Scientists in China have carried out a proof-of-concept study for an intelligent drug delivery system that could target tumours with unprecedented accuracy.
Many anticancer drugs – whilst potentially lifesaving – come with a host of side effects, since they can damage not only the tumour but healthy cells in the body. These side effects can range from fatigue and hair loss to fertility problems and serious infection.
This is why a great deal of cancer research focuses on drug delivery systems that can get the medicine straight to the tumour without interacting with the rest of the body. These usually take the form of nanocapsules – tiny particles that can be loaded with the drug and swallowed or injected.
The nanocapsules are designed to only open when they are in the presence of the tumour. This enhanced accuracy means that far smaller doses can be used, and there is a lower risk of the drug being exposed to areas that don’t need it.
Of course the huge challenge in all this is how to control the opening of the nanocapsule. Fortunately tumours come with a number of ‘red flags’ – changes in their environment that signal their presence. We can use these red flags as triggers for opening the capsule. For example, a common red flag is acidity – the environment directly around a tumour cell is usually more acidic than that of healthy cells – so many researchers are designing nanocapsules that open when they detect a change in acidity.
However, despite all the progress being made in this area of research, existing drug delivery systems are still not as accurate as they need to be. Because human biology is so complex, there are a number of ways in which ‘false positive’ signals can occur, meaning that the drug is released too early and in the wrong part of the body.
Weihong Zhu and his team from East China University of Science and Technology have carried out a proof-of-concept study for an intelligent drug delivery system that could target tumours with unprecedented accuracy. They have designed their capsule to have a ‘sense of logic’ – meaning it must detect two different signals for cancer, and not only that but in a particular sequence. Only when the capsule has detected the two signals, and in the right order, does it open and release the drug.
Previous researchers have designed systems that can detect two different red flags, but they usually operate using ‘OR’ logic – meaning that the capsule will open if either red flag is detected. Weihong’s system operates using ‘AND’ logic – meaning that the capsule will only open if both red flags are detected.
To show that this type of system can work, Weihong and his team have designed a capsule that responds first to decreased pH (that is, increased acidity), and then to the presence of glutathione – a chemical that is produced in the presence of tumours.
The final flourish is a fluorophore – a component of the drug that becomes fluorescent once the change in pH is detected. This fluorescence can be detected in real time, meaning that the scientists can follow the progress of the drug. This means that the drug doesn’t just treat the tumour, it also shows us its precise location, meaning the system can act as a diagnostic tool.
The system consists of a number of long molecules each comprising a fluorescent unit, an anticancer prodrug (a molecule that can metabolize to produce an anticancer drug once released into the body), and a long polymer ‘tail’.
At normal pH levels the long molecules cluster together in a sphere, with the ‘tails’ pointing outwards. This formation suppresses the fluorophore, and so no fluorescence is detected. At slightly lower pH levels the sphere – known as a ‘micelle’ – dissociates and the long molecules are freed. The fluorescent component is now detectable.
Once the long molecules are free, they can react with the glutathione, which breaks the molecular bridge between the prodrug and the rest of the molecule, causing it to break away. The prodrug, now freed from its delivery system, and in the correct place in the body, is now able to go on and treat the cancer.
The breaking of the long molecule causes a shift in the wavelength of fluorescence emitted, meaning that this second event can also be observed.
Weihong believes that his research will pave the way for the design of a new generation of drugs, designed in precise ways to respond to specific stimuli. “This sense-of-logic nanoprobe provides a prototype to development of in vivo intelligent biosensing probes for precise programmable drug delivery systems”, he says.
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