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Fewer Flashy Drug Delivery Papers, Please

Drug delivery – now that’s a tricky field. The variety of drug substances is large, and the ways that they’re taken up and distributed in living systems are many. And we’d like control over the process, which we don’t often have. A typical kid’s question is “How does the aspirin know where the headache is?” and the pharmacokinetic answer is “Hah! It doesn’t! That’s why we soak every part of your body in it that the bloodstream can reach!”

And that’s still the norm – get it into the bloodstream and hope for the best, which is sometimes a big enough problem all by itself. You can get slightly more refined by choosing diseases that occur in places where compounds are distributed unusually, although I wouldn’t necessary use “refined” to describe injecting something right into the eye (for example). This is also the thinking of the “Well, we know that this is never going to make it past the liver, so let’s see if we can find something for it to do in the liver” school of thought.

This editorial (from Jean-Cristoph Leroux at the ETH in Zürich) looks at the drug delivery field and asks if perhaps some things are going wrong:

Today, drug delivery is experiencing a major expansion. Recent progress in the field of molecular biology, biotechnology, and material sciences has resulted in the emergence of interesting technologies, which may hold great potential for the development of more efficient and safer pharmacological therapies. Paradoxically, the concomitant upsurge in published reports on drug-delivery systems does not correlate with therapeutic advances.

I know what he means. For some years now, the journals have prominently featured all sorts of highly engineered drug delivery systems – tissue-directed nanospheres and that sort of thing. The work is conceptually quite interesting and seems to hold a lot of potential, but you know, it has been some years now since this stuff started to appear, and the number of these things that have made a dent in the real world is small. Admittedly, there’s a pretty severe time delay involved, with regulatory concerns a big part of it. But the editorial is worried that there’s been too much of a trend towards exotic, overengineered formulations and delivery platforms that will have trouble making it through such hurdles in the first place.

Some of the assumptions behind these efforts may not hold up, either:

Indeed, a large proportion of what is nowadays published, especially in chemistry and nonspecialized journals, relates to nanosized carriers (nanoparticles, nanocapsules, drug–polymer conjugates, etc.) aimed at directing anticancer drugs to neo- plastic tissues. In such systems, the tumor-targeting principle generally relies on the enhanced permeation and retention (EPR) effect. However, this constitutes the main limitation of the “nanomedicine” dogma, since the EPR effect is increasingly recognized to be much less prominent in humans than in the classical rodent models employed to demonstrate antitumoral activity.

One might ask whether some of these things are “funding bait”, going after high-profile subjects like cancer with high-profile approaches like nanotechnology. It would be unfair to characterize the whole field like this, but it would be unrealistic to pretend that this isn’t a factor, either. And by “funding”, I have in mind both academic grants and industrial biopharma money as well.

They’re certainly “publication bait” in many cases, and that’s one of LeRoux’s big points: the specialist journals in this area are publishing a bit less of the gaudy stuff, which is instead showing up in the broader-interest journals. And that stuff is perhaps not getting the detailed reviewing it should when it moves up in this fashion, which is a general problem in the literature. You end up with a situation where the highest-profile publications end up as some of the less potentially reproducible ones, a situation that the chemists and biologists in the crowd will be familiar with. Toxicity is just one of the issues that can get swept under the scientific rug under these conditions.

Reproducibility is another thing that LeRoux highlights, and he makes the (valid) point that in a field as close to the clinic as drug formulation and delivery that it really should have higher standards than usual. These are technologies that could have direct impact on human patients and volunteers, and some serious money will be spent in that regard. The field is not well served by the excuse that finicky details are hard to translate from one lab to another – this is an area, like process chemistry, that is supposed to be hammering those sorts of things out, not using them to rationalize trouble. The whole point is generating robust work.

35 comments on “Fewer Flashy Drug Delivery Papers, Please”

  1. myma says:

    No kidding. I have had to wade through the ocean of papers in the recent past for a client, and it seems like one could pick up the Journal of Controlled Release from any year and see essentially the same papers. Nanothis, nanothat, now we use this bioabsorbable, now its that one, “tuning” the parameters, “tailored delivery” etc.

  2. luysii says:

    How do the pills know where to go doc? This is not a dumb question at all, and led me to discuss receptors and their specificity with my patients. Only patients with no post-secondary education were secure enough to ask it. No college graduate was ever brave enough to as a dumb question like that.

    1. dearieme says:

      Out of the mouth of babes and sucklings ….

    2. Kent G. Budge says:

      A typical kid’s question is “How does the aspirin know where the headache is?””

      Out of the mouths of babes and sucklings, Thou has perfected praise ….

    3. Wavefunction says:

      As Chomsky says, the average auto mechanic is probably smarter than the average college professor.

      1. Hap says:

        1) Or the average bass fisherman – the Foxworthian obsession with shiny things explains a lot of the problems with reproducibility.

        Maybe someone could offer some of the main offenders some bubble wrap so that they could have a better hobby. Think win-win.

        2) The Bob I’d have thought of starts companies, and while there’s a lot of bass boat owners in the funding sector, I assumed that if you wanted money, you’d keep the crappy results in papers and let someone else start the companies (and that if you had lots of crap results in drug delivery, eventually funders would find someone else with the shinies and leave you alone).

      2. Kommi says:

        I’ve developed a tendency to call him Noam Chompy. Because he likes to bite people’s ideas right in the ass and send them running.

  3. DeBunker says:

    One of the biggest purveyors of drug delivery hogwash is the esteemed Prof. “Bob” at a certain Boston-area university…

    1. featherson says:

      Agreed whole heartedly

    2. postdoc says:

      best comment ever!

  4. Imaging guy says:

    Drug delivery at cell level is very important. When a drug fails in a human trial, we have to determine whether it is due to 1) irrelevant/wrong target or 2) inability of the drug to engage the target molecule (pharmacokinetics failure). If you can exclude the pharmacokinetics failure, you can safely assume that the target is wrong and don’t have to pursue the target again with different molecules (e.g. small molecule, siRNA or CRISPR). Recently you reported antisense oligonucleotide against Smad7 (Mongersen) failed in a clinical trial. I wonder whether the drug which is orally given enters the immune cells and engages the Smad7 mRNA.
    http://blogs.sciencemag.org/pipeline/archives/2017/10/23/mongersen-fails

  5. bannonymous says:

    Same goes for cell-penetrating peptides. Typically, serum is removed from media and voila, charged peptides are inside the cells. And also typically, they do not mention that cells are half-dying and desperate, and are ready to gobble up anything floating around.

    1. evil postdoc says:

      makes me nostalgic about postdoc years

  6. anon says:

    And fewer cross-coupling papers please.

  7. Barry says:

    After Vagelos’ group at Merck showed that HMGCoA-reductase inhibitors compactin and mevinolin can reduce circulating cholesterol levels, everyone launched a statin. It was some time later–after Lipitor became the biggest-selling drug in the world, and after Bayer’s Baychol had to be yanked from the market–that anyone figured out that the tolerability of statins correlates with tissue-distribution (liver exposure good; muscle exposure bad).
    This was drug delivery, but quite unplanned. You might likewise point to sulfa drugs that self-deliver themselves the the urinary tract (tough luck if you were trying to treat an infection elsewhere).

    1. WikiLeaks says:

      That’s not self-delivery- that’s simple pharmacokinetics

  8. JB says:

    There have been a few fleeting papers over the years describing some types of nanoparticles as being genotoxic since they have some type of DNA interaction(s) that causes damage. Some hand waving explanations including things like inducing ROS. There needs to be increased scrutiny placed on toxicity testing of new types of NPs and not more focus placed on fancier versions of the technology. If you put ‘nano’ in front of the word the lay public automatically is convinced it must be high-tech and awesome.

  9. milkshaken says:

    I came to conclusion shared by some of my former colleagues, that the entire field of nanoparticle-based drug delivery is well over its zenith, that 20+ years of research into therapeutics nanoparticles brought little return in terms of improved drugs, and there is lots of irreproducible published stuff polluting the field

    It is not that the subject is too hard but rather that it was over-promoted like combichem – useful concept, but the groups and startups advancing have been more interested in impressing the potential investors and grant agencies than in doing good biology research

    1. Andre says:

      ….and usually fail to test the novel reagents in animal models.

  10. MoMo says:

    One also needs to worry their toxicity, which is of major concern. Nanotubes especially, as they are organic persisters in the extreme.

    1. Barry says:

      Some of us have noticed that bisphosphonate drugs bio-persist to the grave, but drug companies go on selling $billions of them, and sneer at the notion that a drug that will never clear the body needs more than a few months Clinical to demonstrate “safety”

      1. Druid says:

        Bisphosphonates are complexed by calcium (thus long residence in bone) and made not to be absorbed (which is why they have to be taken long before food), so unless you live on very acid soil, try not to worry 😉

        1. Barry says:

          Sure, a lot of the (orally) administered dose of bisphosphonates is never absorbed. But the fraction that is absorbed is largely retained for life. Clinicians are now urging users to take “holidays” from the drugs so that they can lay down *some* normal bone tissue, but they’ll carry drug substance in their bone matrices to the grave. Whether their risks of anomalous hip and jaw fractures ever regress toward normal remains to be seen.

          1. Druid says:

            Sure. Healthy bone requires breakdown and replacement around microscopic fractures in very thin bone – otherwise they spread and weaken the whole structure. As bisphosphonates only inhibit the breakdown of bone, micro-fractures do not get repaired. But, a drug-holiday would have to be very long because as you say, BPs have a long residence in bone.

  11. Druid says:

    Far too much believing their own hype from the nanotechnologists for sure. How many groups have “discovered” that polyamines and highly cationic peptides are toxic in vivo? It always comes as a big surprise, but not a disappointment, because “we just have to solve this one last problem”. Where the NCE people have been wearing hair shirts for decades, nanotechs never take their party clothes off, and who wants to spoil a party?
    On a broader subject, in my view, it is wrong that unfavorable toxicity studies just don’t get published. How much wiser would we all be if we got to see the results? In my view, it should be part of the social contract that allows us to use animals in research that what we learn should be open to all. Just as is supposed to happen for the results of clinical trials …

  12. Scott says:

    It’s usually about, what, ~10 years from “hey, we think we found a new way to get drug X where it needs to be” to FDA approval?

    But honestly, I’m more worried about *breathing* nanotubes than ingesting most nanoparticles. Can you say pulmonary fibrosis?

  13. Drug Delivery Guy says:

    Using nanotechnology, here is a series of papers that captures many of the arguments quite nicely:
    https://www.nature.com/articles/natrevmats201614
    https://www.nature.com/articles/natrevmats201673
    https://www.nature.com/articles/natrevmats201674

    1. WikiLeaks says:

      You mean a series of reviews.

  14. NotHF says:

    As somebody working in nanotech (whatever that actually means these days), I think there’s been a lot of overhype in many areas: catalysis, drug delivery, energy, etc. As a chemist I think the main reason is that a lot of the early adopters in the nanomaterials field came from physics, engineering, and materials science and not so much from chemistry. I’ve noticed at conferences a lack of bench-marking for nanoparticle based systems to existing state-of-the-art, particularly in catalysis & biology. I think that can broadly be traced to people not talking across subfields often enough, or reading broadly enough in the literature, which is unfortunate.

    There’s also not nearly enough tracing “targeting” particles in whole animal systems where the immune & metabolomic systems are intact. And some of the work that is out there seems to say that macrophages end up sequestering a lot of particles in the liver regardless of the surface chemistry, which is a bit of a problem for the whole targeting idea.

    I still think there’s potential for nanostuff to be useful in biology, but I think the field has generally tried to get to “look we can deliver drugs!” and similar high-profile excitements without first doing the less flashy fundamental studies to really flesh out in vivo behavior.

    1. milkshaken says:

      The difficulty is not that there is not enough incentive, but that there is actually counter-incentive to do the biology research right.

      I heard of a blatant case where a biotech company suppressed unfavorable animal data about the poor stability of their nanoparticle-formulated clinical candidate, by firing the person who dared to present it at the company research meeting. It then embargoed publication of all his results that contradicted the company propaganda.

  15. JK says:

    Certainly some good points, with some of the weaknesses being recognized elsewhere too of course.

    Poor animal models plague much preclinical research. More broadly the problematic academic incentives around reproducibility are well known. Measures such as double blinding certainly need to be taken much more seriously. In my experience this is rarely done in academia – is that also the case in industry?

    More positively, the field is not completely un-self critical. I thought this contribution from Frank Caruso’s group was useful:
    http://pubs.acs.org/doi/abs/10.1021/acsnano.7b04855

  16. Guy Furness says:

    The drug delivery field is a lot broader and more successful (ie at developing novel technologies through to market where they have improved and saved and are improving and saving millions of lives) than this article and most of the comments give it credit for.

    Whilst I agree that in the narrow area of targeted delivery of molecules within the body, and in particular “nanotech”, there is a lot of hype and it has somehow persisted for >2 decades now without yielding so much in the way of bone fide new products, there is in fact a far bigger picture.

    At the more commercial end of the drug delivery business – ie where real products are reaching or close to reaching real patients – it’s all about devices. Parenteral delivery systems that are so well designed that patients can take home biologic-based therapeutics and self administer them SC with minimal training, little or no pain and little or no disruption to their daily routine are coming through the pipeline fast now (see companies like Ypsomed, SHL, West, Enable Injections, Sensile Medical etc).

    The benefits of this in terms of improved adherence, convenience, reduced cost to the healthcare system etc are real and substantial when looking at improving existing pharmaceutical products, not to mention the potential for restarting the development of investigational molecules that are brilliantly therapeutically active but had been shelved due to difficult delivery challenges (large volumes (too long dosing times), high viscosity (large painful needles), need for dosing in the clinical setting (too costly, too inconvenient) etc etc…

    Outside injection, the lung as a route for systemic delivery of both small molecules and biotherapeutics is bouncing back after the disappointment of Exubera a few years back, and –
    among various projects – a new much improved inhalable insulin product is coming through.

    Neurological compounds delivered using nasal delivery systems are also reaching patients – already proven with sumatriptan, various other compounds are reaching the market.

    Proper product development programmes, products using novel delivery systems, are going through clinical trials and regulatory approval with microneedle patches, robotic pills for timed release in specific areas of the gut, closed loop systems, such as artificial pancreases, and much much more.

    And I won’t even start to talk about the burgeoning field of connectivity. The potential for improved therapeutic outcomes when, just to give an example, you connect an asthma inhaler to the internet, is mind boggling.

    Here I’ve not even scratched the surface of what is going on in drug delivery – check it out!

    So I’d say please don’t tar the whole of drug delivery with the same brush. A lot of very smart people are working very hard in this field on realistic projects that are not just concepts or nice ideas but real products reaching real patients.

    Quite the contrary to the message of the article, drug delivery IS delivering!

    Guy Furness
    Publisher, ONdrugDelivery Magazine.

    1. WikiLeaks says:

      Guy- “Far bigger picture” and “huge potentials” are mere euphemisms or deflecting of the truth. If two decades worth of funding has not generated anything meaningful then perhaps it’s time to use that money elsewhere. Science should be data driven, not “promise” or “potential” driven, and data is stacked up against nanotechnology as a viable drug delivery platform.

  17. Mol Biologist says:

    “More on simple pharmacokinetics” . Is the speed of Aspirin transport to target tissue exceeds the diffusion rate? I guess yes, it is exceed where more intensive consumption occurs in organs of storage – acting as acceptors. It should be noted that transport is two-sided: thus, the storage organs can act as an acceptor, and as a donor in the decomposition.

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