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Review
. 2015 Aug 18;16(8):19518-36.
doi: 10.3390/ijms160819518.

Intracellular Delivery of Molecular Cargo Using Cell-Penetrating Peptides and the Combination Strategies

Hua Li  1   2 , Tung Yu Tsui  3 , Wenxue Ma  4
Affiliations
Review

Intracellular Delivery of Molecular Cargo Using Cell-Penetrating Peptides and the Combination Strategies

Hua Li et al. Int J Mol Sci. .

Abstract

Cell-penetrating peptides (CPPs) can cross cellular membranes in a non-toxic fashion, improving the intracellular delivery of various molecular cargos such as nanoparticles, small molecules and plasmid DNA. Because CPPs provide a safe, efficient, and non-invasive mode of transport for various cargos into cells, they have been developed as vectors for the delivery of genetic and biologic products in recent years. Most common CPPs are positively charged peptides. While delivering negatively charged molecules (e.g., nucleic acids) to target cells, the internalization efficiency of CPPs is reduced and inhibited because the cationic charges on the CPPs are neutralized through the covering of CPPs by cargos on the structure. Even under these circumstances, the CPPs can still be non-covalently complexed with the negatively charged molecules. To address this issue, combination strategies of CPPs with other typical carriers provide a promising and novel delivery system. This review summarizes the latest research work in using CPPs combined with molecular cargos including liposomes, polymers, cationic peptides, nanoparticles, adeno-associated virus (AAV) and calcium for the delivery of genetic products, especially for small interfering RNA (siRNA). This combination strategy remedies the reduced internalization efficiency caused by neutralization.

Keywords: TAT peptide; calcium; cell-penetrating peptides (CPPs); combination delivery; liposome; nanoparticles.

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Figures

Figure 1
Figure 1
Enhanced drug delivery system by the combination of CPPs with other carriers. Drugs (far left) can be incorporated into the typical carrier systems, which can be modified with CPPs. Under this circumstance, the CPPs-modified drug carrier system not only dramatically enhances the intracellular delivery efficiency, but also improves the endosomal escape through the alteration of its biodistribution.
Figure 2
Figure 2
CPPs-modified liposome. (A) The original liposome; (B) The CPPs conjugated directly to the surface of the liposome; (C) The CPPs modified to the surface of PEG first, and then conjugated to the liposome. The blue circle in the figure panel typifies liposome, # represents the CPPs, Δ stands for other modified cargo (e.g., PEG) and * symbolizes the transferred cargo.
Figure 3
Figure 3
CPPs-based drug carriers. (A) Nanoparticles modified with CPPs; (B) poly CPPs as the vector; (C) The CPPs-loaded nanoparticles; (D) Nanoparticle formed by the bounding of CPPs with positive charge to drugs and cargoes with the negative charge; (E) Nanoparticles formed when CPP coated the carriers. b represents CPPs in the figure. b, colored in purple in above figure panel stands for CPPs; blue color represents nanoparticle in panel A, chemical links in panel B, Drugs in panel C, negative charge drugs (e.g., siRNA, etc.) in panel D, and other carriers (e.g., viral vectors, etc.) in panel E.
Figure 4
Figure 4
The potential use of CPPs. CPPs has been widely used as modulators or vehicles for the delivery of various biological products into cells. In order to overcome the neutralization and aggregation of CPPs that result in the inability to cross the cell membrane, calcium can be used to improve the nucleic acid delivery. The nucleic acids could be assembled with the typical drug carrier (e.g., liposome, cationic peptide, polymer, viral carrier and nanoparticle), and then be further modified with CPPs, consequently dramatically enhancing the nucleic acid transferring efficiency.
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