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Inhaled Nanoparticles – Good Ones, That Is

Never give up on drug delivery ideas – that’s one of the big points I get out of this paper. The authors, part of a multi-center team from sites in Italy and Germany, have previously shown that calcium phosphate nanoparticles could be a good carrier for delicate cargo such as microRNAs. Such things tend to get degraded pretty quickly in the rough-and-tumble of the bloodstream; our bodies do not particularly want lots of nucleic acid strands floating around from organ to organ. Therapeutic peptides suffer from similar disadvantages – anyone working on one usually ends up spending significant amounts of time modifying the original peptide structure to keep it around long enough in the body to be effective.

This paper shows that the CaP nanoparticles are indeed effective carriers of therapeutic peptides, but what’s really startling is that they show them working through inhalation. What gave them this idea? Air pollution:

The rationale for the use of this unconventional administration route for targeting of the heart is based on the concepts that (i) during respiration the oxygenated blood moves from the pulmonary circulation first to the heart via the pulmonary vein and (ii) combustion-derived nanoparticles and ultrafine particulates inhaled through polluted air were recently shown by us (16) and others (17) to be present in the heart and causally associated with cardiac arrhythmia and dysfunction, suggesting that inhaled nanoparticles are deposited in the heart. Furthermore, CaPs can protect peptides from immediate enzymatic degradation and, because of their negative surface charge, provide cellular permeability via the membrane internalization.

As a test case, they used some of the group’s recent work on peptidomimetics targeting calcium channels (voltage-dependent L-type, a longstanding cardiovascular target) to improve cardiac muscle function. The group checked the idea by using a near-infrared fluorophore loaded into the nanoparticles, since NIR penetrates tissue pretty well (and certainly enough to watch things move around in mice and rats). The particles were dosed as a fine mist of aqueous suspension via a rodent respirator – something that sounds like you’d want some experienced hands for – and the team could indeed see the fluorescent signal in the lungs at first, and moving to the heart within an hour. They compared the inhalation route with administration via oral gavage, intraperitoneal injection, and intravenous injection, and the inhalation was definitely the best for targeting the heart tissue.

Encapsulating the therapeutic peptides was the next step, and the paper has very solid data on the effects of the inhaled nanoparticle route in a mouse model of cardiomyopathy (streptozotocin-induced). Cardiac function was basically restored completely. The paper even goes on to try the inhalation technique in (healthy) pigs, demonstrating that the (non-drug-loaded) particles do cross out of the lungs and target the heart in the porcine model, without showing any acute effects on lung or heart function.

There are plenty of issues to address, as the paper itself notes. For one thing, as with all inhalation routes, you have to wonder about the variation in lung function, both in healthy and diseased patients. Long-term studies of the effects on lung tissue would be needed, as well as a lot more pharmocokinetic work in general. The actual detailed mechanisms by which such particles get into the pulmonary bloodstream are pretty much unknown, and you’d want to dig into that, too. So this is not going to be heading for the clinic next month, but that said, I’m really amazed that this approach works at all, and especially that it seems to work so well. It’ll be interesting to see what can be made of it.

19 comments on “Inhaled Nanoparticles – Good Ones, That Is”

  1. A Nonny Mouse says:

    Reminds me of the old renin days when the only good result in terms of bioavailability was when they accidentally put the test molecule into the lung rather than the stomach of the animal. Lead to a good month or so of “structure optimisation”.

    1. Chrispy says:

      ha ha ha… thanks for this!

  2. cato says:

    How does using CaP nanoparticles avoid the inflammation health issues associated with inhaling fine particles like asbestos and silica?

    1. Some idiot says:

      Not my field, but I would guess that it would have something to do with particle morphology. Asbestos is a mess of fine needles that stick into everything, with inflammation a byproduct (and I think the same applies to silicates).

      If these CaP particles were more rounded, then one would expect different profiles. I don’t know, but this is my best guess…

      1. Peter Shenkin says:

        Calcium phosphate is soluble, though not very – unlike silicates, which are completely insoluble. Presumably, over time, the substrate will dissolve.

        1. Paul D. says:

          I suspect some nesosilicates would show dissolution in tissue. Have there been experiments using olivine nanoparticles?

      2. Kyle says:

        It’s the same thing as bone remodeling. How do you think they’re changed in vivo.

      3. MBP says:

        Aspect ratio, hydrodynamic radius, and solubility are the principal physical factors that affect the toxicity of inhaled particles. Asbestos fibers are insoluble and the most toxic ones have aspect ratios of approximately 3:1, so they would be expected to have a much different toxicological profile than the CaP particles discussed in this article.

  3. Vampyricon says:

    Very clever!

  4. Jim Mowreader says:

    Derek, if you’re up for another “Things I Won’t Work With,” I found a real doozy…

    “Polycyclic aromatic energetic materials.” What a concept!

    1. Paul D. says:

      On a vaguely similar note, John D. Clark’s “Ignition!: An Informal History of Liquid Rocket Propellants” is finally being reprinted.

      1. Parker Huellmantel says:

        Oh happy day! My local library has a copy, but I’ve been wanting my own for ages.

    2. David Edwards says:

      That publication features a whole host of compounds that will fall into Derek’s “Things I Won’t Work With” remit … pentanitroaniline being one of them. I suspect both Derek and I will have trouble recalling many pentanitro compounds …

      1. milkshaken says:

        Germans did lot of work on penta and hexanitrobenzene-related compounds during WWII (for armor piercing shaped charges). You can make them by oxidation of nitroanilines. They are not that touchy on impact or static charge but hydrolytic instability is a problem

        1. David Edwards says:

          So, not a good choice for rainy environments then … 😀

          I happen to live not too far from Manchester in the UK, which has a singular reputation for attracting rain, so I suspect even a lab synthesis would be troublesome at the local university chemistry departments …

  5. Major PI says:

    Grad students need to be taught a hardcore lesson. First, respect. Secondly, show respect for your elders and betters. Third, manual labor. Until then, very little scientific progress is possible.

    1. Once a Grad Student. says:

      Major PI. Really? Where I’m from respect is earned. You can demand it is much as you want. But if you aren’t getting any you have only yourself to blame. If you act in a way that compels respect it won’t be a problem for you. Elders and betters. Ha! I certainly respect my elders, but elder =/= older. Not anymore. Because it used to imply a level of wisdom attained with age. In todays western society, there are a lot of people who are older, but there are very few who would qualify as elders.
      “Better” is a relative term and a value judgement. Careful how you use it.
      I don’t dispute the last point. Manual labor is the backbone of all good science, but I caution you, it takes many many different forms.

      1. Derek Lowe says:

        “Major PI” is a troll.

  6. Scale it up says:

    I’m not sure the Cy7 dye chosen here was the best choice? Sure it’s water soluble but charged derivatives tend to have an effect on bio-distribution mainly occurrences of non-specific binding. Would be interested to see a piece on NIR dyes with clinical potential!

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