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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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July 14, 2014

Modifying Red Blood Cells As Carriers

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Posted by Derek

What's the best carrier to take some sort of therapeutic agent into the bloodstream? That's often a tricky question to work out in animal models or in the clinic - there are a lot of possibilities. But what about using red blood cells themselves?

That idea has been in the works for a few years now, but there's a recent paper in PNAS reporting on more progress (here's a press release). Many drug discovery scientists will have encountered the occasional compound that partitions into erythrocytes all by itself (those are usually spotted by their oddly long half-lives after in vivo dosing, mimicking the effect of plasma protein binding). One of the early ways that people have attempted to try this deliberately was forcing a compound into the cells, but this tends to damage them and make them quite a bit less useful. A potentially more controllable method would be to modify the surfaces of the RBCs themselves to serve as drug carriers, but that's quite a bit more complex, too. Antibodies have been tried for this, but with mixed success.

That's what this latest paper addresses. The authors (the Lodish and Ploegh groups at Whitehead/MIT) introduce modified surface proteins (such as glycophorin A) that are substrates for Ploegh's sortase technology (two recent overview papers), which allows for a wide variety of labeling.

Experiments using modified fetal cells in irradiated mice gave animals that had up to 50% of their RBCs modified in this way. Sortase modification of these was about 85% effective, so plenty of label can be introduced. The labeling process doesn't appear to affect the viability of the cells very much as compared to wild-type - the cells were shown to circulate for weeks, which certainly breaks the records held by the other modified-RBC methods.

The team attached either biotin tags and specific antibodies to both mouse and human RBCs, which would appear to clear the way for a variety of very interesting experiments. (They also showed that simultaneous C- and N-terminal labeling is feasible, to put on two different tags at once). Here's the "coming attractions" section of the paper:

he approach presented here has many other possible applications; the wide variety of possible payloads, ranging from proteins and peptides to synthetic compounds and fluorescent probes, may serve as a guide. We have conjugated a single-domain antibody to the RBC surface with full retention of binding specificity, thus enabling the modified RBCs to be targeted to a specific cell type. We envision that sortase-engineered cells could be combined with established protocols of small-molecule encapsulation. In this scenario, engineered RBCs loaded with a therapeutic agent in the cytosol and modified on the surface with a cell type-specific recognition module could be used to deliver payloads to a precise tissue or location in the body. We also have demonstrated the attachment of two different functional probes to the surface of RBCs, exploiting the subtly different recognition specificities of two distinct sortases. Therefore it should be possible to attach both a therapeutic moiety and a targeting module to the RBC surface and thus direct the engineered RBCs to tumors or other diseased cells. Conjugation of an imaging probe (i.e., a radioisotope), together with such a targeting moiety also could be used for diagnostic purposes.

This will be worth keeping an eye on, for sure, both as a new delivery method for small (and not-so-small) molecules, fof biologics, and for its application to all the immunological work going on now in oncology. This should keep everyone involved busy for some time to come!

Comments (7) + TrackBacks (0) | Category: Biological News | Chemical Biology | Pharmacokinetics


COMMENTS

1. mdacc grad on July 14, 2014 4:20 PM writes...

I have some biology questions.

1. Assuming you load the cytosol and the cell has specific targeting, what is the trigger for the release of the drugs? Or do you have to load insane amounts into the cell to compensate for it leaking as it moves to the location?

2. This all assumes dropping drugs in a cytosol won't alter that cells' other mechanisms. Some that may cause the cell to destroy it self or those that may cause the cell to behave more favorably to the pathology. This would also distort yout disease markers. If you are talking about a 100% cure this doesn't matter, however if it is anything but, altering diagnostics isn't going to be something physicians will like. And if a VC can't see a good way to sell it to the gatekeeper physician then they won't touch the tech. Especially as everyone is moving into these odd ultra sensitive realms of blood vesicle/RNA blah blah diagnostics.

3. Are they certain that this will not cause a runaway autoimmune response? If the immune system targets this odd conjugate, might it also start targeting other RBCs? More suppressants for patients?

I've always fancied the engineered enzyme targeting, but a we have a long way to go indeed.

Permalink to Comment

2. sg on July 14, 2014 6:48 PM writes...

RBCs lack a nucleus, don't express MHC, and thus don't elicit immune responses dependent on MHC presentation. Lacking a nucleus makes them a poor target for virii anyway. But lacking MHC makes them a great hideout for certain parasites (I'm looking at you P. falciparum).

Permalink to Comment

3. matt on July 15, 2014 4:32 AM writes...

Wait...what? Up to 50% of RBCs modified with substrate, up to 85% of that takes up an antibody. Antibody attaches to target...where did my red blood cells go? Isn't this like introducing the wrong blood type instantly throughout the body? Or does antibody binding somehow release the antibody from the RBC?

Did I miss something protecting the red blood cells currently occupied by shuttling metabolic materials around? Or are antibodies just a cautionary example?

Permalink to Comment

4. NJBiologist on July 15, 2014 9:50 AM writes...

@3 Matt: I don't think they're protected, actually. I base that on the fact that they're not lasting the usual RBC lifespan of 120 days. I suspect the extra stuff on the exterior of the cell is getting them into the fast lane for clearance. But hey, if these guys are getting weeks where others got days, it's a less-express express lane, and that sounds like progress.

Permalink to Comment

5. Vader on July 15, 2014 11:44 AM writes...

My recollection is that metformin tends to be taken up by RBCs, which slows its clearance from the bloodstream by quite a lot. Not the same mechanism as here though.

Permalink to Comment

6. oliver on July 19, 2014 2:52 AM writes...

RBC's........ Hello?!?!
What about the pesky main function of those..?
That funny business with that O2?
Is that affected in any way by messing with the RBC's

Or, am I missing something fundamental here?

Permalink to Comment

7. oliver on July 19, 2014 2:53 AM writes...

RBC's........ Hello?!?!
What about the pesky main function of those..?
That funny business with that O2?
Is that affected in any way by messing with the RBC's

Or, am I missing something fundamental here?

Permalink to Comment

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