Nanoparticles (well, papers about nanoparticles) have been impossible to avoid for. . .what, ten years now, would you say? There’s so much potential there in so many fields, and there are so many things to try, that the literature is a gigantic pile that gets more deliveries dumped on it every week. And how many times have you heard about some great new nanoparticle drug delivery idea, especially targeting cancer? What exactly has happened to all of them?
This paper in Nature Reviews Materials has the answer, or answers. Working out that delivery and PK aspects of these things was already known to be a challenge, but it’s proven to be even more of one than anybody thought:
In this article, we explore the influence of delivery on the efficacy of nanoparticles for cancer-targeting applications. Delivery is important because systemically administered nanoparticle carriers cannot function as designed if they do not access the diseased cells and tissues at a sufficiently high dosage. Nanoparticles, once injected into the body, face both physical and biological barriers (for example, diffusion, flow and shear forces, aggregation, protein adsorption, phagocytic sequestration and renal clearance) that affect the percentage of administered nanoparticles reaching target diseased tissue and cells. We provide a quantification of the delivery efficiency of nanoparticles, review the fundamental principles and the current state and misconception of the biological mechanisms of the nanoparticle delivery process, and describes research strategies that may enhance the delivery efficiency.
Looking over the last ten years of publications, for example, the authors find that the efficiency of nanoparticle delivery to tumors has not improved at all over this period. There are over two hundred papers to work with, but only about half of them gave enough data to be useful (“More time points might have allowed a more precise calculation of the AUC, but very few researchers presented data with more than three time points“). They even contacted authors looking for more data, which is real dedication. But overall, about 0.7% of a systemic dose of nanoparticles actually reaches tumor tissue, it seems, so if you’re looking to do better, there’s the mark to shoot for. Only four papers report values over 5%, and (for what it’s worth) they’re all using particles under 100 nm diameter that are electrically neutral. But working in that space is still no guarantee of success, by any means. It’s also noted that all of these numbers may prove to be overestimates, because it can be difficult to tell if the nanoparticles were actually hitting the malignant cells, or just going into the tumor matrix, etc.
The authors go on to show that typical nanoparticle loadings in these papers would, based on mouse studies, extrapolate to unfeasible human doses – 90 to 200 mL of nanoparticle suspension, which is a rather unlikely clinical strategy. Even synthesizing the nanoparticles on that scale would currently be a challenge. Then you’re faced with that dosing problem, and then you have to worry about the off-target effects of the glass full of nanoparticles that don’t make it to the tissue of interest. The big point here is that the state of the art for cancer nanoparticles is still well short of what it needs to be: dosing efficiencies are going to have to go up by at least an order of magnitude to have any chance.
That makes a nice lead-in to the news that Bind Therapeutics this week filed for bankruptcy protection. Bind has been one of the big names in cancer nanoparticle therapy, but it hasn’t been easy for them, to say the least. I last wrote about them here, after some disappointing clinical results, and those have clearly been a problem for the company since then. The sorts of problems described in this new review article are surely just the sort of things that have been slowing their progress (and are, by the way, the same issues facing the various nanoparticle diagnostic ideas out there as well). In all of these, you’re seeing a very promising concept (several, actually) running up against some severe bioengineering constraints.
The current paper also has a number of interesting things to say about how nanoparticles behave, specifically, how they get out of blood vessels (extravasate) into tumor tissue. The dominant view is that this happens through leaks in the tumor vasculature, gaps between endothelial cells, but the authors suggest that this may well be mistaken, and that new approaches need to be tried:
Distinguishing between intercellular gaps and transendothelial cell pores is difficult, and intercellular gaps can only be demonstrated definitively by labelling the margins with selective junctional markers such as vascular endothelial cadherin; to our knowledge, this has never been attempted. However, the mechanisms and pathways that mediate nanoparticle transport to the tumour are important. If the extravasation is mediated primarily by the transcellular route, nanoparticles that will actively target this transport pathway can be designed. At present, the nanotechnology community has not investigated this transport mechanism. Instead, a heavy emphasis has been placed on studying nanoparticle transport through intercellular gaps via the EPR mechanism — an approach that has thus far yielded poor delivery efficiency. Therefore, there is a need to probe the tumour endothelium transport mechanism to guide the future design of nanoparticles.
EPR is “enhanced permeability and retention”, and the problem is that there doesn’t seem to be very much enhancement going on. There are also a lot of fluid-flow issues inside the tumor tissue itself, even once your nanoparticles have made it there, with plenty of issues yet to be worked out. Overlaying all of these, of course, are the traditional PK issues of having the therapeutic agent sluicing through high-blood-flow organs like the liver and kidneys, as well as partitioning into other tissues you don’t want. Macrophages are especially problematic, since they’re ready and able to go after unidentified particles in this size range. None of these issues are (in theory) unsolvable, but it’s equally clear that no one has solved them yet. As it is, the few approvals in this area have been less targeted and more outcomes-based:
Nanoparticles can be approved for human use by health agencies if they offer an improvement in diagnosis, therapeutic index and/or a reduction of toxicity. At present, only a few non-targeted nanoparticle formulations (for example, Abraxane and Doxil) have been clinically approved because they alter the toxicological profile of drugs in patients. Interestingly, these formulations did not yield significant improvements in therapeutic index or diagnostics. The approval process was based on end-outcome measurements, which are strongly related to how the nanoparticles alter the transportation and function of the small molecule anticancer agent in the body. This suggests the importance of understanding and controlling the delivery of nanoparticles in vivo.
So keep this in mind next time a breathless press release comes out in the field. Those are a bit less common than they used to be (ten or fifteen years of grinding away at these problems has eroded enthusiasm somewhat), but there’s still plenty of room for hype. The good news is that as the hype recedes, and the real problems become more apparent, people are getting to work on them. Nanoparticles may yet be a wonderful delivery vehicle; the promise is still there. But it’s already been a slower road than people were hoping for, and the good results are (once again) probably going to sneak up on us at their own pace.