spectrocopyNOW Blog-Nanosubmarine: NMR watches self destruction

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Nanomotor

Nuclear magnetic resonance (NMR) spectroscopy and other techniques have been used to characterise and observe the properties of a redox-sensitive stomatocyte nanomotor that could be used to

deliver and release drugs directly to cells in the body.

The targeting of drugs to particular disease sites in the body has been a major focus for many in pharmaceutical research for many years. Autonomous targeting and release of drugs, of course, is hoped to boost efficacy and reduce side effects and nanoparticles and nanosystems have become an important component of developing such systems. Now, a team of Dutch scientists has designed a nanomotor that can carry a pharmaceutical payload to a specific site and then release its contents. In their proof of principle, described in the journal Angewandte Chemie, the team reports on an antitumour drug encapsulated in a self-propelled, self-assembled stomatocyte. This system is transported across the cell membrane and release the anticancer drug within the target cell when it experiences the appropriate chemical redox signal to disassemble its vesicle membrane.

On target

Yingfeng Tu, Fei Peng, Paul White, and Daniela Wilson of the Institute for Molecules and Materials at Radboud University in Nijmegen, The Netherlands, suggest that self-propelled nanovesicles fuelled by hydrogen peroxide can take up directed motion responding to a concentration gradient, for instance. As such, they have combined the ideas of self-propelled nanomotors, drug encapsulation, and the triggered destruction of the nanocarrier, to create their system, all of which is sealed within a block copolymer shell made from polyethylene glycol (PEG) and polystyrene the polymer chains of which are linked with disulfide bridges. This shell opens to release the therapeutic payload only when the system encounters a raised concentration of the redox molecule glutathione.

The antioxidant glutathione is a tripeptide present in cells which acts as a scavenger of reactive oxygen species and is known to protect plants, animals, fungi, and some bacteria and archaea from reactive oxygen species such as free radicals, peroxides, lipid peroxides, and heavy metals. It is also a biomolecular feedstock for the near-ubiquitous amino acid cysteine. Glutathione levels are often much higher than normal in tumour cells and so Wilson and her team have latched on to the idea that a system that recognised and responded to such raised concentrations might be useful in their efforts at site-targeted drug delivery.

Redox release

"The small glutathione can enter into the PEG shell of the nanomotor and then break down the redox-responsive disulfide bonds...resulting in cleavage of the outside PEG shell," the team explains. Thus, upon cleavage of the disulfide bonds between the polymers of the shell, the redox molecule glutathione triggers the vesicle membrane to fall apart, and its contents to spill out into the target cell, where they will carry out their primary function. In this instance of killing the tumour cell.

To build the system the team encapsulates the hydrophilic anticancer drug within a vesicle formed from the disulfide bridged polymers. This is fashioned into a bowl-shaped stomatocyte, a vesicle with a special dent or groove, by adding platinum nanoparticles which act as the engine of the system. The platinum nanoparticles catalyse the degradation of hydrogen peroxide, which is typically produced by tumour cells, and the degradation releases gases that propel the stomatocytes forward, across the tumour cell membrane. Once inside, the glutathione carries out its job, opens the vesicle, and releases the drug. At the same time, this throws a biochemical spanner in the platinum engine, halting motion.

The team has now demonstrated functionality in human cell cultures, wherein they could internalize the stomatocyte nanomotors, observe degradation, and drug release.