Pharmacokinetics, Biodistribution, Stability and Toxicity of a Cell-Penetrating Peptide−Morpholino Oligomer Conjugate

Amantana, Adams; Moulton, Hong M.; Cate, Melissa L.; Reddy, Muralimohan T.; Whitehead, Tom; Hassinger, Jed N.; Youngblood, Derek S.; Iversen, Patrick L.

doi:10.1021/bc070060v

Cited by 179 publications

(160 citation statements)

References 49 publications

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“…For instance, Tat and penetratin conjugated with the siRNA of p38 gene, inhaled by laboratory mice, caused a transient decrease in the expression of p38 MAP kinase gene, which was observed mainly in lung macrophages and adjacent pneumocytes [82]. In Sprague Dawley rats, after intravenous administration of RXR4 fusion peptide (X = 6-aminocaproic acid) was bound to PMO (phosphorodiamidate morpholino oligomer), a threshold below 15 mg/kg was established at which fusion CPP was not toxic, whereas the dose of 150 mg/kg was associated with adverse side effects such as lethargy, weight loss, and elevated serum creatinine [83].…”

Section: In Vivo Studies Of Cppsmentioning

confidence: 99%

Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells

Ruczyński

Wierzbicki²,

Kogut-Wierzbicka³

et al. 2015

Folia Histochem Cytobiol.

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Many biologically active compounds, including macromolecules that are used as various kinds of drugs, must be delivered to the interior of cell or organelles such as mitochondria or nuclei to achieve a therapeutic effect. However, very often, lipophilic cell membrane is impermeable for these molecules. A new method in the transport of macromolecules through the cell membrane is the one based on utilizing cell-penetrating peptides (CPPs). Invented 25 years ago, CPPs are currently the subject of intensive research in many laboratories all over the world. CPPs are short compounds comprising up to 30 amino acid residues, which penetrate the cell membrane but do not cause cell damage. Additionally, CPPs can transfer hydrophilic molecules (peptides, proteins, nucleic acids) which exceed their mass, and for which the cell membrane is generally impermeable. In this review, we concentrate on the cellular uptake mechanism of CPPs and a method of conjunction of CPPs to the transported molecules. We also highlight the potential of CPPs in delivering various kinds of macromolecules into cells, including compounds of therapeutic interest.

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Section: In Vivo Studies Of Cppsmentioning

confidence: 99%

Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells

Ruczyński

Wierzbicki²,

Kogut-Wierzbicka³

et al. 2015

Folia Histochem Cytobiol.

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“…CPPs can be taken up by living cells and can deliver different covalently coupled cargoes into cells both in vitro [2] or in vivo [3,4]. Among transport peptides penetratin [5], Tat-peptide [6], oligoarginine [7], and transportan (TP) [8] belong to the best characterized.…”

Section: Introductionmentioning

confidence: 99%

Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines

Wierzbicki

Kogut-Wierzbicka

Ruczyński

et al. 2015

Folia Histochem Cytobiol.

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Introduction. Cell penetrating peptides (CPPs) have the ability to translocate through cell membranes with high efficiency and therefore can introduce biological agents with pharmaceutical properties into the cell. Transportan (TP) and its shorter analog transportan 10 (TP10) are among the best studied CPPs, however, their effects on viability of and cargo introduction into colorectal cancer (CRC) cells have yet not been investigated. The aim of our study was to evaluate the cytotoxic effects of TP and TP10 on representative CRC lines and the efficiency of protein (streptavidin) and siRNA cargo delivery by TP-biotinylated derivatives (TP-biot). Material and methods. HT29 (early stage CRC model) and HCT116 (metastatic CRC model) cell lines were incubated with TP, TP10, TP-biot1, TP-biot13 and TP10-biot1. The effects of studied CPPs on cell viability and cell cycle were assessed by MTT and annexin V assays. The uptake of streptavidin-FITC complex into cells was determined by flow cytometry and fluorescence microscopy, with the inhibition of cellular vesicle trafficking by brefeldin A. The efficiency of siRNA for SASH1 gene delivery was measured by quantitative PCR (qPCR). Results. Since up to 10 µM concentrations of each CPP showed no significant cytotoxic effect, the concentrations of 0.5-5 µM were used for further analyses. Within this concentration range none of the studied CPPs affected cell viability and cell cycle. The efficient and endocytosis-independent introduction of streptavidin-FITC complex into cells was observed for TP10-biot1 and TP-biot1 with the cytoplasmic location of the fluorescent cargo; decreased SASH1 mRNA level was noticed with the use of siRNA and analyzed CPPs. Conclusions. We conclude that TP, TP10 and their biotinylated derivatives can be used as efficient delivery vehicles of small and large cargoes into CRC cells.

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“…Unlike CPP-PNA conjugates, the pharmaceutical properties of CPP-PMO conjugates have been evaluated in an extensive scope besides specific gene modulators (Amantana & et al, 2007). In general, the conjugation of CPP to PMO enhances the PMO pharmacokinetic profile, tissue uptake, and subsequent retention .…”

Section: Tissue Distribution Pharmacokinetics and Stabilitymentioning

confidence: 99%

“…CPP-PMO conjugates targeting bacterial essential genes have been evaluated to confirm their bacteriocidal antisense effect in several animal bacteremia models, and have proven to be efficacious with an excellent safety profile (Amantana & et al, 2007) within doeses for 100% survival 48h after treatment. They have also found that survival was significantly reduced for mice treated with 2×300 mg and 2×1 mg of the 11-base AcpP peptide-PMO, indicating toxicity at these high doses.…”

Section: Toxicitymentioning

confidence: 99%

Antisense Antibacterials: From Proof-Of-Concept to Therapeutic Perspectives

Bai¹,

Luo²

2012

A Search for Antibacterial Agents

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Pharmacokinetics, Biodistribution, Stability and Toxicity of a Cell-Penetrating Peptide−Morpholino Oligomer Conjugate

Abstract: This study demonstrates that conjugation of CPP to PMO enhances the PMO pharmacokinetic profile, tissue uptake, and subsequent retention. Therefore, when dosed at < or = 15 mg/kg, CPP is a promising transporter for enhancing PMO delivery in therapeutic settings.

Cited by 179 publications

References 49 publications

Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells

Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells

Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines

Antisense Antibacterials: From Proof-Of-Concept to Therapeutic Perspectives

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