Macrophages are scavengers of the living biological systems. They are known to take up foreign substance, contrast agents are among many, of the body. I am not familiar with your model, what is RES? for example. How macrophages ablating is done and why?

Hi Philip, we did abalte the macrophages as described in the attached paper. What is your thought on the influence of the macrophage abaltion to the fate of the contrast media probe?

It may be due to 1. dosing of the imaging probe (maybe various doses should be tried) 2. time intervals after administration and 3. altered distribution in different organs.

Indian ink iv injected into mice is still found in the liver (distributed along the endothelia of sinuses) after macrophage depletion, but the distribution pattern shows differences. Not the usual concentrated patches representing macrophages. More material will longer be sticking to endothelial surfaces ? Also we found a difference in the distribution over spleen and liver. See also e.g. 1. Ref. Bioch. Bioph Acta 802 (1984) 428-434. Effect of elimination of macrophages on the tissue distribution of liposomes containing 3H-methotrexate. This paper shows that reduced uptake in liver will lead to increased uptake in spleen in spite of the fact that macrophages are also depleted in the latter organ. & 2. Ref. Bioch. Bioph. Acta 1190 (1994) 99-107. Effect of liposome size on the circulation time and intra-organ distribution of PEG-PE liposomes.

Like I said, macrophages are one takes up a lot of injected CA, especially those without target. Macrophage is one of defense mechanism that biological system has, and I do not know why you want to get ride of them, especially the defense is gone which may affect the toxic effect of CA. May I ask what is your contrast agent?

your result may indicate what people suspect for a long time, molecular imaging may be reporting macrophage, if there eis no targeting component in the CA. Try to consult J Bulte's paper they compare stem cells (with iron oxide) tracking and found CAs can be transferred to other cell types, one of which can be macrophage.

We have gene targeting CA and MRI show they report only targeted cells, not macrophage.

we have performed similar experiments and the data are shown in the attached paper.

Be happy to discuss the data

Mauro

@PhilipLiu: RES is reticulo-endothelial system, in more recent terminology the MMS=monocyte-macrophage-system.

@the Authors: Congrats for your nice thoughtful study. I am experimenting a lot with several liposome-like and other membrane-compartment (nano) particles which are not just evaluated by CT but SPECT and PET as we label them with 99mTc, 64Cu, 125I, 177Lu and other isotopes.

My question is if you could also perform the same line of study but using a more quantitative and more sensitive imaging method other than micro-CT.

Secondly, could not the specific Aluminium-containing particles you applied in your study be maleficial to the RES / or the whole organism thereby causing death as it is known that for microCT and MRI huge amounts of metal should be injected systematically for the appropriate and detectable signal/noise ratio. If you did the same study with SPECT or PET, the amount to be injected would be just traces hopefully without any interference with your readout data from the experiment. (George de Hevesy's tracer principle&practice)

Best regards from Budapest:

Domokos

@Carlo Bo: Excellent work!

@Domokos: Thanks.

I think one may need data from inducible couple-plasma mass spect (ICP-MS) for precise distribution to make sure where FE is and if the data match MRI (FASEB J. 26:1652, 2012)..

The findings in this article is interesting, however, it seems a little strange that proplongation or increase of contrast enhancement in blood pool was not observed in spite of less uptake in RES. In my experience using Kupffer cell-depletion model rats by clodronate liposome, contrast enhancement of bood pool was prolonged after injection of a particle agent (ultrasound contrast agent). Is it special for this contrast agent? One of my concerns is high death rate of animals. Isn't it caused by some pathologic conditions, for example, severe inflammation in the peritoneal cavity, which might recruit phagocytic cells at the region?

Interesting results. It might be possible that the mechanism of transport of your contrast lyposomes from the peritoneal cavity to the blood pool is accelerated through the presence of RES cells. That would explain the lower blood levels throughout all of the time points in ablated mice. In this context, also the higher mortality could be explained by some sort of foreign-body peritonitis, as Rira sugested above.

Hi Mr. Avruch,

this is not the case. Please review the cited paper. Injecting the liposomes into the peritoneal cavity to eliminate the macrophages within the blood and organs of the RES is very well established.

Please study the (non-language :) ) schematics that are attached to this answer. Both ways (iv and ip injection) reduce the amount of circulating macrophages. However, the question that you are asking - the relationship between the amount of circulating macrophages and contrast media enhancement of the blood pool remains the key question that might not be sufficiently answered by our study.

http://www.clodronateliposomes.org/ashwindigital.asp?docname=injection#