Directed discovery of high-loading nanoaggregates enabled by drug-matched oligo-peptide excipients Journal Article
| Authors: | Berisha, N.; Farahpour, A.; Ramakrishnan, M.; Chen, C.; McPhee, S. A.; Wang, T.; Li, T. D.; Hema, K.; Panagiotakopoulou, M.; Athiyarath, V.; Coste, M.; Marciano, Y.; Sherman, E.; Ulijn, R. V.; Heller, D. A. |
| Article Title: | Directed discovery of high-loading nanoaggregates enabled by drug-matched oligo-peptide excipients |
| Abstract: | Nanoparticles can improve drug pharmacokinetics, but low loading efficiencies can limit treatment efficacy. Drug-aggregation-based nanoparticles have demonstrated improved loadings of up to 90%, but few excipients facilitate efficient co-assembly. We investigated peptides as designer excipients because of their diverse chemical space and inherent biodegradability. We designed pentapeptide scaffolds to mimic the structure of known indocyanine excipients by modulating aromaticity, rigidity, and charge. We screened 184 formulations by using diverse drug cargoes. We found drug-peptide combinations that formed nanoparticles with up to 98% drug loading. Molecular dynamics simulations and mass spectrometry analysis demonstrated that tryptophan-drug interactions and solvent exposure of charged amino acid residues drove the formation of core-shell structures. Peptide-drug formulations containing the JAK2/FLT3 inhibitor lestaurtinib were investigated in acute myeloid leukemia models, resulting in enhanced anti-tumor efficacy. This work found that oligopeptides can be designed to efficiently co-assemble with therapeutic cargoes to result in high-loading nanoparticles that improve anti-tumor efficacy. © 2024 |
| Keywords: | nanoparticle; oligopeptides; drug delivery; excipient; co-assembly; directed discovery; nanocarrier design; sdg3: good health and well-being |
| Journal Title: | Chem |
| Volume: | 11 |
| Issue: | 6 |
| ISSN: | 24519308 |
| Publisher: | 2024 |
| Date Published: | 2025-01-01 |
| Start Page: | 102404 |
| Language: | English |
| DOI: | 10.1016/j.chempr.2024.102404 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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