Cell-penetrating peptides for the delivery of nucleic acids

doi:10.1517/17425247.2012.689285

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Cell-penetrating peptides for the delivery of nucleic acids

Journal Article•DOI•

Cell-penetrating peptides for the delivery of nucleic acids

Taavi Lehto¹, Kaido Kurrikoff¹, Ülo Langel¹•Institutions (1)

University of Tartu¹

20 Jun 2012-Expert Opinion on Drug Delivery (Expert Opin Drug Deliv)-Vol. 9, Iss: 7, pp 823-836

TL;DR: This review will discuss recent advances of CPP-mediated delivery of nucleic acid-based cargo, concentrating on the delivery of plasmid DNA, splice-correcting ONs, and small-interfering RNAs.

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Abstract: Introduction: Different gene therapy approaches have gained extensive interest lately and, after many initial hurdles, several promising approaches have reached to the clinics. Successful implementation of gene therapy is heavily relying on finding efficient measures to deliver genetic material to cells. Recently, non-viral delivery of nucleic acids and their analogs has gained significant interest. Among non-viral vectors, cell-penetrating peptides (CPPs) have been extensively used for the delivery of nucleic acids both in vitro and in vivo. Areas covered: In this review we will discuss recent advances of CPP-mediated delivery of nucleic acid-based cargo, concentrating on the delivery of plasmid DNA, splice-correcting ONs, and small-interfering RNAs. Expert opinion: CPPs have proved their potential as carriers for nucleic acids. However, similarly to other non-viral vectors, CPPs require further development, as efficient systemic delivery is still seldom achieved. To achieve this, CPPs should be modified...

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Journal Article•DOI•

Cell-penetrating peptides: 20 years later, where do we stand?

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Cherine Bechara¹, Sandrine Sagan¹•Institutions (1)

Centre national de la recherche scientifique¹

19 Jun 2013-FEBS Letters

TL;DR: This review is dedicated to CPP fundamentals, with an emphasis on the molecular requirements and mechanism of their entry into eukaryotic cells.

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783 citations

Cites background from "Cell-penetrating peptides for the d..."

...nanoparticles [18], peptides [18,19], proteins [20,21], antisense oligonucleotides [20,22], small interfering RNA [23], double stranded DNA [18] and liposomes [18]....
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Journal Article•DOI•

Cell-Penetrating Peptides : Design, Synthesis, and Applications

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Dana Copolovici¹, Kent Langel¹, Elo Eriste¹, Ülo Langel¹, Ülo Langel² - Show less +1 more•Institutions (2)

University of Tartu¹, Stockholm University²

28 Feb 2014-ACS Nano

TL;DR: The intrinsic property of cell-penetrating peptides to deliver therapeutic molecules to cells and tissues in a nontoxic manner has indicated that they may be potential components of future drugs and disease diagnostic agents.

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Abstract: The intrinsic property of cell-penetrating peptides (CPPs) to deliver therapeutic molecules (nucleic acids, drugs, imaging agents) to cells and tissues in a nontoxic manner has indicated that they may be potential components of future drugs and disease diagnostic agents. These versatile peptides are simple to synthesize, functionalize, and characterize yet are able to deliver covalently or noncovalently conjugated bioactive cargos (from small chemical drugs to large plasmid DNA) inside cells, primarily via endocytosis, in order to obtain high levels of gene expression, gene silencing, or tumor targeting. Typically, CPPs are often passive and nonselective yet must be functionalized or chemically modified to create effective delivery vectors that succeed in targeting specific cells or tissues. Furthermore, the design of clinically effective systemic delivery systems requires the same amount of attention to detail in both design of the delivered cargo and the cell-penetrating peptide used to deliver it.

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751 citations

Cites background from "Cell-penetrating peptides for the d..."

...Therefore, the induction of dystrophin expression in cardiac muscle is critical for DMD treatment.186 Using the same arginine-rich peptide B covalently attached to PMO, the efficient PPMO-mediated exon-skipping therapy in DMD patients was demonstrated for the first time to improve treatment for cardiac hypertrophy and diastolic dysfunction.187 Stearoyl-(RxR)4 mediated the delivery of oligonucleotides in both in vitro and in vivo models for DMD.53,188 A stable solid formulation of a chemicallymodified TP10-basedCPP, PepFect14, and a splice-correcting oligonucleotide that is highly soluble in water was demonstrated to have efficient activity in mdx mouse myotubes, a model for DMD.23 Stroke Treatment....
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...Stearoyl-(RxR)4 mediated the delivery of oligonucleotides in both in vitro and in vivo models for DMD.(53,188) A stable solid formulation of a...
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Journal Article•DOI•

The delivery of therapeutic oligonucleotides.

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Rudolph L. Juliano¹•Institutions (1)

University of North Carolina at Chapel Hill¹

19 Aug 2016-Nucleic Acids Research

TL;DR: A variety of current approaches for enhancing the delivery of oligonucleotides including molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugate and small molecules that improve oligon nucleotide delivery are examined.

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Abstract: The oligonucleotide therapeutics field has seen remarkable progress over the last few years with the approval of the first antisense drug and with promising developments in late stage clinical trials using siRNA or splice switching oligonucleotides. However, effective delivery of oligonucleotides to their intracellular sites of action remains a major issue. This review will describe the biological basis of oligonucleotide delivery including the nature of various tissue barriers and the mechanisms of cellular uptake and intracellular trafficking of oligonucleotides. It will then examine a variety of current approaches for enhancing the delivery of oligonucleotides. This includes molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugates and small molecules that improve oligonucleotide delivery. The merits and liabilities of these approaches will be discussed in the context of the underlying basic biology.

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609 citations

Cites background from "Cell-penetrating peptides for the d..."

...CPPs have been extensively studied for oligonucleotide delivery (74,206)....
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Journal Article•DOI•

Non viral vectors in gene therapy- an overview.

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Murali Ramamoorth, Aparna Narvekar

01 Jan 2015-Journal of clinical and diagnostic research : JCDR

TL;DR: This review will see in detail about various types of non-viral vectors highlighting promising development and recent advances that had improved the non-Viral gene transfer efficiency of translating from "Bench to bedside".

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Abstract: Non-viral vectors are simple in theory but complex in practice. Apart from intra cellular and extracellular barriers, number of other challenges also needs to be overcome in order to increase the effectiveness of non-viral gene transfer. These barriers are categorized as production, formulation and storage. No one-size-fits-all solution to gene delivery, which is why in spite of various developments in liposome, polymer formulation and optimization, new compounds are constantly being proposed and investigated. In this review, we will see in detail about various types of non-viral vectors highlighting promising development and recent advances that had improved the non-viral gene transfer efficiency of translating from "Bench to bedside".

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556 citations

Journal Article•DOI•

Cellular Uptake of Nanoparticles versus Small Molecules: A Matter of Size.

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Jesús Mosquera, Isabel García, Luis M. Liz-Marzán¹•Institutions (1)

Ikerbasque¹

29 Aug 2018-Accounts of Chemical Research

TL;DR: Particular attention is paid to approaches that allow conditional regulation of the cell internalization process using external triggers, such as activable cell penetrating peptides, due to the impact these systems may have in drug delivery and sensing applications.

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Abstract: ConspectusThe primary function of the cell membrane is to protect cells from their surroundings. This entails a strict regulation on controlling the exchange of matter between the cell and its environment. A key factor when considering potential biological applications of a particular chemical structure has to do with its ability to internalize into cells. Molecules that can readily cross cell membranes are frequently needed in biological research and medicine, since most therapeutic entities are designed to modulate intracellular components. However, the design of molecules that do not penetrate cells is also relevant toward, for example, extracellular contrast agents, which are most widely used in clinical diagnosis.Small molecules have occupied the forefront of biomedical research until recently, but the past few decades have seen an increasing use of larger chemical structures, such as proteins or nanoparticles, leading to unprecedented and often unexpectedly novel research. Great achievements have be...

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239 citations

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References

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Open Access

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Journal Article•DOI•

Nanoparticle therapeutics: an emerging treatment modality for cancer

[...]

Mark E. Davis¹, Zhuo Georgia Chen², Dong M. Shin²•Institutions (2)

California Institute of Technology¹, Emory University²

01 Sep 2008-Nature Reviews Drug Discovery

TL;DR: The features of nanoparticle therapeutics that distinguish them from previous anticancer therapies are highlighted, and how these features provide the potential for therapeutic effects that are not achievable with other modalities are described.

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Abstract: Nanoparticles — particles in the size range 1–100 nm — are emerging as a class of therapeutics for cancer. Early clinical results suggest that nanoparticle therapeutics can show enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumours and active cellular uptake. Here, we highlight the features of nanoparticle therapeutics that distinguish them from previous anticancer therapies, and describe how these features provide the potential for therapeutic effects that are not achievable with other modalities. While large numbers of preclinical studies have been published, the emphasis here is placed on preclinical and clinical studies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with cancer.

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3,975 citations

"Cell-penetrating peptides for the d..." refers background in this paper

...For example, the size of the nanoparticles reduces their clearance by the kidneys and condensation into the nanoparticle offers better protection to nucleic acids from the degradation [90]....
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Journal Article•DOI•

Knocking down barriers: advances in siRNA delivery

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Kathryn A. Whitehead¹, Robert Langer¹, Daniel G. Anderson¹•Institutions (1)

Massachusetts Institute of Technology¹

01 Feb 2009-Nature Reviews Drug Discovery

TL;DR: An update on the progress of RNAi therapeutics is provided and novel synthetic materials for the encapsulation and intracellular delivery of nucleic acids are highlighted.

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Abstract: In the 10 years that have passed since the Nobel prize-winning discovery of RNA interference (RNAi), billions of dollars have been invested in the therapeutic application of gene silencing in humans. Today, there are promising data from ongoing clinical trials for the treatment of age-related macular degeneration and respiratory syncytial virus. Despite these early successes, however, the widespread use of RNAi therapeutics for disease prevention and treatment requires the development of clinically suitable, safe and effective drug delivery vehicles. Here, we provide an update on the progress of RNAi therapeutics and highlight novel synthetic materials for the encapsulation and intracellular delivery of nucleic acids.

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2,710 citations

Journal Article•DOI•

A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus

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Eric Vivès¹, Priscille Brodin¹, Bernard Lebleu¹•Institutions (1)

Centre national de la recherche scientifique¹

20 Jun 1997-Journal of Biological Chemistry

TL;DR: The main determinants required for Tat translocation within this sequence are delineated by synthesizing several peptides covering the Tat domain from residues 37 to 60 and the domain extending from amino acid 37 to 47, which corresponds to the α-helix structure, is not required for cellular uptake and for nuclear translocation.

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2,459 citations

"Cell-penetrating peptides for the d..." refers methods in this paper

...Transportan GWTLNSAGYLLGKINLKALAALAKKIL-NH2 Chimeric [95] TP10 AGYLLGKINLKALAALAKKIL-NH2 Chimeric [96] MPG GALFLGWLGAAGSTMGAPKKKRKV-cya Chimeric [38] Pep-1 KETWWETWWTEWSQPKKKRKV-cya Chimeric [97] Penetratin RQIKIWFQNRRMKWKK Protein derived [85] MAP KLALKLALKALKAALKLA-NH2 Synthetic [98] CADY GLWRALWRLLRSLWRLLWRA-cya Synthetic [81] Tat (48-60) GRKKRRQRRRPPQ Protein derived [99] Oligoarginine (R)n Synthetic [27]...
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Journal Article•DOI•

Design and development of polymers for gene delivery

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Daniel W. Pack¹, Allan S. Hoffman², Suzie H. Pun², Patrick S. Stayton²•Institutions (2)

University of Illinois at Urbana–Champaign¹, University of Washington²

01 Jul 2005-Nature Reviews Drug Discovery

TL;DR: With the growing understanding of polymer gene-delivery mechanisms and continued efforts of creative polymer chemists, it is likely that polymer-based gene-Delivery systems will become an important tool for human gene therapy.

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Abstract: The lack of safe and efficient gene-delivery methods is a limiting obstacle to human gene therapy. Synthetic gene-delivery agents, although safer than recombinant viruses, generally do not possess the required efficacy. In recent years, a variety of effective polymers have been designed specifically for gene delivery, and much has been learned about their structure–function relationships. With the growing understanding of polymer gene-delivery mechanisms and continued efforts of creative polymer chemists, it is likely that polymer-based gene-delivery systems will become an important tool for human gene therapy.

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2,361 citations

"Cell-penetrating peptides for the d..." refers background in this paper

...Thirdly, several important general in vitro characteristics play role in intracellular delivery, such as stability in the transfection media, including in the presence of serum, association with membrane, and cellular internalization, endosomal escape, cytoplasmic trafficking, nuclear internalization, if necessary, dissociation of the nanoparticles before or at the site of action of the cargo, either in the cytoplasm or nucleus (for extensive reviews see Refs [5,86,87])....
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...Non-viral vectors are usually based on different cationic entities, for example different lipids, synthetic polymers or peptides [5]....
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Journal Article•DOI•

The third helix of the Antennapedia homeodomain translocates through biological membranes

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D Derossi¹, Anne Joliot¹, Gérard Chassaing¹, Alain Prochiantz¹•Institutions (1)

Centre national de la recherche scientifique¹

08 Apr 1994-Journal of Biological Chemistry

TL;DR: It is reported here that a polypeptide of 16 amino acids in length corresponding to the third helix of the homeodomain deleted of its N-terminal glutamate is still capable of translocating through the membrane, suggesting an energy-independent mechanism of translocation not involving classical endocytosis.

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2,149 citations

"Cell-penetrating peptides for the d..." refers methods in this paper

...CPPs have been successfully utilized for the delivery of nucleic acids since their discovery in 1994 [85]....
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...Transportan GWTLNSAGYLLGKINLKALAALAKKIL-NH2 Chimeric [95] TP10 AGYLLGKINLKALAALAKKIL-NH2 Chimeric [96] MPG GALFLGWLGAAGSTMGAPKKKRKV-cya Chimeric [38] Pep-1 KETWWETWWTEWSQPKKKRKV-cya Chimeric [97] Penetratin RQIKIWFQNRRMKWKK Protein derived [85] MAP KLALKLALKALKAALKLA-NH2 Synthetic [98] CADY GLWRALWRLLRSLWRLLWRA-cya Synthetic [81] Tat (48-60) GRKKRRQRRRPPQ Protein derived [99] Oligoarginine (R)n Synthetic [27]...
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