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Advanced Drug Delivery Reviews (v.60, #4-5)

Editorial Board (pp. ii).

Protein and peptide transduction, twenty years later a happy birthday by Alain Prochiantz (pp. 448-451).
This commentary underscores the following aspects of Cell Permeable Peptides/Transduction Peptides (CPP/PTD) research. First the discovery of CPP/PTD takes its origin in the observation that some full-length transcription factors navigate between cells. The latter physiological origin is of interest as the significance of this new mode of signal transduction is not yet fully understood. A second point is that most breakthroughs in the domain have been made possible by long lasting collaborations between biologists, chemists and physicists. It is beyond doubt that the understanding of the mechanisms of secretion and internalization, in parallel with the development of new transduction compounds, not only peptides, will require that such collaborative efforts be amplified. Finally, although the domain is flourishing and our minds full of hope, it must be said that many points need to be resolved before getting close to bedside. Among these points are bio-disponibility, toxicity and specific addressing to body regions, cell types and intracellular compartments. In brief, beyond this happy birthday, there is still plenty of home work!

Keywords: Cell penetrating peptide; Transduction peptides; Messenger proteins


The design of guanidinium-rich transporters and their internalization mechanisms by Paul A. Wender; Wesley C. Galliher; Elena A. Goun; Lisa R. Jones; Thomas H. Pillow (pp. 452-472).
The ability of a drug or probe to cross a biological barrier has historically been viewed to be a function of its intrinsic physical properties. This view has largely restricted drug design and selection to agents within a narrow log P range. Molecular transporters offer a strategy to circumvent these restrictions. In the case of guanidinium-rich transporters (GRTs), a typically highly water-soluble conjugate is found to readily pass through the non-polar membrane of a cell and for some across tissue barriers. This activity opens a field of opportunities for the use of GRTs to enable delivery of polar and non-polar drugs or probes as well as to enhance uptake of those of intermediate polarity. The field of transporter enabled or enhanced uptake has grown dramatically in the last decade. Some GRT drug conjugates have been advanced into clinical trials. This review will provide an overview of recent work pertinent to the design and mechanism of uptake of GRTs.

Keywords: Molecular transporters; Cell-penetrating peptides; Oligoarginine; Bidentate hydrogen bond; Endocytosis; Adaptive translocation; HIV Tat; Dendrimers; Drug delivery


Proline-rich, amphipathic cell-penetrating peptides by Sílvia Pujals; Ernest Giralt (pp. 473-484).
Proline-rich peptides are a chemically and structurally diverse family of cell-penetrating vectors characterised by the presence of pyrrolidine rings from prolines. Amphipathic Pro-rich peptides are particularly effective, demonstrating efficient cellular uptake and non-cytotoxicity. Derivatives with hydrophobic moieties, such as fatty acids or silaproline, have shown highly improved internalisation efficiency; an all D-amino acid version of the CPP SAP was shown to be completely protease resistant and was evaluated in a preliminary in vivo study. CD and TEM studies regarding the self-assembly properties of this family of peptides highlight the possible role of aggregated species in the internalisation process. Finally, these CPPs were shown to be internalised via caveolae or lipid-rafts mediated endocytosis, which circumvents the lysosomal route of degradation.

Keywords: Abbreviations; CD; circular dichroism; CF; carboxyfluorescein; CLSM; confocal laser scanning microscopy; CPP(s); cell-penetrating peptide(s); DOPC; dioleoylphosphatidylcholine; PPI; polyproline I; PPII; polyproline II; RES; reticuloendothelial system; SAP; sweet arrow peptide; TEM; transmission electron microscopyAmphipathic peptide(s); Cell-penetrating peptide(s); Drug delivery; Internalisation mechanism; in vivo; studies; Proline-rich peptides; Proteolytic resistance; Self-assembly; Sweet arrow peptide


Calcitonin-derived peptide carriers: Mechanisms and application by Robert Rennert; Ines Neundorf; Annette G. Beck-Sickinger (pp. 485-498).
Among the family of the so-called cell-penetrating peptides (CPP) sequences derived from the native peptide hormone human calcitonin (hCT) have recently proven to translocate different bioactive molecules across cellular membranes. Herein, we give an extensive summary of the development of hCT-derived carrier peptides, beginning with the therapeutic nasal administration of full-length hCT. Hence, N-terminally truncated hCT fragments were investigated and subsequently optimised to extend their field of application. The latest generation of hCT-derived carrier peptides are highly effective, branched peptides. The current state of the art is reviewed concerning the structural requirements, mechanistic assumptions and metabolic features of these peptides as well as experiments proving their excellent carrier potential.

Keywords: Cell-penetrating peptides; Cell transfection; Cellular delivery; Human calcitonin; Metabolic stability; Uptake mechanism


PTD-mediated delivery of anti-cell death proteins/peptides and therapeutic enzymes by Sadamitsu Asoh; Shigeo Ohta (pp. 499-516).
Millions of unnecessary cells are removed from our body everyday by apoptosis to ensure our survivals. Apoptosis is a highly coordinated process. Failure in apoptotic regulation results in disease. A large number of studies have demonstrated that accelerated apoptosis is involved in degenerative diseases, ischemic injuries, immunodeficiency and infertility. These studies have also revealed the molecular mechanisms of apoptosis signal transduction to provide therapeutic targets. On the other hand, protein transduction technology has been developed to deliver full-length proteins to various tissues including the brain. So far, many studies have shown that in vivo delivery of therapeutic proteins/peptides, including anti-apoptotic proteins, an anti-oxidant enzyme, a neuroprotectant, enzymes involved in purine or tyrosine metabolism, caspase inhibitors, c-Jun N-terminal kinase inhibitors and an NF-κB inhibitor, by protein transduction technology mitigates various diseases in animal models.

Keywords: Apoptosis; Bcl-2 family; Enzyme replacement; Ischemia/reperfusion injury; Necrosis; Neurodegenerative diseases; Peptide inhibitors; Protein therapy


Cell penetrating peptide conjugates of steric block oligonucleotides by Bernard Lebleu; Hong M. Moulton; Rachida Abes; Gabriela D. Ivanova; Said Abes; David A. Stein; Patrick L. Iversen; Andrey A. Arzumanov; Michael J. Gait (pp. 517-529).
Charge neutral steric block oligonucleotide analogues, such as peptide nucleic acids (PNA) or phosphorodiamidate morpholino oligomers (PMO), have promising biological and pharmacological properties for antisense applications, such as for example in mRNA splicing redirection. However, cellular uptake of free oligomers is poor and the utility of conjugates of PNA or PMO to cell penetrating peptides (CPP), such as Tat or Penetratin, is limited by endosomal sequestration. Two new families of arginine-rich CPPs named (R-Ahx-R)4 AhxB and R6Pen allow efficient nuclear delivery of splice correcting PNA and PMO at micromolar concentrations in the absence of endosomolytic agents. The in vivo efficacy of (R-Ahx-R)4 AhxB PMO conjugates has been demonstrated in mouse models of Duchenne muscular dystrophy and in various viral infections.

Keywords: CPP; PNA; PMO; Splicing modulation; Nuclear delivery; Bioavailability


Enhancing the cellular uptake of siRNA duplexes following noncovalent packaging with protein transduction domain peptides by Bryan R. Meade; Steven F. Dowdy (pp. 530-536).
The major limitation in utilizing information rich macromolecules for basic science and therapeutic applications is the inability of these large molecules to readily diffuse across the cellular membrane. While this restriction represents an efficient defense system against cellular penetration of unwanted foreign molecules and thus a crucial component of cell survival, overcoming this cellular characteristic for the intracellular delivery of macromolecules has been the focus of a large number of research groups worldwide. Recently, with the discovery of RNA interference, many of these groups have redirected their attention and have applied previously characterized cell delivery methodologies to synthetic short interfering RNA duplexes (siRNA). Protein transduction domain and cell penetrating peptides have been shown to enhance the delivery of multiple types of macromolecular cargo including peptides, proteins and antisense oligonucleotides and are now being utilized to enhance the cellular uptake of siRNA molecules. The dense cationic charge of these peptides that is critical for interaction with cell membrane components prior to internalization has also been shown to readily package siRNA molecules into stable nanoparticles that are capable of traversing the cell membrane. This review discusses the recent advances in noncovalent packaging of siRNA molecules with cationic peptides and the potential for the resulting complexes to successfully induce RNA interference within both in vitro and in vivo settings.

Keywords: RNA interference; Peptide transduction domain; Cell penetrating peptide; siRNA delivery; Macromolecular delivery; HIV-1 TAT peptide


Delivery of proteins and nucleic acids using a non-covalent peptide-based strategy by Sébastien Deshayes; May Morris; Frédéric Heitz; Gilles Divita (pp. 537-547).
The recent discovery of new potent therapeutic molecules which do not reach the clinic due to poor delivery and low bioavailability have made of delivery a key stone in therapeutic development. Several technologies have been designed to improve cellular uptake of therapeutic molecules, including cell-penetrating peptides (CPPs), which have been successfully applied for in vivo delivery of biomolecules and constitute very promising tools. Distinct families of CPPs have been described; some require chemical linkage between the drug and the carrier for cellular drug internalization while others like Pep-and MPG-families, form stable complexes with drugs depending on their chemical nature. Pep and MPG are short amphipathic peptides, which form stable nanoparticles with proteins and nucleic acids respectively. MPG and Pep based nanoparticles enter cells independently of the endosomal pathway and efficiently deliver cargoes in a fully biologically active form into a large variety of cell lines as well as in animal models . This review will focus on the mechanisms of non-covalent MPG and Pep-1 strategies and their applications in cultured cells and animal models.

Keywords: Cell-penetrating peptide; siRNA; DNA-mimics; Drug delivery; Nanoparticle; Non-covalent delivery system


Tat peptide-mediated intracellular delivery of pharmaceutical nanocarriers by Vladimir P. Torchilin (pp. 548-558).
Cell-penetrating peptides (CPPs) including TAT peptide (TATp) have been successfully used for intracellular delivery of a broad variety of cargoes including various nanoparticulate pharmaceutical carriers (liposomes, micelles, nanoparticles). Here, we will consider the main results in this area, with a special emphasis on TATp-mediated delivery of liposomes and DNA. We will also address the development of “smart” stimuli-sensitive nanocarriers, where cell-penetrating function can be activated by the decreased pH only inside the biological target minimizing thus the interaction of drug-loaded nanocarriers with non-target cells.

Keywords: Cell-penetrating peptides; TAT peptide; Pharmaceutical nanocarriers; Liposomes; DNA; Intracellular delivery


Multifunctional envelope-type nano device (MEND) as a non-viral gene delivery system by Kentaro Kogure; Hidetaka Akita; Yuma Yamada; Hideyoshi Harashima (pp. 559-571).
In this review, we describe a key role of octaarginine (R8) in developing our new concept of “Programmed Packaging”, by which we succeeded in creating a multifunctional envelope-type nano device (MEND) as a non-viral gene-delivery system. This concept can be applied not only to nuclear targeting of plasmid DNA (pDNA) but also to cytosolic delivery of functional nucleic acids such as oligonucleotides or siRNA. This concept has been extended to other organelles such as mitochondria as a foundation for innovative nanomedicine. Finally, we discuss the rate-limiting step in gene delivery by comparing non-viral and viral gene delivery systems, which clearly indicates the importance of nuclear disposition of pDNA for efficient transfection.

Keywords: Abbreviations; Bmpr1a; bone morphogenetic protein receptor type 1 A; CAR; coxsackie and adenovirus receptor; CHEMS; cholesteryl hemisuccinate; Chol; cholesterol; CIDIQ; Confocal image-assisted 3-dimensionally integrative quantification; CPP; cell-penetrating peptide; CW; cell wall; DCs; dendritic cells; DOPE; dioleoylphosphatidylethanolamine; EPC; egg phosphatidylcholine; GFP; green fluorescent protein; HIV-1; human immunodeficiency virus; HSPGs; heparan sulfate proteoglycans; IL-12; interleukin-12; LA2000; LipofectAmine2000; LFN; lipofectamine PLUS; MEND; multifunctional envelope-type nano device; mtDNA; mitochondrial DNA; MTS; mitochondrial targeting signal peptide; N/P; nitrogen/phosphate; NBD; 4-nitrobenzo-2-oxa-1,3-diazolyl; NLS; nuclear localization signal; ODN; oligodeoxynucleotide; ODN-MEND; ODN-encapsulated R8-MEND; pDNA; plasmid DNA; PLL; poly-L-lysine; PTD; protein transduction domain; R7W; R7 modified with a tryptophan residue in the C-terminus; R8; octaarginine; R8-Lipo; R8-modified liposomes; R8-Lipo-HD; liposomes modified with high density R8; R8-Lipo-HD-E; empty R8-Lipo-HD; R8-Lipo-LD; liposomes modified with low density R8; R8-Lipo-LD-R; R8-Lipo-LD containing a rhodamine aqueous phase; R8-MEND; MEND modified with high-density R8 peptide; siRNA; short interfering RNA; siRNA-MEND; siRNA-encapsulated R8-MEND; S-Rho; Sulfo-Rhodamine; STR-R8; stearylated R8; TAT-mMDH-GFP; TAT fusion protein that consisted of an MTS derived from mitochondrial malate dehydrogenase and green fluorescent protein.Octaarginine; Gene delivery; Nanoparticle; Membrane fusion; Nuclear deposition; Multifunctional; Nano device; Programmed packaging; MEND; siRNA


Predicting cell-penetrating peptides by Mats Hansen; Kalle Kilk; Ülo Langel (pp. 572-579).
Possibility to predict short peptide sequences capable to penetrate the plasma membrane opens new opportunities for developing peptide based intracellular delivery vectors, called cell-penetrating peptides (CPPs). Predictions of CPPs, however are often based on trial and error and may not always lead to new potent sequences. In this review we discuss different problems associated with CPP prediction. Additionally, the used methods of CPP prediction are compared. Also, a few suggestions are made for designing new CPP sequences and improvement of predictions.

Keywords: Cell-Penetrating peptide; Cellular uptake; Prediction; Classification; Multivariate analysis; Bioinformatics; QSAR


Thermodynamic studies and binding mechanisms of cell-penetrating peptides with lipids and glycosaminoglycans by André Ziegler (pp. 580-597).
Cell-penetrating peptides (CPPs) traverse the membrane of biological cells at low micromolar concentrations and are able to take various cargo molecules along with. Despite large differences in their chemical structure, CPPs share the structural similarity of a high cationic charge density. This property confers to them the ability to bind electrostatically membrane constituents such as anionic lipids and glycosaminoglycans (GAGs). Controversies exist, however, about the biological response after the interaction of CPPs with such membrane constituents. Present review compares thermodynamic binding studies with conditions of the biological CPP uptake. It becomes evident that CPPs enter biological cells by different and probably competing mechanisms. For example, some amphipathic CPPs traverse pure lipid model membranes at low micromolar concentrations — at least in the absence of cargos. In contrast, no direct translocation at these conditions is observed for non-amphipathic CPPs. Finally, CPPs bind GAGs at low micromolar concentrations with potential consequences for endocytotic pathways.

Keywords: Carrier proteins; Cell-penetrating peptides; Genetic vectors; Gene therapy; Endocytosis; Lipid bilayers; Lipofectants; Permeability; Polyamines; Proteoglycans; Transfection


Methodological and cellular aspects that govern the internalization mechanisms of arginine-rich cell-penetrating peptides by Ikuhiko Nakase; Toshihide Takeuchi; Gen Tanaka; Shiroh Futaki (pp. 598-607).
Peptides including HIV-1 Tat peptide and oligoarginines represent arginine-rich membrane-permeable vectors that attain efficient intracellular delivery of bioactive molecules. The importance of the arginine residues or their guanidino functions is now appreciated for efficient internalization of the Tat peptide, and based on this, various novel arginine/guanidino-rich vectors have now been developed. However, molecular detail of their method(s) of internalization are still debated. This review summarizes our current understandings of endocytic and non-endocytic aspects of internalization of arginine-rich peptide vectors. We highlight the possibility of simultaneous employment of multiple internalization pathways, the contribution of which is dependent on a number of factors. Similarities and dissimilarities among the internalization methods of typical peptide vectors and other guanidino-rich vectors including branched-chain, β-peptide, and sugar-based vectors, are also discussed.

Keywords: Arginine-rich peptide; Membrane-permeable peptide; Endocytosis; Macropinocytosis; Membrane translocation; Non-endocytic uptake; Counter anion


Homeoproteins as natural Penetratin cargoes with signaling properties by Alain Joliot; Alain Prochiantz (pp. 608-613).
Most of this volume is dedicated to a very important and pragmatic issue which is to design ways of internalizing active pharmacological compounds into cells. In fact, many vectors have now been developed and the improvement in the technology can be seen on two main fronts. A first one is the identification of extremely efficient cargoes, for example siRNAs, which can enter the cells once attached to the vectors. A second one is the development of chemical vectors designed after the properties of the peptides and of tags allowing in vivo addressing to specific organs, for example the brain, cell types or sub-cellular compartments.This chapter is of a different nature, as it is devoted to the physiological significance of protein transduction and to the comparative analysis of the Penetratin PTD with its parental proteins, the homeoproteins. Although very academic, these two issues are of practical interest for the rational design of new vectors and the identification of unforeseen pathological mechanisms and pharmacological targets.

Keywords: Homeoproteins; PTD; CPP; Translocation; Compartmentalization; Signal transduction; Messenger proteins; Morphogens
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