This article is based around a talk given by Ben Newland from Cardiff University, UK, at the NANOMED conference hosted by the NANOSMAT Society in Manchester on the 26-28th June 2018. In his talk, Ben talks about how he uses soft and flexible poly(ethylene glycol) (PEG) nanotubes to provide a sustained and localized delivery of therapeutic drugs.
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Dr. Newland, a lecturer at Cardiff University, has been dealing with PEG nanotubes for approximately ten years after they came about as a side project to his other research. It should be noted that these nanotubes are not like carbon nanotubes, in that they are not electronically confined in 2 dimensions (i.e., a 1D material), nor are they carbon nanotubes functionalized with PEG at the surface. They are strictly hollow cylinders that are made entirely of PEG, and only bear the name nanotube because that is what they most closely resemble (without the capped end).
The research came about after previously working on carbon nanopipes, where a porous template was used to create hollow carbon nanostructures; in conjunction with another area of Ben’s research, which looks at using cyclized knotted polymers as drug delivery agents. To combine these areas, Ben poured a polymer solution (with a photo-initiator) into a porous template and shone UV light on it, which in turn cross-linked the polymers and created tube-like structures. This was the starting point of this research.
Since starting the research, Ben has incrementally polished the process and now produces polymer nanotubes which are 200 nm in diameter and up to 60 micrometers in length. Cyclized knot polymers are required to construct these nanotubes and can be made with commercially available PEG materials that contain di-vinyl groups. Different polymers have been trialed, and the PEG nanotubes were found to be the softest.
The possibility of using these for drug delivery applications came about after they were found to uptake rhodamine (a tracer dye). On the process side, Ben’s research team discovered that when the templates are dissolved (with sodium hydroxide) to leave just the nanotubes, the process breaks some of the ester bonds and creates an abundance of negative charges on the surface of the nanotubes.
The anti-cancer drug, doxorubicin, was also found to be actively uptaken out of solution by the negatively charged nanotubes, and it is a straightforward procedure to determine the uptake and release of doxorubicin as it is intrinsically fluorescent and has a colored appearance. Ben’s work has led him to look at the release of doxorubicin from the nanotubes and found that they release most of the drug payload within the first five days, but there is a sustained delivery of 2-3 micrograms over 35 to 40 days. Some of the doxorubicin was found to stay in the nanotube, so while it is not perfect at the moment regarding the release, these nanotubes do show a lot of promise as new material as drug delivery agents.
One aspect of any delivery agent is that it needs to be biocompatible and low in cytotoxicity. In-vitro cell viability tests have been performed for these nanotubes at varying concentrations, and up to the point where the nanotubes are completely covering the cell. The results showed that even at the end (fully covered cells) the nanotubes did not kill the cell. Other cell viability studies on drug-loaded nanotubes found that the release of the drugs was killing the cells, and thus confirmed its position as a potential drug delivery agent.
The research has been taken further and has been tested on metastatic breast cancer cells in mice in conjunction with researchers from the University of Strathclyde. These studies have shown that the doxorubicin-loaded nanotubes reduced the tumor growth and reduced metastasis (the creation of secondary tumors away from the primary tumor site) in the mice.
Future studies will look at the cytotoxicity of the polymer nanotubes in-vivo and will look at how the drug release profile can be improved. Other areas will look at varying the size of the nanotubes, changing the chain length to alter the stiffness and entanglement of the nanotubes and looking at the effects of functionalizing the nanotubes with different nanoparticles.
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