Recent<i>in vivo</i>advances in cell-penetrating peptide-assisted drug delivery

Kurrikoff, Kaido; Gestin, Maxime; Langel, Ülo

doi:10.1517/17425247.2016.1125879

Cited by 118 publications

(99 citation statements)

References 77 publications

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“…Further, as of 2015, more than 100 peptide therapeutics were in clinical trials for wide spectrum of clinical conditions, a number that is expected to increase in the future (7). It has also been shown that cell-penetrating peptides (CPPs) and other peptide delivery vehicles may be used to deliver macromolecules such as oligonucleotide (8) and promising small molecules to their intracellular targets (9). Results like these combined with a vast available sequence space will continue to drive peptide-based biomedical research.…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial peptides are degraded by the cytosolic proteases of human erythrocytes

Starr¹,

Wimley²

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Well-studied and promising antimicrobial peptides (AMPs), with potent bactericidal activity, in vitro, have yet to have a significant impact in human medicine beyond topical applications. We previously showed that interactions of AMPs with concentrated human erythrocytes inhibit many of them, and suggested that screens and assays should be done in their presence to mimic host cell inhibition. Here, we use AMPs to characterize the activity of proteases that are associated with human erythrocytes. The representative AMPs, ARVA and indolicidin, are degraded significantly during incubation with dilute, washed erythrocytes and yield a variety of degradation products, suggesting significant exopeptidase activity. Comparison of these fragments with those obtained from incubation with serum shows that the proteolytic activity associated with cells yields unique products that are not explained by residual serum proteases. By separately testing the membrane and cytosolic fractions, we show that erythrocyte proteolytic activity is found only in the cytosol. Finally, we incubated a diverse cross-section of natural and synthetic linear AMPs with human erythrocyte cytosolic extracts and observed degradation of all of them. These results show that, in addition to cell binding, proteolysis can also contribute significantly to host cell inhibition of AMPs in vitro and possibly also in vivo.

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Section: Introductionmentioning

confidence: 99%

Antimicrobial peptides are degraded by the cytosolic proteases of human erythrocytes

Starr¹,

Wimley²

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…Among them, arginine-rich CPPs such as Tat peptide from a human immunodeficiency virus (HIV)-1 trans-activator protein TAT, [1][2][3] Penetratin peptide from a Drosophila homeodomain Antennapedia 4,5) and oligoarginines 6,7) show high efficiency of internalization, facilitating intracellular delivery of a wide range of hydrophilic molecules including small compounds, peptides, proteins, nucleic acids, nanoparticles, liposomes, and others that would be otherwise difficult to enter cells. [8][9][10] Arginine-rich CPPs have, therefore, attracted much attention as one of the promising carriers for intracellular delivery of therapeutic molecules including nucleic acids and drug candidates. [8][9][10] So far, a number of peptide sequences have been reported as CPPs, which are classified by their physicochemical characteristics, such as basic/amphiphilic CPPs that contain several basic amino acids including arginine and lysine, and hydrophobic CPPs (Table 1): interestingly, polyhistidine peptide such as histidine 16-mer (H16) is recently reported as CPPs.…”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10] Arginine-rich CPPs have, therefore, attracted much attention as one of the promising carriers for intracellular delivery of therapeutic molecules including nucleic acids and drug candidates. [8][9][10] So far, a number of peptide sequences have been reported as CPPs, which are classified by their physicochemical characteristics, such as basic/amphiphilic CPPs that contain several basic amino acids including arginine and lysine, and hydrophobic CPPs (Table 1): interestingly, polyhistidine peptide such as histidine 16-mer (H16) is recently reported as CPPs. 11) Although the molecular mechanisms as to how argininerich CPPs enter cells have not been fully understood and still remain debated, it is commonly accepted that internalization of these peptides involves endocytosis.…”

Section: Introductionmentioning

confidence: 99%

Current Understanding of Direct Translocation of Arginine-Rich Cell-Penetrating Peptides and Its Internalization Mechanisms

2016

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Arginine-rich cell-penetrating peptides (CPPs) including Tat, Penetratin and oligoarginine peptides are a series of short peptides that can be efficiently internalized into cells and have been widely used as carriers for intracellular delivery of bioactive molecules. In the early phase of the study, CPPs, as well as their conjugates, were thought to rapidly enter cells by direct penetration through membranes, which was later found to be an experimental artifact that was concluded from observations in fixed cells. Although re-evaluation using living unfixed cells revealed that endocytosis has a major role in internalization of these peptides, there are a number of studies reporting that, even if fixation is avoided, direct translocation across plasma membranes and cytosolic distribution of arginine-rich CPPs are still observed in cells without membrane perturbation. In addition, amphiphilic counteranions such as pyrenebutyrate dramatically accelerate direct translocation of these peptides into cells. These results suggest that there are at least two pathways, i.e., endocytosis and direct translocation, both of which would contribute to cellular internalization of arginine-rich CPPs. In this review, we first introduce the story of fixation artifact, which indeed led to the critical progress in CPP study, and then summarize the current understanding for direct translocation of arginine-rich CPPs. Comprehensive understanding of direct translocation of these peptides and its mechanistic elucidation would provide useful knowledge for developing methodologies that would enable efficient intracellular delivery.

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“…To address this need, a new approach employing ''cell-penetrating peptides (CPPs)'' for drug delivery seems promising (Kurrikoff et al, 2016). They have the ability to enter cells via an unsaturated pathway, either alone or in conjugation with small molecules or bulky cargo.…”

Section: Introductionmentioning

confidence: 99%

Thermosensitive magnetic liposomes with doxorubicin cell-penetrating peptides conjugate for enhanced and targeted cancer therapy

et al. 2016

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Institute of Pharmacology and Toxicology, Beijing, P.R. China AbstractTo specifically deliver cytotoxic drug to tumor cells and enhance cellular uptake is the key for effective cancer therapy. In this paper, we described a novel drug targeting system, which is designed to combine features of biological (cell-penetrating peptides, CPPs) and physical (magnetic) drug targeting for use in the magnetic hyperthermia-triggered release. A doxorubicin-CPPs conjugate (DOX-CPPs) was loaded into thermosensitive magnetic liposomes (TSMLs) (DOX-CPPs/TSMLs), and in vitro DOX-CPPs thermosensitive release activity, anti-proliferation effect, in vivo targeted delivery as well as in vivo antitumor activity were determined. The results demonstrated that the DOX-CPPs/TSMLs showed good physicochemical properties, effective anti-proliferation effect in MCF-7 cells in vitro. Additionally, in vivo study, DOX-CPPs/TSMLs under AC magnetic field displayed superior in vivo targeted delivery efficacy, antitumor efficacy in an MCF-7 xenograft murine model. In conclusion, the application of DOX-CPPs/TSMLs under AC magnetic field may provide a strategy for the selective and efficient delivery of drug.

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Recentin vivoadvances in cell-penetrating peptide-assisted drug delivery

Cited by 118 publications

References 77 publications

Antimicrobial peptides are degraded by the cytosolic proteases of human erythrocytes

Antimicrobial peptides are degraded by the cytosolic proteases of human erythrocytes

Current Understanding of Direct Translocation of Arginine-Rich Cell-Penetrating Peptides and Its Internalization Mechanisms

Thermosensitive magnetic liposomes with doxorubicin cell-penetrating peptides conjugate for enhanced and targeted cancer therapy

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