Self-assembling anticancer drugs

It is possible to exploit different assembly pathways to hook together camptothecin derivatives in filamentous supramolecular structures that could have applications in imaging and chemotherapy, according to researchers in China. [Liang, C.H., et al. Appl. Mater. Today (2020); DOI: 10.1016/j.mattod.2020.09.028]

The idea of using the self-assembly of low weight molecules into larger entities that can mimic functional biomacromolecules is a much simpler prospect than manipulating the biomacromolecules themselves. Indeed, efforts to modulate the behavior of living cells with biomacromolecules for cell inhibition (to halt cancerous cell replication), in tissue engineering, and in imaging have been limited by the complex practicalities and laborious schemes for replicating the original biomacromolecules and then finding ways to apply them to tune cell behavior. There have been efforts to utilize assemblies of smaller fragments of such biomacromolecules but these too have significant limitations, such as spontaneous degradation and the overall high cost of creating libraries of such materials.

Researchers from Nankai University in Tianjin and colleagues at Westlake University in Hangzhou, China, have now demonstrate how to use different self-assembly pathways of a conjugate of laminin derivative peptide and hydroxycamptothecin (a pyranoindolizinoquinoline) to build distinctive nanostructures of confined conformation. 10-hydroxycamptothecin is itself in clinical studies as a possible treatment for myelodysplastic syndrome a group of cancers in which blood cells do not mature properly in the bone marrow.

In aqueous solution, the team writes, the hydroxycamptothecin units self-assemble into nanoparticles with a sheet structure not dissimilar to that formed by certain protein sequences. If they use phosphorylated hydroxycamptothecin and control the self-assembly enzymatically they were able to generate alpha-helices, another well-known protein motif, one that is present in laminins, these matrix proteins are associated with the progression of several types of cancer. The team writes that the different assemblies they have generated have disparate cellular distributions and activities in vivo. Indeed, some of their assemblies would accumulate predominantly on the cell surface and in the cytoplasm of certain types of cancer cell in the laboratory. Whereas nanofibers of hydroxycamptothecin enter the cancer cell nucleus. Each type of assembly saw a different response in tumor-bearing mice models treated with each.

The team points out that there is a vast reservoir of peptide structures that might be exploited as the building blocks for the self-assembly of such structures each perhaps tuned to target a particular cancer cell type and in different regions of those cells for either chemotherapy or for imaging purposes.

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