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Review
. 2021 Jun 7;11(6):1508.
doi: 10.3390/nano11061508.

Use of Protamine in Nanopharmaceuticals-A Review

Ivana Ruseska  1 , Katja Fresacher  1 , Christina Petschacher  1 , Andreas Zimmer  1
Affiliations
Review

Use of Protamine in Nanopharmaceuticals-A Review

Ivana Ruseska et al. Nanomaterials (Basel). .

Abstract

Macromolecular biomolecules are currently dethroning classical small molecule therapeutics because of their improved targeting and delivery properties. Protamine-a small polycationic peptide-represents a promising candidate. In nature, it binds and protects DNA against degradation during spermatogenesis due to electrostatic interactions between the negatively charged DNA-phosphate backbone and the positively charged protamine. Researchers are mimicking this technique to develop innovative nanopharmaceutical drug delivery systems, incorporating protamine as a carrier for biologically active components such as DNA or RNA. The first part of this review highlights ongoing investigations in the field of protamine-associated nanotechnology, discussing the self-assembling manufacturing process and nanoparticle engineering. Immune-modulating properties of protamine are those that lead to the second key part, which is protamine in novel vaccine technologies. Protamine-based RNA delivery systems in vaccines (some belong to the new class of mRNA-vaccines) against infectious disease and their use in cancer treatment are reviewed, and we provide an update on the current state of latest developments with protamine as pharmaceutical excipient for vaccines.

Keywords: nanoparticles; novel vaccine technologies; protamine; proticles.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Application fields of protamine. This review will especially focus on protamine in nanopharmaceuticals as well as its approach in vaccines.
Figure 2
Figure 2
Impact of NP properties on their biodistribution in lungs, spleen, kidneys and liver. Especially NP size, shape and surface charge are dictating the biodistribution. Particles smaller than 5 nm are filtered by the kidneys. With increasing size (20–150 nm) higher amounts of NPs are detectable in liver and spleen. Even more NPs are entrapped in liver, spleen and lungs when the size is over 150 nm. It is said that these NPs are proven for long-lasting circulation [101,102]. Cylindrical shapes seem to be quite favorable because a lot of these NPs are distributed in lungs, liver and spleen but also discoidal forms exhibit high accumulation capacities [103]. Positive surface charges of NPs lead to a prioritized sequestration in lungs, liver and spleen. NPs with slightly negative or neutral surfaces show longer circulation times and lower accumulation in these organs [104]. Regarding the NP shape and surface charge data, it is important to mention that the size of the discussed NPs is said to range from 20 to 150 nm [101].
Figure 3
Figure 3
Scheme of self-assembling process between the positively charged Protamine and DNA as negatively charged ODN component. Electrostatic interactions provoked by Protamine’s cationic amino acid groups and the negative phosphate backbone of the ODN result in a self-assembled ODN/Protamine complex.
Figure 4
Figure 4
Schematic depiction of the impact of PEGylation on NPs. PEGylation is a common strategy to modify and further functionalize NPs. It was shown that the use of PEG increased NP size and therefore prolonged the circulation half-life by evading renal filtration [29,137]. Moreover, it led to a reduction in receptor binding affinity [133], provokes steric hindrance [131], increased the NP stability in salty environment [140] and it prevented the NPs from opsonization by macrophages [138].
Figure 5
Figure 5
Types of vaccines being developed. Vaccines can contain live, whole pathogens, inactivated pathogens, toxoids, and parts of the pathogen. Novel concepts include vectors as delivery systems, and nucleic acid-based vaccines. Reprinted from [158]. CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/), accessed on 21 January 2021.
Figure 6
Figure 6
Schematic representation of nanoparticle vaccine production. Reprinted from [153]. CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/), accessed on 8 February 2021.
Figure 7
Figure 7
Interaction of cell-penetrating peptides (CPPs) with dendritic cells (DCs), when used as delivery systems for antigens. (1) The CPP–antigen complex interacts with the negatively charged glycosaminoglycans (GAGs) on the surface of dendritic cells. This can trigger the uptake of the complex, usually by endocytosis. When taken up by the cells, the complex is most likely to end up in endosomes. Thanks to the structure of CPPs, the complex can escape the endosomal pathway. After endosomal escape, the complex is degraded in the proteasome, and the antigen is transported to the cell surface by vesicles containing MHC class II receptors. Another possibility is that the antigen is transported though the endoplasmic reticulum-Golgi pathway, and afterwards presented on the cell surface by an MHC class I receptor. If the complex remains in the endosomes, however, it is a subject of lysosomal degradation, after which the antigen is presented on the cell surface by an MHC class II receptor. (2) The free antigen can also undergo endocytosis and enter the cytoplasm of DCs, thus enter the endosomal pathway. Since free antigens are less likely to escape the endosomes, they are subjected to lysosomal degradation, and then presented on the cell surface by MHC class II receptors. Reprinted and edited from [257]. CC BY-NC 4.0 (https://creativecommons.org/licenses/by-nc/4.0/), accessed on 14 March 2021.
Figure 8
Figure 8
Mechanism of action of protamine vaccines. When protamine is complexed with antigens, it forms NPs that can be used as delivery systems for the antigens. Whether applied in vitro or in vivo, protamine vaccines stimulate the antigen-presenting cells (APCs), such as dendritic cells, which in turn start releasing cytokines and chemokines. These signaling molecules further activate the humoral immunity (B-cells which produce antibodies) and cellular immunity (T-helper cells and cytotoxic T-cells).
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