Cell penetrating peptides fail to induce an innate immune response in epithelial cells in vitro: Implications for continued therapeutic use

Carter, Edward; Lau, Chun Yin; Tosh, David; Ward, Stephen G.; Mrsny, Randall J.

doi:10.1016/j.ejpb.2013.03.024

Cited by 30 publications

(17 citation statements)

References 27 publications

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“…It was found that both in vivo and in vitro, all peptides were shown to be nontoxic and nonimmunogenic at concentrations of 5 and 10 mM and potentially without the risk of inflammatory reactions (Suhorutsenko et al, 2011). Moreover, in another study, it was determined that three of the most commonly used CPPs-HIV Tat , anntennapedia, and transportan-linked to a model bovine serum albumin protein cargo failed to induce a significant increase in the release of the inflammatory cytokines or activate nuclear factor kB in epithelial cells in vitro (Carter et al, 2013).…”

Section: Cpps and Host Immune Responsementioning

confidence: 99%

Viral and Other Cell-Penetrating Peptides as Vectors of Therapeutic Agents in Medicine

Durzyńska

Przysiecka

Nawrot

et al. 2015

J Pharmacol Exp Ther

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Efficient delivery of heterologous molecules for treatment of cells is a great challenge in modern medicine and pharmacology. Cellpenetrating peptides (CPPs) may improve efficient delivery of a wide range of macromolecular cargos, including plasmid DNA, small interfering RNA, drugs, nanoparticulate pharmaceutical carriers, and anticancer drugs. In this paper, we present the history of CPPs' discovery with special attention drawn to sequences of viral origin. We also describe different CPP families with regard to their physicochemical properties and numerous mechanisms of CPP cell uptake by direct penetration and endocytotic pathways. A detailed description is focused on formation of carrier-cargo complexes, which are needed for practical use of CPPs in medicine and biotechnology. Examples of successful application of CPPs in treatment of human diseases are also presented, including decreased tumor growth and induction of cancer cell death. Finally, we review modern design approaches to novel CPPs and prediction of their activity. To sum up, the current review presents a thorough and up-to-date knowledge of CPPs and may be a valuable source of information for researchers in pharmacology designing new therapeutic agents.

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Section: Cpps and Host Immune Responsementioning

confidence: 99%

Viral and Other Cell-Penetrating Peptides as Vectors of Therapeutic Agents in Medicine

Durzyńska

Przysiecka

Nawrot

et al. 2015

J Pharmacol Exp Ther

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“…Furthermore, they failed to induce an innate immune response, as no activation of phosphorylated NFjB, a signalling molecule downstream of toll-like receptors was observed [71]. Likewise, no secretion of epithelial-specific interleukins IL-6 and IL-8 was detected [71]. Similar results were seen after incubation of TAT fusion proteins with peripheral blood mononuclear cell lines both in vitro and in vivo [72].…”

Section: Discussionmentioning

confidence: 65%

“…The TAT fusion protein successfully internalized the cells without altering their viability. Furthermore, they failed to induce an innate immune response, as no activation of phosphorylated NFjB, a signalling molecule downstream of toll-like receptors was observed [71]. Likewise, no secretion of epithelial-specific interleukins IL-6 and IL-8 was detected [71].…”

Section: Discussionmentioning

confidence: 99%

TAT‐MTS‐MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM‐deficient cells

Erlich

Hadad

Feldman

et al. 2017

J Cellular Molecular Medi

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Methylmalonic aciduria (MMA) is a disorder of organic acid metabolism resulting from a functional defect of the mitochondrial enzyme, methylmalonyl‐CoA mutase (MCM). The main treatments for MMA patients are dietary restriction of propiogenic amino acids and carnitine supplementation. Liver or combined liver/kidney transplantation has been used to treat those with the most severe clinical manifestations. Thus, therapies are necessary to help improve quality of life and prevent liver, renal and neurological complications. Previously, we successfully used the TAT‐MTS‐Protein approach for replacing a number of mitochondrial‐mutated proteins. In this targeted system, TAT, an 11 a.a peptide, which rapidly and efficiently can cross biological membranes, is fused to a mitochondrial targeting sequence (MTS), followed by the mitochondrial mature protein which sends the protein into the mitochondria. In the mitochondria, the TAT‐MTS is cleaved off and the native protein integrates into its natural complexes and is fully functional. In this study, we used heterologous MTSs of human, nuclear‐encoded mitochondrial proteins, to target the human MCM protein into the mitochondria. All fusion proteins reached the mitochondria and successfully underwent processing. Treatment of MMA patient fibroblasts with these fusion proteins restored mitochondrial activity such as ATP production, mitochondrial membrane potential and oxygen consumption, indicating the importance of mitochondrial function in this disease. Treatment with the fusion proteins enhanced cell viability and most importantly reduced MMA levels. Treatment also enhanced albumin and urea secretion in a CRISPR/Cas9‐engineered HepG2 MUT (‐/‐) liver cell line. Therefore, we suggest using this TAT‐MTS‐Protein approach for the treatment of MMA.

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“…Similarly, an in vitro study reported more recently by Carter et al showed that HIV-TAT, Antennapedia and TP failed to induce a significant increase in the release of the inflammatory cytokines IL8 and IL6 in epithelial cells. 70 The presence and origin of cargo molecules in CPP-cargo conjugates also influences toxicity and may exert a different effect from that produced by the peptide alone. Research has indicated that toxic effects may be derived from conjugation of different cargoes to CPPs.…”

Section: Toxicity and Immunogenicitymentioning

confidence: 99%

Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers

Kebebe¹,

Liu²,

Wu³

et al. 2018

IJN

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Cancer has become one of the leading causes of mortality globally. The major challenges of conventional cancer therapy are the failure of most chemotherapeutic agents to accumulate selectively in tumor cells and their severe systemic side effects. In the past three decades, a number of drug delivery approaches have been discovered to overwhelm the obstacles. Among these, nanocarriers have gained much attention for their excellent and efficient drug delivery systems to improve specific tissue/organ/cell targeting. In order to enhance targeting efficiency further and reduce limitations of nanocarriers, nanoparticle surfaces are functionalized with different ligands. Several kinds of ligand-modified nanomedicines have been reported. Cell-penetrating peptides (CPPs) are promising ligands, attracting the attention of researchers due to their efficiency to transport bioactive molecules intracellularly. However, their lack of specificity and in vivo degradation led to the development of newer types of CPP. Currently, activable CPP and tumor-targeting peptide (TTP)-modified nanocarriers have shown dramatically superior cellular specific uptake, cytotoxicity, and tumor growth inhibition. In this review, we discuss recent advances in tumor-targeting strategies using CPPs and their limitations in tumor delivery systems. Special emphasis is given to activable CPPs and TTPs. Finally, we address the application of CPPs and/or TTPs in the delivery of plant-derived chemotherapeutic agents.

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Cell penetrating peptides fail to induce an innate immune response in epithelial cells in vitro: Implications for continued therapeutic use

Cited by 30 publications

References 27 publications

Viral and Other Cell-Penetrating Peptides as Vectors of Therapeutic Agents in Medicine

Viral and Other Cell-Penetrating Peptides as Vectors of Therapeutic Agents in Medicine

TAT‐MTS‐MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM‐deficient cells

Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers

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