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.