A multifunctional drug delivery system based on switchable peptide-stabilized emulsions

Daniel Boas; Alexander van Teijlingen; Zohar Shpilt; Deborah E. Shalev; Edit Y. Tshuva; Tell Tuttle; Meital Reches

doi:10.1016/j.chempr.2024.02.003

A multifunctional drug delivery system based on switchable peptide-stabilized emulsions

Daniel Boas, Alexander van Teijlingen, Zohar Shpilt, Deborah E. Shalev^*, Edit Y. Tshuva^*, Tell Tuttle^*, Meital Reches^*

^*Corresponding author for this work

Pure And Applied Chemistry

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

Abstract

Emulsions are commonly used for drug delivery, yet they are usually limited to exclusively delivering either lipophilic or hydrophilic compounds. This separation negates possible synergetic therapeutic roles between such compounds. Here, we introduce a design for a short peptide that can stabilize emulsions. Upon binding certain metal ions, the peptide acts as a molecular switch, changes conformation, and becomes amphiphilic. Spectroscopic methods, NMR, and molecular dynamics provide information on the mechanism of this complexation-triggered amphiphilicity. The stability of these unique emulsions is based on histidine-metal bonds, which break at low pH values, selectively releasing their contents at the extracellular pH of tumors. Paclitaxel-encapsulated emulsion demonstrates strong activity against HeLa cells with an IC₅₀ of 70 nM, possibly enhanced by the simultaneous release of Zn²⁺ ions. Importantly, the emulsion is easily functionalized with various hexahistidine-tagged motifs that can supply the emulsion with many functions beyond drug delivery.

Original language	English
Pages (from-to)	1821-1838
Number of pages	18
Journal	Chem
Volume	10
Issue number	6
Early online date	29 Feb 2024
DOIs	https://doi.org/10.1016/j.chempr.2024.02.003
Publication status	Published - 13 Jun 2024

Funding

D.B. acknowledges the Hebrew University Center for Nanoscience and Nanotechnology for his Ph.D. fellowship. E.Y.T. is an incumbent of the Lester Aronberg Chair in Applied Chemistry. We thank Prof. Assaf Friedler for his help with the CD measurements and Prof. Raed Abu-Reziq for his help with DLS and ζ-potential measurements. D.B. designed the materials, synthesized the peptides, performed the emulsion characterization experiments, analyzed the NMR results, and performed the MTT assays. A.v.T. performed the molecular dynamics simulations. Z.S. performed the MTT assays. D.E.S. performed the NMR measurements and analyzed the results. M.R. T.T. and E.Y.T. supervised the research. The manuscript was written and reviewed by all authors. M.R. and D.B. have filed a provisional patent application (63468693).

Keywords

amphiphilic peptides
drug delivery
emulsion functionalization
metal-binding peptides
peptide-stabilized emulsions
SDG3: Good health and well-being

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10.1016/j.chempr.2024.02.003

https://www.researchsquare.com/article/rs-3121613/v1Licence: CC BY 4.0

Cite this

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title = "A multifunctional drug delivery system based on switchable peptide-stabilized emulsions",

abstract = "Emulsions are commonly used for drug delivery, yet they are usually limited to exclusively delivering either lipophilic or hydrophilic compounds. This separation negates possible synergetic therapeutic roles between such compounds. Here, we introduce a design for a short peptide that can stabilize emulsions. Upon binding certain metal ions, the peptide acts as a molecular switch, changes conformation, and becomes amphiphilic. Spectroscopic methods, NMR, and molecular dynamics provide information on the mechanism of this complexation-triggered amphiphilicity. The stability of these unique emulsions is based on histidine-metal bonds, which break at low pH values, selectively releasing their contents at the extracellular pH of tumors. Paclitaxel-encapsulated emulsion demonstrates strong activity against HeLa cells with an IC50 of 70 nM, possibly enhanced by the simultaneous release of Zn2+ ions. Importantly, the emulsion is easily functionalized with various hexahistidine-tagged motifs that can supply the emulsion with many functions beyond drug delivery.",

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AU - Tshuva, Edit Y.

AU - Tuttle, Tell

AU - Reches, Meital

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AB - Emulsions are commonly used for drug delivery, yet they are usually limited to exclusively delivering either lipophilic or hydrophilic compounds. This separation negates possible synergetic therapeutic roles between such compounds. Here, we introduce a design for a short peptide that can stabilize emulsions. Upon binding certain metal ions, the peptide acts as a molecular switch, changes conformation, and becomes amphiphilic. Spectroscopic methods, NMR, and molecular dynamics provide information on the mechanism of this complexation-triggered amphiphilicity. The stability of these unique emulsions is based on histidine-metal bonds, which break at low pH values, selectively releasing their contents at the extracellular pH of tumors. Paclitaxel-encapsulated emulsion demonstrates strong activity against HeLa cells with an IC50 of 70 nM, possibly enhanced by the simultaneous release of Zn2+ ions. Importantly, the emulsion is easily functionalized with various hexahistidine-tagged motifs that can supply the emulsion with many functions beyond drug delivery.

KW - amphiphilic peptides

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KW - emulsion functionalization

KW - metal-binding peptides

KW - peptide-stabilized emulsions

KW - SDG3: Good health and well-being

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A multifunctional drug delivery system based on switchable peptide-stabilized emulsions

Abstract

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Keywords

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