Supramolecular machines attached to nanoparticles allow the controlled release of their encapsulated cargo

US researchers have developed a nano-sized drug delivery system that only releases its payload in specific pH conditions, a feature that could prove particularly useful for targeted delivery of cancer treatments. 

Many cancer drugs are highly toxic and need to be delivered specifically to tumour cells to avoid damaging healthy tissue and causing unpleasant side effects. While many approaches to develop drug delivery vehicles have met with considerable success, the ability to fine tune them to only deliver drugs in response to specific biological conditions has been harder to attain. 

But now, a collaboration between US researchers in Fraser Stoddart’s team at Northwestern University, Illinois and Jeffrey Zink’s team at the University of California, Los Angeles (UCLA), has led to the development of ’mechanised nanoparticles’ that release their payload in response to a change in pH.

At the heart of the system is a mesoporous silica nanoparticle of around 200nm in size which would carry the drug and is easily absorbed by cells. But the payload would leak through the particle’s pores without what Stoddart describes as all-important ’nanovalves’.

These nanovalves are ’stalks’ that carry a ring, like a cyclodextrin or cucurbituril, explains Stoddart, which controls the release of the cargo from the core of the mesoporous particle. 

The stalks are made of a chain consisting of three nitrogen atoms, separated by a series of carbon atoms positioned so that they hydrogen bond with the oxygen atoms around the rims of the cucurbituril ring. 

Two ammonium groups close to the nanoparticle are separated by four carbon atoms while the ’terminal’ anilinium nitrogen is separated from the central nitrogen atom by six carbon atoms. 

In the current study, propidium iodide, a fluorescent dye often used for cellular imaging, was encapsulated in the mechanised nanoparticles and its release studied using a luminescence spectrometer. At a pH of 6.5, virtually no dye was released over a 30-minute period, whereas when the pH was adjusted to a mildly acidic 3.4, all the dye within the nanoparticle was released.

’I think it’s remarkable that the ring is so efficient at holding the cargo inside,’ says Stoddart. ’Until you change the pH you see very little leakage over time.’


Source: © J. Am. Chem. Soc.

The mechanised nanoparticles respond to particular pH conditions, either releasing their payload or ’closing’ to prevent molecules leaving or entering

At a pH lower than 5.4, all the nitrogen groups on the stalk are protonated and the ring sits in the ’open’ position, letting molecules leave or enter the nanoparticle. When the system becomes less acidic, the anilinium group is deprotonated and the ring moves over the two ammonium groups into the ’closed’ position, stopping any molecules escaping from the capsule.

If the solution is adjusted to pH 10, both the ammonium and anilinium groups are deprotonated, causing the rings to fall off the stalks and releasing the entire payload.

The pH at which the nanoparticle opens and closes can be tuned by adjusting the substituent on the aniline in the para position to the nitrogen. Stoddart’s team are currently developing a series of stalks that will allow the nanoparticle’s payload to be delivered at a precise pH.

According to Stoddart, the system works just as well in complex biological media as in water, and the team is currently collaborating with biochemists, biologists and medics at Northwestern University and UCLA to study the system in biological systems. 

’We are conducting in vitro studies using the anticancer drug camptothecin and some of these are looking very, very promising,’ says Stoddart 

Alberto Credi, an expert in nanomachinery at the University of Bologna, Italy, believes the work is particularly important as the pH in tumour cells is very different from healthy cells, making pH ’a very good trigger for delivering anticancer drugs’.

’This is a very important result that was based on a previous study from the same group, however the problem in that first work was that the cargo was only released at quite high pH,’ says Credi. ’In this paper not only have they adjusted the pH at which the cargo is released, but they have also shown they can tune the pH by chemical substitution.’ 

Matt Wilkinson