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Article

Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery

1
Institute of Technology, University of Tartu, 1 Nooruse Street, 50411 Tartu, Estonia
2
Institute of Molecular and Cell Biology, University of Tartu, 23b Riia Street, 51010 Tartu, Estonia
3
Institute of Physics, University of Tartu, 1 Wilhelm Ostwaldi, 51014 Tartu, Estonia
4
Chemistry Section, Stockholm University, SE-10691 Stockholm, Sweden
5
CellPept Sweden AB, 10B Kvarngatan, 11847 Stockholm, Sweden
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Pharmaceutics 2023, 15(2), 396; https://doi.org/10.3390/pharmaceutics15020396
Received: 2 January 2023 / Revised: 16 January 2023 / Accepted: 19 January 2023 / Published: 24 January 2023

Abstract

Cell-penetrating peptides (CPPs) are highly promising transfection agents that can deliver various compounds into living cells, including nucleic acids (NAs). Positively charged CPPs can form non-covalent complexes with negatively charged NAs, enabling simple and time-efficient nanoparticle preparation. However, as CPPs have substantially different chemical and physical properties, their complexation with the cargo and characteristics of the resulting nanoparticles largely depends on the properties of the surrounding environment, i.e., solution. Here, we show that the solvent used for the initial dissolving of a CPP determines the properties of the resulting CPP particles formed in an aqueous solution, including the activity and toxicity of the CPP–NA complexes. Using different biophysical methods such as dynamic light scattering (DLS), atomic force microscopy (AFM), transmission and scanning electron microscopy (TEM and SEM), we show that PepFect14 (PF14), a cationic amphipathic CPP, forms spherical particles of uniform size when dissolved in organic solvents, such as ethanol and DMSO. Water-dissolved PF14, however, tends to form micelles and non-uniform aggregates. When dissolved in organic solvents, PF14 retains its α-helical conformation and biological activity in cell culture conditions without any increase in cytotoxicity. Altogether, our results indicate that by using a solvent that matches the chemical nature of the CPP, the properties of the peptide–cargo particles can be tuned in the desired way. This can be of critical importance for in vivo applications, where CPP particles that are too large, non-uniform, or prone to aggregation may induce severe consequences.
Keywords: cell-penetrating peptides; solvent; nanoparticle formation; nucleic acid delivery cell-penetrating peptides; solvent; nanoparticle formation; nucleic acid delivery

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MDPI and ACS Style

Biswas, A.; Maloverjan, M.; Padari, K.; Abroi, A.; Rätsep, M.; Wärmländer, S.K.T.S.; Jarvet, J.; Gräslund, A.; Kisand, V.; Lõhmus, R.; Pooga, M. Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery. Pharmaceutics 2023, 15, 396. https://doi.org/10.3390/pharmaceutics15020396

AMA Style

Biswas A, Maloverjan M, Padari K, Abroi A, Rätsep M, Wärmländer SKTS, Jarvet J, Gräslund A, Kisand V, Lõhmus R, Pooga M. Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery. Pharmaceutics. 2023; 15(2):396. https://doi.org/10.3390/pharmaceutics15020396

Chicago/Turabian Style

Biswas, Abhijit, Maria Maloverjan, Kärt Padari, Aare Abroi, Margus Rätsep, Sebastian K.T.S. Wärmländer, Jüri Jarvet, Astrid Gräslund, Vambola Kisand, Rünno Lõhmus, and Margus Pooga. 2023. "Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery" Pharmaceutics 15, no. 2: 396. https://doi.org/10.3390/pharmaceutics15020396

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