This is a supplementary page, for "Titanium biology".
As noted with the main listing, Titanium biology (September 29, 2008), this item is based on a seminar by Ann Valentine, from Yale.
Some parts of this are primarily intended for certain people, with particular interests. They will know who they are. But I thought it would be broadly "fun".
Valentine started by noting that we probably did not expect that there was enough known about Ti biology for an hour talk -- but that she would set us straight.
Ti is usually not considered a bio-active element. No essential role is recognized.
The distribution of Ti in the sea -- higher concentration at the bottom, lower at the top -- suggests that there is some depletion process. She would like to suggest that it is bio-accumulation -- but that is largely speculative.
There are organisms -- a few -- that accumulate Ti. She mentioned some sea squirts and some diatoms. Apparently it is a sporadic property, found in a few members of those groups, not broadly characteristic of them. Is there any relationship between some tunicates accumulating Ti and some using a V-based blood? Don't know.
She noted that some consumer products use TiO2 as a filler. She mentioned multi-vitamins. It is now recognized that we do absorb some Ti from such products (though it was perhaps thought otherwise originally?). People who have Ti-implants also absorb Ti from those materials in the body. I don't know if this is new info for the person here looking into Ti effects, but it might be a good lead to explore, to see what is known.
I had gotten into the topic of Ti-based (anti-cancer) drugs recently, and concluded it was going nowhere. (The successful development of Pt-based drugs had led people to explore the use of other metals. The best known of the Ti drugs is titanocene dichloride.) After the host's introduction and her first remarks on this, I was beginning to think I had it wrong. But not really. She agrees that all Ti drugs have been pulled from clinical trials, because of toxicity: apparently it is sort of like having white paint in your blood. (Hm, can you imagine having not only an unusual glucose level, but also white blood!) It is, of course, common enough that a drug can look good in cell culture and even in rodents, but fail in humans.
But she does not accept this failure as the final word. She thinks it worthwhile to study the metabolism of Ti, and elucidate the details of both the activity and the toxicity. It then may be possible to design better drugs with a higher ratio of the former to the latter (i.e., a higher "therapeutic index"). In fact, almost nothing is known -- not too surprising for a metal whose biological role has substantially been denied. She now has some info, though certainly not an answer.
The most important finding is that Ti is almost certainly carried by transferrin. She has measured the binding constant of Ti to transferrin; it is the highest of any metal tested, in agreement with prediction. It is thus likely that there is essentially no free (soluble) Ti around.
This result is in some ways not too surprising. It is common with trace mineral ions that they are never free. Careful studies of Cu metabolism have suggested that there is essentially zero level of inorganic Cu around.
Now, that story is obviously incomplete. What are the other players? How does the Ti end up as TiO2 in the blood? Etc. But at least it is a start toward tracking the Ti.
This is relevant to cell culture work with Ti. As you move on from cell culture to animal, the circulatory system becomes an issue. The animal may have protective mechanisms that the cells lack. Whether the protective mechanism works in any given case (i.e., against any particular type and level of exposure) is open. But doing cell culture work is only a starting point; it may or not be the big biological answer.
The dominating one is the tendency of Ti complexes to hydrolyze, resulting in TiO2(s). (She was quite obsessed with white paint.) She suspects that a key problem with the drug candidates is that they hydrolyze before reaching their target. She might now restate that as hydrolyze before reaching transferrin. Hydrolysis leads to precipitation of TiO2. What is wanted is enough stability so that the drug gets delivered to the transferrin. It is plausible that it is then targeted to cancer cells, which often have increased level of transferrin receptor. This is the kind of thinking that guides her work, but it is rather speculative at this point. She has worked on developing Ti complexes of proper stability -- not hydrolyzed too fast, but not so stable that they don't do anything.
Analytical... She noted that measuring Ti is difficult.
The issue of some diatoms accumulating Ti came up in the question period. She said that there is some Ti in the skeleton. The inevitable question was then whether there are any diatoms whose skeleton consists entirely of Ti structures. None that she knows of -- but it is quite possible that no one has really looked.
Hm, I wonder... If those diatoms can be grown in the lab, why not try adapting them to growing on increasing ratios of Ti to Si.
Return to this item on main page: Titanium biology (September 29, 2008).
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