Hi Ferdinand,

Thank you.

The larger SPIO (like Ferridex) had been used extensively for liver scan since late 80s. No severe or long term bad effects have been reported. Pharmacokinetics using radioactive Ferridex (Fe-59) showed incorporation into normal iron metabolisms and association with Hb. I have seen most of the use in Japan and Europe. Very limited use had been reported in USA. Ferridex is taken out of market probably due to lack of interest in the clinical use. I do not know about USPIO (like combidex), whether the discontinuation is due to lack of interest or toxicity. However, ferumoxytol (another USPIO) is being used in renal failure patients (end stage kidney failure) to supplement iron.

Ferridex does not get into tumor cells when IV administered. Ferridex is taken up by RES following IV administration. On the other hand if you load tumor cells with Ferridex, most of loaded ferridex will be kicked out of cells. However, ferridex that remain inside endosome-lysosome will be dissolved. Usually low pH (~ 4 pH) will start disintegrating ferric into ferrous form which is the active ionic form for all sorts of metabolic activity.

In a clinical scenario, ferridex will not be inside tumor cells and will not enhance tumor grwth.

wow!!! nice explanation by Ali Arbab thank you

Yes, we know this from the USPIO - however several questions remain:

RES is in many organs

how much will come to the cell or LN of relevance

where it will stay

what about toxicity

these are the problems

therefore no approval yet

thankful for answers

There are many (U)SPIO already approved for human use by FDA and EU health authorities, although except ferumoxytol, most of the (U)SPIOs are not in the market due to lack of use in the clinics. Distribution to different organs and associated RES depends on the size and surface charges of (U)SPIO. Ferridex quickly disappears from blood (6-8 minutes blood half-life) and mostly goes to RES of Liver and Spleen. Ferridex is larger (~150 nm) with a surface charge of -42mv. RES associated with LN will take up very small USPIO, such as combidex, which is 20nm is size with a surface charge almost neutral and very long blood half-life.

We almost received an IND approved from FDA to use ferridex labeled cells for human use but unfortunately the company stopped producing ferridex. The project did not go forward.

dear ali

thanks for your answer

but what we see is that USPIO don't really come in clinical routine.

why?

is it just the company?

I believe that we don't know enough about toxicity - especially long time effects

Gd based MRI have show the NSF problem after years?

companies have become very careful - or

Hi Ferdinand,

Thank you.

The larger SPIO (like Ferridex) had been used extensively for liver scan since late 80s. No severe or long term bad effects have been reported. Pharmacokinetics using radioactive Ferridex (Fe-59) showed incorporation into normal iron metabolisms and association with Hb. I have seen most of the use in Japan and Europe. Very limited use had been reported in USA. Ferridex is taken out of market probably due to lack of interest in the clinical use. I do not know about USPIO (like combidex), whether the discontinuation is due to lack of interest or toxicity. However, ferumoxytol (another USPIO) is being used in renal failure patients (end stage kidney failure) to supplement iron.

hi ali

thanks for very helpful comment

we always see and report very good results of USPIO - i.e. prostate cancer advanced - however never became approval and is now out of the market

is interesting - if something seems to work - why is the company not interested

however there are several issues - which we don't know

Hi ali,

thanks for your taught process!!!

I dont say that tumors cells takes up ferridex. Thing is that after ferridex injection, ferritin are increased, and it is usually increased for a period for a week. After that it get reduced. So the increased ferritin when get into normal value, where does this iron goes??? Maybe the question sounds silly. But pl do answer it...

Have you checked CD71 expression level on the tumor cells? Ferritin is iron binding protein and probably increased to cope up with the increased amount of free iron present in the system. CD71 is the receptor for iron and activation of CD71 (increased number) could activate the production of Ferritin to covert free iron into bound iron and remain in the iron pool. Once ferritin got saturated CD71 expression also goes down thereby also the production of ferritin. Does it make sense!!!!

Total amount of iron injected with a clinical dose of ferridex is very little compared to the total iron pool present in the body.

Hi ali,

thanks for the answer. i havent checked cd71 expression. I will get back to you once i check 4 their expersion.!!!

May be just to enhance the regulatory knowledge a bit in the community: Ferumoxytol is approved for iron substitution in severe renally impaired patients only and not for imaging.

The issue for the iron particles in liver imaging was that they did not allow for dynamic imaging but just for a later phase when the compound was taken up by the RES. This may be the reason why it was not widely used in the last years in any of the countries where it was approved. With regard to USPIOs like combidex- it never received FDA or EMA approval. If you want more information on this please visit the FDA webpage as the documentation is public.

Several superparamagnetic iron oxide nanoparticles were FDA approved as MRI contrast agents but only one of these, Gastromark that was approved in 1996, continues to be used to date. Gastromark was approved earlier in Europe in 1993. Gastromark is a product of Mallinckrodt, Inc. The details of the FDA approval is open and available to the public. It is found at http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31723.

Although the use of SPIOs as MRI contrast agents were more accurate leading to less false positives than non-enhanced MRI, some that were FDA approved were taken out of the market because of safety concerns including thickening of the skin, swelling, burning sensation, stiffness in joints and limbs, pain in hip bones, etc.

It's good idea. But radioisotop particles with iron wasn't effective years before. ( especially in lung carcinoma) But nanoparticles ...

Hi! We investigated USPIO in MRI of a bone tumor model in rabbits years ago. At least in our VX2 carcinoma model, USPIO localized to the region of peritumoral edema, not to the tumors themselves.

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