Here's something that's been sort of a dream of medicinal chemists and pharmacologists, and now can begin to be realized: single-cell pharmacokinetics. For those outside the field, you should know that we spend a lot of time on our drug candidates, evaluating whether they're actually getting to where we want them to. And there's a lot to unpack in that statement: the compound (if it's an oral dose) has to get out of the gut and into the bloodstream, survive the versatile shredding machine of the liver (which is where all the blood from from the gut goes first), and get out into the general circulation.
But all destinations are not equal. Tissues with greater blood flow are always going to see more of any compound, for starters. Compounds can (and often do) stick to various blood components preferentially (albumin, red blood cells themselves, etc.), and ride around that way, which can be beneficial, problematic, or a complete non-issue, depending on how the med-chem gods feel about you that week. The brain is famously protected from the riff-raff in the blood supply, so if you want to get into the CNS, you have more to think about. If your compound is rather greasy, it may find other things it likes to stick to rather than hang around in solution anywhere.
And we haven't even talked about the cellular level yet. Is your target on the outside of the cells, or do you have to get in? If you do, you might find your compounds being pumped right back out. There are ongoing nasty arguments about compounds being pumped in in the first place, too, as opposed to just soaking through the membranes. The inside of a cell is a strange place, too, once you're there. The various organelles and structures all have their own affinities for different sorts of compounds, and if you need to get into the mitochondria or the nucleus, you've got another membrane barrier to cross.
At this point, things really start to get fuzzy. It's only been in recent years that it's been possible to follow the traffic of individual species inside a cell, and it's still not trivial, by any means. Some of the techniques used to do it (fluorescent tags of various kinds) also can disturb the very systems you're trying to study. This latest paper uses such a fluorescent label, so you have to keep that in mind, but it's still quite impressive. The authors took a poly(ADP) ribose polymerase 1 (PARP1) inhibitor (part of a class that has had all kinds of trouble in the clinic, despite a lot of biological rationale), attached a fluorescent tag, and watched in real time as it coursed through the vasculature of a tumor (on a time scale of seconds), soaked out into the intracellular space (minutes), and was taken up into the cells themselves (within an hour). Looking more deeply, they could see the compound accumulating in the nucleus (where PARP1 is located), so all indications are that it really does reach its target, and in sufficient amounts to have an effect.
But since it doesn't, there must be something about PARP1 and tumor biology that we're not quite grasping. Inhibiting DNA repair by this mechanism doesn't seem to be the death blow that we'd hoped for, but we now know that that's the place to figure out the failure of these inhibitors. Blaming some problems of delivery and distribution won't cut it.