Packaged paclitaxel: NMR unravels cyclodextrin

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  • Published: Jul 15, 2018
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Packaged paclitaxel: NMR unravels cyclodextrin

Nanoassemblies

A combination of natural microtubules and synthetic macrocyclic receptors allows for the light-controlled, reversible aggregation of the microtubules into larger nanostructures. As Chinese scientists have reported in the journal Angewandte Chemie

Supramolecular nanoassemblies that can emulate and perhaps modulate biological processes have become a focus of research. Nuclear magnetic resonance (NMR) spectroscopy and other techniques have now been used to follow one such self-assembled system, a cyclodextrin molecule bearing a photoisomer and hooked to cellular microtubules using the anticancer agent paclitaxel.

Writing in the Wiley journal Angewandte Chemie researchers from China explain how a combination of natural microtubules and synthetic macrocyclic receptors allows them to create larger nanostructures through the light-controlled, reversible aggregation of the microtubules. Placed in a cellular environment leads these aggregated microtubules to change cell morphology, causing cell death, which could lead to a novel approach to treating disorders in which abnormal aggregation of proteins takes place, such as Alzheimer's disease, Parkinson's disease, and infectious prion diseases, such as BSE, bovine spongiform encephalopathy, variant Creutzfeldt-Jakob disease (vCJD) in people, and scrapie in sheep.

Microtubule dynamics

Dynamic microtubules are protein filaments that combine with other components to form the cytoskeletons of our cells. Under normal conditions such molecular aggregation processes forming superstructures plays an important role in biology. Indeed, during the normal cell cycle, microtubules constantly assemble and disassemble. Now, scientists from Nankai University and the Collaborative Innovation Center of Chemical Science and Engineering, in Tianjin, China, have come up with the idea of combining the natural behaviour of microtubules to make larger supramolecular aggregates using synthetic “receptors”. Their hope was to produce innovative biomaterials and gain new knowledge about normal biological aggregation processes, as well as perhaps find a way to modulate or repair abnormal aggregation processes.

The team used an anticancer drug, paclitaxel (which has the well-known trade name of Taxol) as the anchoring their synthetic receptors to the microtubules. Paclitaxel works against cancer cells through its disruptive interaction with microtubules. Yu Liu and colleagues explain that the binding process essentially blocks deconstruction of the cytoskeleton, stopping cell division and causing cell death of the cancer cells, which are rapidly dividing in a tumour. For their receptor, the team opted for a large cup-shaped molecule from the cyclodextrin family. These "host" compounds are in one sense simply rings of oligomeric sugar chains and can accommodate a range of molecules as “guests” within their cavities. The guest in the present study is arylazopyrazole (AAP), a molecule with two aromatic rings bridged by a nitrogen-nitrogen double bond. AAP exists as cis and trans forms but only the trans form fits the cyclodextrin “cup”. However, it relatively easy to switch between cis and trans forms by radiating the molecule with one of two wavelengths of light.

Connector

With the paclitaxel acting as a connector between microtubule and loaded cyclodextrin cup, the team could then test the effect of visible and ultraviolet radiation on switching on and off the AAP and thence the aggregated and non-aggregated form. Spectroscopic and microscopic examination reveal the success of the process. The team explains that their aggregates take on a broad range of morphological variations, ranging from nanofibres to nanoribbons and nanoparticles of different sizes. They explain that of particular note is the fact that the aggregation of the microtubules can also be triggered within living cells. This causes the cells to shrink and die, which demonstrates that the cytotoxic effect of paclitaxel can be increased significantly.

The next step will be to look into how these supramolecular assemblies might be used as tools to investigate physiological and pathological protein nanoassembly. It is plausible that such systems or a derivative thereof might find applications the treatment of diseases caused by the improper aggregation of proteins.

Related Links

Angew Chem Int Edn Engl 2018, online: "Photo-Controlled Reversible Microtubule Assembly Mediated by Paclitaxel-Modified Cyclodextrin"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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