kg–1 body weight).
Toxicity study:
Highest dose used was 700 mg Au kg–1 body weight.
Comparison:
The imaging study used nearly 4-fold higher dose than the top dose in the toxicity study (i.e. 2700/700 mg kg–1 = 3.9).
The LD50 parameter is only 3.2 g Au kg–1 in comparison with the usual concentration of Au nanoparticles injected into mouse (2.7 g Au kg–1). Normally in toxicity studies it is anticipated that LD50 is to be much higher than the usual concentration of injected material to be rendered safe [2].
The highest dose in the toxicity study was nearly one fifth of the LD50 dose (i.e. 700/3200 mg kg–1 = 0.22) – but the imaging study used a dose that was only 16% less than the LD50 dose (i.e. 2700/3200 mg kg–1 = 0.84), so it would depend on the steepness of the lethality dose–response curve. However, you might expect some of the imaging study animals to have died from intravenous tail vein injection of 2700 mg kg–1, but this paper only states that mice injected with this dose "survived over 1 year without signs of illness".
It is widely accepted that the therapeutic dose should be as far from the lethal dose as possible, i.e. a high therapeutic index (TI = LD50/ED50; Margin of safety = LD1/ED99).
In Table 2, the aspartate aminotransferase (AST) value shows large variations and also its value is high.
This table deals with animals receiving 0.2 ml (presumably 0.01 ml kg–1 of 270 mg Au ml–1 = 54 mg Au 20 g–1 mouse) to achieve an initial dose of 10 mg Au ml–1 blood (presumably whole blood?). But, as the total mouse blood volume (72 ml kg–1) of a 20 g mouse is about 1.44 ml, this implies that 54 mg Au dosed intravenous would instead initially reach about 35 mg Au ml–1 blood.
The control group AST values from this study were 39, 61 and 123 Units (usually IU l–1 are reported) with a wide variation in control mean values of 10, 7 and 52, respectively (again the paper does not mention whether this is SD or SE). The "Day 1 Gold" AST data is 368 ± 698 Units – the higher mean value and very large variance indicates that there was transient liver damage in some of the animals in this group, but not all animals. A similar trend is seen in the alanine aminotransferase (ALT) results and supports the transient liver damage event. This effect on the liver is not surprising as the liver (containing Kupffer cells, the resident macrophages) is very important in removing many forms of particulate material from the blood – this is confirmed by the pharmacokinetic plot in Figure 4, which shows that 7% of the injected dose is accumulated in the liver at 24 h. A similar amount accumulated in the kidney at the same 24 h timepoint.
The "AST/ALT ratio" values in Table 2 also appear to be incorrect in many cases when comparing the AST and ALT data within each group.
Figure 4 should be plotted on a semi-logarithmic scale. Please note, this study states that 0.2 ml of gold nanoparticles were injected into a mouse (which must have been a 20 g mouse, using the previous dose volume of 0.01 ml g–1 body weight). This graph plots the percentage of injected dose per gram of tissue wet weight. The text states, that 77.5% of total injected dose was cleared after 5 h, but did not report the value at 24 h.
The pharmacokinetic data should have been plotted as log dose vs linear time scale to show the biphasic elimination curve (a linear–linear plot suggests this but the log–linear plot is the standard practice in pharmacokinetic studies to demonstrate this feature) more clearly. The initial rapid decline (
phase) in blood concentration is a combination of distribution to tissues and elimination via the urine, while the slower elimination phase (
phase) is due to clearance of the nanoparticles from deposition sites back into the blood and then to the urine. Consequently, no pharmacokinetic parameters were calculated (e.g. elimination rates and half-lives for the and phases) as should have been done using the blood concentration values.
Nevertheless, the linear plot clearly shows that the nanoparticles collect in the tumour in preference to muscle tissue because of the leakier endothelial cell connections in the vasculature of the tumour – however, it should be noted that the kidney (organ of elimination by filtering through the glomerulus) and liver (organ clearing particles from the blood and containing a very high sulfhydryl peptide content which can bind gold ions) retained a higher proportion of the injected dose than the tumour. Unfortunately the pharmacokinetic study ended at 24 h, when it should have continued for a longer period to determine liver and kidney accumulation after 48 h or longer. Also, other tissues should have been collected and analysed for Au content (particularly at 24 h) to measure accumulation: brain, heart, lung, spleen, gonads and tail region containing the injection site.
Yours etc.
Division of Medical Radiations, School of Medical Sciences, RMIT-University, Bundoora Camp- Bundoora Victoria 3083, Australia
References
| ||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| BJR | DMFR | IMAGING | ALL BIR JOURNALS |
