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Open accessJournal ArticleDOI: 10.1080/14712598.2021.1823368

Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics.

04 Mar 2021-Expert Opinion on Biological Therapy (Expert Opin Biol Ther)-Vol. 21, Iss: 3, pp 361-370
Abstract: In this review, recent developments and applications with cell-penetrating peptides (CPP) are discussed. CPPs are widely used tools for the delivery of various macromolecular therapeutics, such as ...

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Topics: Drug delivery (52%)

16 results found

Open accessJournal ArticleDOI: 10.3390/BIOMEDICINES9040416
12 Apr 2021-Biomedicines
Abstract: Antisense technologies consist of the utilization of oligonucleotides or oligonucleotide analogs to interfere with undesirable biological processes, commonly through inhibition of expression of selected genes. This field holds a lot of promise for the treatment of a very diverse group of diseases including viral and bacterial infections, genetic disorders, and cancer. To date, drugs approved for utilization in clinics or in clinical trials target diseases other than bacterial infections. Although several groups and companies are working on different strategies, the application of antisense technologies to prokaryotes still lags with respect to those that target other human diseases. In those cases where the focus is on bacterial pathogens, a subset of the research is dedicated to produce antisense compounds that silence or reduce expression of antibiotic resistance genes. Therefore, these compounds will be adjuvants administered with the antibiotic to which they reduce resistance levels. A varied group of oligonucleotide analogs like phosphorothioate or phosphorodiamidate morpholino residues, as well as peptide nucleic acids, locked nucleic acids and bridge nucleic acids, the latter two in gapmer configuration, have been utilized to reduce resistance levels. The major mechanisms of inhibition include eliciting cleavage of the target mRNA by the host’s RNase H or RNase P, and steric hindrance. The different approaches targeting resistance to β-lactams include carbapenems, aminoglycosides, chloramphenicol, macrolides, and fluoroquinolones. The purpose of this short review is to summarize the attempts to develop antisense compounds that inhibit expression of resistance to antibiotics.

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Topics: Oligonucleotide (53%), Gene silencing (50%)

4 Citations

Journal ArticleDOI: 10.1021/ACS.BIOCONJCHEM.0C00659
Ben Woods1, Rúben D M Silva2, Claudia Schmidt3, Darren Wragg3  +8 moreInstitutions (5)
Abstract: The biomedical application of discrete supramolecular metal-based structures, specifically self-assembled metallacages, is still an emergent field of study. Capitalizing on the knowledge gained in recent years on the development of 3-dimensional (3D) metallacages as novel drug delivery systems and theranostic agents, we explore here the possibility to target [Pd2L4]4+ cages (L = 3,5-bis(3-ethynylpyridine)phenyl ligand) to the brain. In detail, a new water-soluble homoleptic cage (CPepH3) tethered to a blood brain barrier (BBB)-translocating peptide was synthesized by a combination of solid-phase peptide synthesis (SPPS) and self-assembly procedures. The cage translocation efficacy was assessed by inductively coupled mass spectrometry (ICP-MS) in a BBB cellular model in vitro. Biodistribution studies of the radiolabeled cage [[99mTcO4]- ⊂ CPepH3] in the CD1 mice model demonstrate its brain penetration properties in vivo. Further DFT studies were conducted to model the structure of the [[99mTcO4]- ⊂ cage] complex. Moreover, the encapsulation capabilities and stability of the cage were investigated using the [ReO4]- anion, the "cold" analogue of [99mTcO4]-, by 1H NMR spectroscopy. Overall, our study constitutes another proof-of-concept of the unique potential of supramolecular coordination complexes for modifying the physiochemical and biodistribution properties of diagnostic species.

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3 Citations

Journal ArticleDOI: 10.1016/J.IJPHARM.2021.120317
Abstract: Glucagon-like peptide-1 (GLP-1) receptor agonists are being increasingly exploited in clinical practice for management of type 2 diabetes mellitus due to their ability to lower blood glucose levels and reduce off-target effects of current therapeutics. Nanomaterials had viewed myriad breakthroughs in protecting peptides against degradation and carrying therapeutics to targeted sites for maximizing their pharmacological activity and overcoming limitations associated with their application. This review highlights the latest advances in designing smart multifunctional nanoconstructs and engineering targeted and stimuli-responsive nanoassemblies for delivery of GLP-1 receptor agonists. Furthermore, advanced nanoconstructs of sophisticated supramolecular assembly yet efficient delivery of GLP-1/GLP-1 analogs, nanodevices that mediate intrinsic GLP-1 secretion per se, and nanomaterials with capabilities to load additional moieties for synergistic antidiabetic effects, are demonstrated.

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3 Citations

Journal ArticleDOI: 10.1021/ACSABM.1C00601
16 Aug 2021-
Abstract: Cell-penetrating peptides (CPPs) are a topical subject potentially exploitable for creating nanotherapeutics for the delivery of bioactive loads. These compounds are often classified into three major categories according to their physicochemical characteristics: cationic, amphiphilic, and hydrophobic. Among them, the group of hydrophobic CPPs has received increasing attention in recent years due to toxicity concerns posed by highly cationic CPPs. The hexapeptide PFVYLI (P, proline; F, phenylalanine; V, valine; Y, tyrosine; L, leucine; and I, isoleucine), a fragment derived from the C-terminal portion of α1-antitrypsin, is a prototypal example of hydrophobic CPP. This sequence shows reduced cytotoxicity and a capacity of nuclear localization, and its small size readily hints at its suitability as a building block to construct nanostructured materials. In this study, we examine the self-assembling properties of PFVYLI and investigate its ability to form noncovalent complexes with nucleic acids. By using a combination of biophysical tools including synchrotron small-angle X-ray scattering and atomic force microscopy-based infrared spectroscopy, we discovered that this CPP self-assembles into discrete nanofibrils with remarkable amyloidogenic features. Over the course of days, these fibrils coalesce into rodlike crystals that easily reach the micrometer range. Despite lacking cationic residues in the composition, PFVYLI forms noncovalent complexes with nucleic acids that retain β-sheet pairing found in amyloid aggregates. In vitro vectorization experiments performed with double-stranded DNA fragments indicate that complexes promote the internalization of nucleic acids, revealing that tropism toward cell membranes is preserved upon complexation. On the other hand, transfection assays with splice-correction oligonucleotides (SCOs) for luciferase expression show limited bioactivity across a narrow concentration window, suggesting that the propensity to form amyloidogenic aggregates may trigger endosomal entrapment. We anticipate that the findings presented here open perspectives for using this archetypical hydrophobic CPP in the fabrication of nanostructured scaffolds, which potentially integrate properties of amyloids and translocation capabilities of CPPs.

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Topics: Nucleic acid (53%), Cell-penetrating peptide (50%)

2 Citations

Open accessJournal ArticleDOI: 10.1016/J.MEDIDD.2021.100092
Martin Matijass1, Ines Neundorf1Institutions (1)
01 Jun 2021-
Abstract: Peptides have gained more and more interest as therapeutics for different fields of medical indications. Built up via a peptide bond from naturally occurring amino acids they stand out by their high target selectivity and good biocompatibility. However, using chemical peptide synthesis also modifications are easily introduced and offer various opportunities to fine-tune their activity spectrum. One of the main areas of the global peptide market is oncology and during the past years, many peptide therapeutics with anti-tumor activity have been reported that evoke metastasis in malignant cells or evasion of cell death. Cell-penetrating peptides (CPPs) are a particular group of bioactive peptides that can be naturally or synthetically derived and have the ability to autonomously translocate in cells and transport various cargoes with them. These versatile carriers have been widely used to deliver different kinds of therapeutic molecules, and have also found application in cancer research. Within this review we will summarize recent efforts made in this direction with a focus on the specific cancer indications for which CPP-related therapeutics have been developed and studied.

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1 Citations


53 results found

Journal ArticleDOI: 10.1016/0092-8674(88)90263-2
Alan D. Frankel1, Carl O. Pabo1Institutions (1)
23 Dec 1988-Cell
Abstract: While developing an assay to measure the activity of the tat protein from human immunodeficiency virus 1 (HIV-1), we discovered that the purified protein could be taken up by cells growing in tissue culture and subsequently trans-activate the viral promoter. Trans-activation is dramatically increased by a variety of lysosomotrophic agents. For example, trans-activation can be detected at tat concentrations as low as 1 nM in the presence of chloroquine. Experiments using radioactive protein show that tat becomes localized to the nucleus after uptake and suggest that chloroquine protects tat from proteolytic degradation. These results raise the possibility that, under some conditions, tat might act as a viral growth factor to stimulate viral replication in latently infected cells or alter expression of cellular genes.

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Topics: Viral replication (53%), Cell culture (52%), Virus (50%)

2,582 Citations

Open accessJournal ArticleDOI: 10.1073/PNAS.0408191101
Tao Jiang1, Emilia S. Olson, Quyen T. Nguyen, Melinda Roy  +2 moreInstitutions (1)
Abstract: We have devised and tested a new strategy for selectively delivering molecules to tumor cells. Cellular association of polyarginine-based, cell-penetrating peptides (CPPs) is effectively blocked when they are fused to an inhibitory domain made up of negatively charged residues. We call these fusions activatable CPPs (ACPPs) because cleavage of the linker between the polycationic and polyanionic domains, typically by a protease, releases the CPP portion and its attached cargo to bind to and enter cells. Association with cultured cells typically increases 10-fold or more upon linker cleavage. In mice xenografted with human tumor cells secreting matrix metalloproteinases 2 and 9, ACPPs bearing a far-red-fluorescent cargo show in vivo contrast ratios of 2-3 and a 3.1-fold increase in standard uptake value for tumors relative to contralateral normal tissue or control peptides with scrambled linkers. Ex vivo slices of freshly resected human squamous cell carcinomas give similar or better contrast ratios. Because CPPs are known to import a wide variety of nonoptical contrast and therapeutic agents, ACPPs offer a general strategy toward imaging and treating disease processes associated with linker-cleaving activities such as extracellular proteases.

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769 Citations

Open accessJournal ArticleDOI: 10.1093/NAR/GKQ1299
Abstract: While small interfering RNAs (siRNAs) have been rapidly appreciated to silence genes, efficient and non-toxic vectors for primary cells and for systemic in vivo delivery are lacking. Several siRNA-delivery vehicles, including cell-penetrating peptides (CPPs), have been developed but their utility is often restricted by entrapment following endocytosis. Hence, developing CPPs that promote endosomal escape is a prerequisite for successful siRNA implementation. We here present a novel CPP, PepFect 6 (PF6), comprising the previously reported stearyl-TP10 peptide, having pH titratable trifluoromethylquinoline moieties covalently incorporated to facilitate endosomal release. Stable PF6/siRNA nanoparticles enter entire cell populations and rapidly promote endosomal escape, resulting in robust RNAi responses in various cell types (including primary cells), with minimal associated transcriptomic or proteomic changes. Furthermore, PF6-mediated delivery is independent of cell confluence and, in most cases, not significantly hampered by serum proteins. Finally, these nanoparticles promote strong RNAi responses in different organs following systemic delivery in mice without any associated toxicity. Strikingly, similar knockdown in liver is achieved by PF6/siRNA nanoparticles and siRNA injected by hydrodynamic infusion, a golden standard technique for liver transfection. These results imply that the peptide, in addition to having utility for RNAi screens in vitro, displays therapeutic potential.

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Topics: Small interfering RNA (55%), Transfection (51%)

265 Citations

Journal ArticleDOI: 10.1517/17425247.2012.689285
Taavi Lehto1, Kaido Kurrikoff1, Ülo Langel1Institutions (1)
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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Topics: Cell-penetrating peptide (55%), Gene delivery (52%)

122 Citations

Open accessJournal ArticleDOI: 10.1016/J.JCONREL.2015.04.038
Abstract: Gene therapy has great potential to treat a range of different diseases, such as cancer. For that therapeutic gene can be inserted into a plasmid vector and delivered specifically to tumor cells. The most frequently used applications utilize lipoplex and polyplex approaches where DNA is non-covalently condensed into nanoparticles. However, lack of in vivo efficacy is the major concern that hinders translation of such gene therapeutic applications into clinics. In this work we introduce a novel method for in vivo delivery of plasmid DNA (pDNA) and efficient tumor-specific gene induction using intravenous (i.v) administration route. To achieve this, we utilize a cell penetrating peptide (CPP), PepFect14 (PF14), double functionalized with polyethylene glycol (PEG) and a matrix metalloprotease (MMP) substrate. We show that this delivery vector effectively forms nanoparticles, where the condensed CPP and pDNA are shielded by the PEG, in an MMP-reversible manner. Administration of the complexes results in efficient induction of gene expression specifically in tumors, avoiding normal tissues. This strategy is a potent gene delivery platform that can be used for tumor-specific induction of a therapeutic gene.

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Topics: Gene delivery (66%), Drug delivery (56%), PEGylation (52%) ... show more

92 Citations

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