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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: Twitter: Dereklowe

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March 25, 2010

Nanoparticles and RNA: Now In Humans

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Posted by Derek

In recent years, readers of the top-tier journals have been bombarded with papers on nanotechnology as a possible means of drug delivery. At the same time, there's been a tremendous amount of time and money put into RNA-derived therapies, trying to realize the promise of RNA interference for human therapies. Now we have what I believe is the first human data combining both approaches.

Nature has a paper from CalTech, UCLA, and several other groups with the first data on a human trial of siRNA delivered through targeted nanoparticles. This is only the second time siRNA has been tried systemically on humans at all. Most of the previous clinical work has been involved direct injection of various RNA therapies into the eye (which is a much less hostile environment than the bloodstream), but in 2007, a single Gleevec-resistant leukaemia patient was dosed in a nontargeted fashion.

In this study, metastatic melanoma patients, a population that is understandably often willing to put themselves out at the edge of clinical research, were injected with engineered nanoparticles from Calando Pharmaceuticals, containing siRNA against the ribonucleotide reductase M2 (RRM2) target, which is known to be involved in malignancy. The outside of the particles contained a protein ligand to target the transferrin receptor, an active transport system known to be upregulated in tumor cells. And this was to be the passport to deliver the RNA.

A highly engineered system like this addresses several problems at once: how do you keep the RNA you're dosing from being degraded in vivo? (Wrap it up in a polymer - actually, two different ones in spherical layers). How do you deliver it selectively to the tissue of interest? (Coat the outside with something that tumor cells are more likely to recognize). How do you get the RNA into the cells once it's arrived? (Make that recognition protein is something that gets actively imported across the cell membrane, dragging everything else along with it). This system had been tried out in models all the way up to monkeys, and in each case the nanoparticles could be seen inside the targeted cells.

And that was the case here. The authors report biopsies from three patients, pre- and post-dosing, that show uptake into the tumor cells (and not into the surrounding tissue) in two of the three cases. What's more, they show that a tissue sample has decreased amounts of both the targeted messenger RNA and the subsequent RRM2 protein. Messenger RNA fragments showed that this reduction really does seem to be taking place through the desired siRNA pathway (there's been a lot of argument over this point in the eye therapy clinical trials).

It should be noted, though, that this was only shown for one of the patients, in which the pre- and post-dosing samples were collected ten days apart. In the other responding patient, the two samples were separated by many months (making comparison difficult), and the patient that showed no evidence of nanoparticle uptake also showed, as you'd figure, no differences in their RRM2. Why Patient A didn't take up the nanoparticles is as yet unknown, and since we only have these three patients' biopsies, we don't know how widespread this problem is. In the end, the really solid evidence is again down to a single human.

But that brings up another big question: is this therapy doing the patients any good? Unfortunately, the trial results themselves are not out yet, so we don't know. That two-out-of-three uptake rate, although a pretty small sample, could well be a concern. The only between-the-lines inference I can get is this: the best data in this paper is from patient C, who was the only one to do two cycles of nanoparticle therapy. Patient A (who did not show uptake) and patient B (who did) had only one cycle of treatment, and there's probably a very good reason why. These people are, of course, very sick indeed, so any improvement will be an advance. But I very much look forward to seeing the numbers.

Comments (8) + TrackBacks (0) | Category: Biological News | Cancer | Clinical Trials | Pharmacokinetics


1. qetzal on March 25, 2010 11:57 AM writes...

These things make for really cool science, but I shudder to think of what they'll be like to develop as products.

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2. barry on March 25, 2010 12:05 PM writes...

Chemists (whatever they call themselves) have been trying to smuggle potential drugs into specific cells for years, long before everything "nano" was cool. Can a monoclonal antibody survive packaging and delivery? Can an antigen be delivered that will then mark the cell for destruction by the host's immune system? How specific is the cell-surface marker? siRNA is just a test case. Targeted delivery is the prize here and the results are still far from conclusive.

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3. vanlang on March 25, 2010 2:16 PM writes...

Product development might be easier if that is even possible to imagine. The RNAi strategy circumvents the need to do HT screens. As long as you have the target (which is not a trivial manner) knocking the target down by siRNA pathways is a much easier problem than, say, monoclonals. And making the drug would be easier than making most biologics since you could chemically synthesize your RNA.

The hard part was the delivery. Seems like a major roadblock has been slightly cleared.

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4. qetzal on March 25, 2010 2:56 PM writes...

Actually, chemical synthesis of therapeutic oligos is not all that straightforward. Maintaining stepwise coupling yields at >= 98% isn't easy at commercial scale even for DNA. RNA is significantly harder. Purifying full length oligos is also non-trivial.

But it's not just making the siRNA. The nanoparticles also include transferrin and two different polymers, so you have to produce those in pharmaceutical grade and quantities. Then you need robust methods to put them all together in reproducible nanoparticles. And you need robust methods to QC those nanoparticles for potency, etc.

Don't get me wrong - I'm sure it can be done if the benefits are large enough. But if we're comparing to, say, mAbs (i.e. "most biologics"), I guarantee these will be much, much harder.

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5. Alf on March 26, 2010 1:40 AM writes...

qetzal, vanlang may have a point. I think while nanoparticles will have significant cmc issues, the synthetic nanoparticle may not be "much, much harder" than a a biologic that requires expensive cellular expression/manufacturing and also have heterogeneity issues. Long-term, this may be the way a lot of drugs are engineered.

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6. qetzal on March 26, 2010 10:16 AM writes...


It's not logically possible for this to be anything but harder.

Think about it: this product includes a biologic - transferrin - and from a pharmaceutical perspective, that's the most conventional and proven component of the whole thing! It also includes a double-stranded siRNA, each strand of which has to be manufactured - a non-trivial challenge. Finally, the whole thing has to be efficiently and reproducibly bundled into nanoparticles with consistent biological activities.

Obviously, we're all just speculating here, but this is a product that combines three large, complex, difficult-to-make APIs into a formulation that's substantially more complex than any parenteral ever marketed. IMO, it's going to be a lot harder to develop than any conventional biologic, especially for the innovators who don't have a proven approach to guide them.

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7. Imaging guy on March 26, 2010 5:06 PM writes...

The authors detected siRNA nanoparticles in biopsy sections with 5 nm gold particle (from Nanopartz) using confocal microscope. The nanoparticle was excited with 488 nm laser and emission is captured with 500-550 emission filter (i.e. fluorescence). As far as I know, 5 nm gold particle does not fluoresce but undergo resonance scattering upon excitation. Therefore they are either detected with confocal "reflectance" (backscattering) mode or darkfiled microscopy which detects forward scattering. Nanopartz does not seem to claim that their nanoparticle fluoresce too.

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8. Marty Schiffenbauer on March 29, 2010 8:10 PM writes...

I believe there was a third siRNA tried systemically on humans. It was by Tekmira:

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