(604a) Biomolecular Co-Assembly of Peptides with Multiple Cancer Drugs into Novel Generations of Nanocarriers

Biomolecular self-assembly of peptides can lead to novel classes of highly attractive nanomaterials with several applications, including drug delivery, where they can be used to facilitate drug release and/or stability and reduce side effects. The potential ability of self-assembling peptides to be efficiently designed to target particular sites, to load a variety and a high load of drugs, as well as to possess triggered drug release at disease sites make them attractive candidates for drug delivery systems, including cancer drug delivery¹. We used a combination of computations and experiments demonstrating that Cyclo-dishistidine (Cyclo-HH) peptides can co-assemble^2,3,4, in the presence of zinc and nitrate ions, successfully with particular cancer drugs of different physicochemical properties, and provided fundamental structural and thermodynamical properties of Cyclo-HH based drug nanocarriers formation⁵. Subsequently, we computationally designed minimalistic peptide-based nanocarriers with the capacity to co-assemble with multiple cancer drugs and coordinate with zinc for enhanced fluorescence. The novel designed biomolecular and biocompatible nanocarriers showed notable drug encapsulation properties for the series of drugs investigated according to both experimental studies, as well as structural and thermodynamical insights from computational studies. They possess enhanced fluorescence, and uptake into HeLa cells using live cell confocal microscopic images. They can potentially serve as programmable materials for the design of new generations of complex nanostructures with modulated assembly, folding and recognition properties for particular cancer systems.

References

1. Kumar VB, Ozguney B, Vlachou A, Chen Y, Gazit E, Tamamis P. Peptide Self-Assembled Nanocarriers for Cancer Drug Delivery. J Phys Chem B. 2023;127(9):1857-1871.
2. Orr AA, Chen Y, Gazit E, Tamamis P. Computational and Experimental Protocols to Study Cyclo-dihistidine Self- and Co-assembly: Minimalistic Bio-assemblies with Enhanced Fluorescence and Drug Encapsulation Properties. Methods Mol Biol. 2022;2405:179-203.
3. Chen Y, Orr AA, Tao K, Wang Z, Ruggiero A, Shimon LJW, Schnaider L, Goodall A, Rencus-Lazar S, Gilead S, Slutsky I, Tamamis P, Tan Z, Gazit E. High-Efficiency Fluorescence through Bioinspired Supramolecular Self-Assembly. ACS Nano. 2020;14(3):2798-2807.
4. Tao K, Chen Y, Orr AA, Tian Z, Makam P, Gilead S, Si M, Rencus-Lazar S, Qu S, Zhang M, Tamamis P, Gazit E. Enhanced Fluorescence for Bioassembly by Environment-Switching Doping of Metal Ions. Adv Funct Mater. 2020;30(10):1909614.
5. Vlachou A, Kumar VB, Tiwari OS, Rencus-Lazar S, Chen Y, Ozguney B, Gazit E, Tamamis P. Co-Assembly of Cancer Drugs with Cyclo-HH Peptides: Insights from Simulations and Experiments. ACS Appl Bio Mater. 2024;7(4):2309-2324.