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  • 1.
    Cerrato, Carmine Pasquale
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Künnapuu, Kadri
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Cell-penetrating peptides with intracellular organelle targeting2017In: Expert Opinion on Drug Delivery, ISSN 1742-5247, E-ISSN 1744-7593, Vol. 14, no 2, p. 245-255Article, review/survey (Refereed)
    Abstract [en]

    INTRODUCTION: One of the major limiting steps in order to have an effective drug is the passage through one or more cell membranes to reach its site of action. To reach the action-site, the specific macromolecules are required to be delivered specifically to the cell compartment/organelle in their (pre)active form.

    AREAS COVERED: In this review, we will discuss cell-penetrating peptides (CPPs) developed in the last decade to transport small RNA/DNA, plasmids, antibodies, and nanoparticles into specific sites of the cell. The article describes CPPs in complex with cargo molecules that target specific intracellular organelles and their potential for pharmacological or clinical use.

    EXPERT OPINION: Organelle targeting is the ultimate goal to ensure selective delivery to the site of action in the cells. CPP technologies represent an important strategy to address drug delivery to specific intracellular compartments by covalent conjugation to targeting sequences, potentially enabling strategies to combat genomic diseases as well as infections, cancer, neurodegenerative and hereditary diseases. They have proven to be successful in delivering various therapeutic agents into cells however, further in vivo experiments and clinical trials are required to demonstrate the efficacy of this technology.

  • 2. Cerrato, Carmine Pasquale
    et al.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Tartu, Estonia.
    An update on cell-penetrating peptides with intracellular organelle targeting2022In: Expert Opinion on Drug Delivery, ISSN 1742-5247, E-ISSN 1744-7593, Vol. 19, no 2, p. 133-146Article, review/survey (Refereed)
    Abstract [en]

    Introduction Cell-penetrating peptide (CPP) technologies represent an important strategy to address drug delivery to specific intracellular compartments by covalent conjugation to targeting sequences, potentially enabling strategies to combat most diseases.

    Areas covered This updated review article provides an overview of current intracellular organelle targeting by CPP. The targeting strategies of CPP and CPP/cargo complexes to specific cells or intracellular organelles are summarized, and the review provides an update on the current data for their pharmacological and therapeutical applications.

    Expert opinion Targeted drug delivery is moving from the level of tissue or specific pathogenic cell to the level of specific organelle that is the target of the drug, an important aspect in drug design and development. Organelle-targeted drug delivery results in improved efficacy, ability to control mode of action, reduction of undesired toxicities and side effects, and the possibility to overcome drug resistance mechanisms.

  • 3. Kurrikoff, Kaido
    et al.
    Gestin, Maxime
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Recent in vivo advances in cell-penetrating peptide-assisted drug delivery2016In: Expert Opinion on Drug Delivery, ISSN 1742-5247, E-ISSN 1744-7593, Vol. 13, no 3, p. 373-387Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Delivery of macromolecular drugs is an important field in medical research. However, macromolecules are usually unable to cross the cell membrane without the assistance of a delivery system. Cell penetrating peptides (CPPs) are unique tools to gain access to the cell interior and deliver a bioactive cargo into the cytosol or nucleus. In addition to macromolecular delivery, CPPs have been used to deliver smaller bioactive molecules. Therefore CPPs have become an intensive field of research for medical treatment.

    Areas covered: In this review, we highlight studies that include CPP in vivo disease models. We review different strategies and approaches that have been used, with specific attention on recent publications. The approaches that have been used include CPP–cargo covalent conjugation strategies and nanoparticle strategies. Various additional strategies have been used to achieve disease targeting, including active targeting, passive targeting, and combined active/passive strategies. As a result, delivery of various types of molecule has been achieved, including small drug molecules, proteins and nucleic acid-based macromolecules (e.g. siRNA, antisense nucleotides and plasmid DNA).

    Expert Opinion: Despite recent advances in the field, confusions surrounding CPP internalization mechanisms and intracellular trafficking are hindering the development of new and more efficient vectors. Nevertheless, the recent increase in the number of publications containing in vivo CPP utilization looks promising that the number of clinical trials would also increase in the near future.

  • 4. Kurrikoff, Kaido
    et al.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Tartu, Estonia.
    Recent CPP-based applications in medicine2019In: Expert Opinion on Drug Delivery, ISSN 1742-5247, E-ISSN 1744-7593, Vol. 16, no 11, p. 1183-1191Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Cell-penetrating peptides (CPP) offer versatile tools for the field of drug delivery and development of macromolecular therapeutics. These tools have matured into applications that allow the use of proteins, nucleic acid, peptides, imaging agents, and low molecular weight drugs as therapeutic entities.

    Areas covered: The progress of the field is discussed in the current review, with the examples from a recent couple of years, in the utilization of CPPs in medicine. Specific focus is on the research articles that include applications that have direct translational value. Progress with protein mimicry and its recent leap in medicine is discussed with special attention, but also achievements with nanoformulation and drug targeting is presented.

    Expert opinion: The opinion section discusses some of the limitations and shortcomings, proposing the areas where more effort should be invested in order to increase the translational value of the current preclinical research.

  • 5. Lehto, Taavi
    et al.
    Kurrikoff, Kaido
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Cell-penetrating peptides for the delivery of nucleic acids2012In: Expert Opinion on Drug Delivery, ISSN 1742-5247, E-ISSN 1744-7593, Vol. 9, no 7, p. 823-836Article, review/survey (Refereed)
    Abstract [en]

    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 with entities that would allow better endosomal escape, targeting of specific tissues and cells, and shielding agents that increase the half-life of the vehicles. Finally, to understand the clinical potential of CPPs, they require more thorough investigations in clinically relevant disease models and in pre-clinical and clinical studies.

  • 6.
    Mäe, Maarja
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry. Karolinska Institutet, Sweden; University of Tartu, Estonia.
    EL Andaloussi, Samir
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Lehto, Taavi
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Chemically modified cell-penetrating peptides for the delivery of nucleic acids2009In: Expert Opinion on Drug Delivery, ISSN 1742-5247, E-ISSN 1744-7593, Vol. 6, no 11, p. 1195-1205Article in journal (Refereed)
    Abstract [en]

    Short nucleic acids targeting biologically important RNAs and plasmids have been shown to be promising future therapeutics; however, their hydrophilic nature greatly limits their utility in clinics and therefore efficient delivery vectors are greatly needed. Cell-penetrating peptides (CPPs) are relatively short amphipathic and/or cationic peptides that are able to transport various biologically active molecules inside mammalian cells, both in vitro and in vivo, in a seemingly non-toxic fashion. Although CPPs have proved to be appealing drug delivery vehicles, their major limitation in nucleic acid delivery is that most of the internalized peptide-cargo is entrapped in endosomal compartments following endocytosis and the bioavailability is therefore severely reduced. Several groups are working towards overcoming this obstacle and this review highlights the evidence that by introducing chemical modification in CPPs, the bioavailability of delivered nucleic acids increases significantly.

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