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Cell-Penetrating Peptides: A Promising Tool for Drug Delivery
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Cell-Penetrating Peptides: A Promising Tool for Drug Delivery

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 7230

Special Issue Editors

Prof. Dr. Keykavous Parang

E-Mail Website
Guest Editor
Center For Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, USA
Interests: peptides as cell-penetrating molecular transporters; drug delivery; protein kinase inhibitors; multifunctional antivirals; anticancer agents; antibacterial agents; peptide nanomaterials
Dr. Sandeep Lohan

E-Mail Website
Guest Editor
Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, USA
Interests: cell-penetrating peptides; antimicrobial peptides; macrocyclic peptides; molecular transporters; targeted drug delivery; siRNA delivery; non-viral gene delivery

Special Issue Information

Dear Colleagues,

The clinical success of any drug molecule mainly depends on its availability at the target site. Physiochemical properties, such as low solubility and/or large molecular size, result in poor pharmacokinetic properties, which eventually hampers their therapeutic applications. Cell-penetrating peptides (CPPs) are one of the potential categories that have been investigated to be used in drug delivery. CPPs are small peptides that contain 5-40 amino acid residues and have emerged as a powerful tool to overcome the plasma membrane barrier of many mammalian cells for the intracellular or transcellular delivery of a variety of cargos, including small molecule drugs, nanoparticles, liposomes, nucleic acids, peptides, and proteins. The unique section of CPPs, also known as protein transduction domains (PTDs), facilitates the cellular uptake of large biologically active molecules with minimum toxicity. Conjugation of CPP to chemotherapeutics has shown to be a powerful approach in the selective delivery of those agents directly into cancer cells and lowering the doses of chemotherapeutic agents that generate undesired side effects and even overcoming resistance mechanisms.

The aim of this Special Issue is to provide recent findings on using linear or cyclic CPPs, including those with natural or non-natural amino acids as drug delivery tools. A major focus will also be on using CPPs with cargo drugs in the physical mixture or conjugation for diagnostic and therapeutic applications. In this Special Issue, original research articles and reviews are welcome.

We look forward to receiving your contributions.

Prof. Dr. Keykavous Parang
Dr. Sandeep Lohan
Guest Editors

Manuscript Submission Information

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Keywords

  • cell-penetrating peptide
  • targeted drug delivery
  • protein delivery
  • small molecule delivery
  • mode of cell penetration

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Published Papers (5 papers)

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Research

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13 pages, 2464 KiB  
Article
In Vitro Study of Tumor-Homing Peptide-Modified Magnetic Nanoparticles for Magnetic Hyperthermia
by Shengli Zhou, Kaname Tsutsumiuchi, Ritsuko Imai, Yukiko Miki, Anna Kondo, Hiroshi Nakagawa, Kazunori Watanabe and Takashi Ohtsuki
Molecules 2024, 29(11), 2632; https://doi.org/10.3390/molecules29112632 - 3 Jun 2024
Viewed by 735
Abstract
Cancer cells have higher heat sensitivity compared to normal cells; therefore, hyperthermia is a promising approach for cancer therapy because of its ability to selectively kill cancer cells by heating them. However, the specific and rapid heating of tumor tissues remains challenging. This [...] Read more.
Cancer cells have higher heat sensitivity compared to normal cells; therefore, hyperthermia is a promising approach for cancer therapy because of its ability to selectively kill cancer cells by heating them. However, the specific and rapid heating of tumor tissues remains challenging. This study investigated the potential of magnetic nanoparticles (MNPs) modified with tumor-homing peptides (THPs), specifically PL1 and PL3, for tumor-specific magnetic hyperthermia therapy. The synthesis of THP-modified MNPs involved the attachment of PL1 and PL3 peptides to the surface of the MNPs, which facilitated enhanced tumor cell binding and internalization. Cell specificity studies revealed an increased uptake of PL1- and PL3-MNPs by tumor cells compared to unmodified MNPs, indicating their potential for targeted delivery. In vitro hyperthermia experiments demonstrated the efficacy of PL3-MNPs in inducing tumor cell death when exposed to an alternating magnetic field (AMF). Even without exposure to an AMF, an additional ferroptotic pathway was suggested to be mediated by the nanoparticles. Thus, this study suggests that THP-modified MNPs, particularly PL3-MNPs, hold promise as a targeted approach for tumor-specific magnetic hyperthermia therapy. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides: A Promising Tool for Drug Delivery)
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15 pages, 2833 KiB  
Article
Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates
by Joshua Grabeck, Tamara Lützenburg, Pia Frommelt and Ines Neundorf
Molecules 2022, 27(19), 6656; https://doi.org/10.3390/molecules27196656 - 7 Oct 2022
Cited by 3 | Viewed by 2299
Abstract
Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. [...] Read more.
Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. The effects of histidine substituents were found to be not meaningful for sC18 uptake and cell selectivity. Moreover, building a nearly perfect amphipathic structure within a shortened sC18 derivative provided a peptide that was highly membrane-active, but also too cytotoxic. As a result, the most promising analog was sC18ΔE, which stands out due to its higher uptake efficacy compared to parent sC18. In the last set of experiments, we let the peptides react with the cytotoxic drug doxorubicin by Thiol–Michael addition to form novel PDCs. Our results indicate that sC18ΔE could be a more efficient drug carrier than parent sC18 for biomedical applications. However, cellular uptake using endocytosis and resulting entrapment of cargo inside vesicles is still a major critical step to overcome in CPP-containing peptide-drug development. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides: A Promising Tool for Drug Delivery)
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Review

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14 pages, 965 KiB  
Review
Beyond Transduction: Anti-Inflammatory Effects of Cell Penetrating Peptides
by Jack Lopuszynski, Jingyu Wang and Maliha Zahid
Molecules 2024, 29(17), 4088; https://doi.org/10.3390/molecules29174088 - 29 Aug 2024
Viewed by 586
Abstract
One of the bottlenecks to bringing new therapies to the clinic has been a lack of vectors for delivering novel therapeutics in a targeted manner. Cell penetrating peptides (CPPs) have received a lot of attention and have been the subject of numerous developments [...] Read more.
One of the bottlenecks to bringing new therapies to the clinic has been a lack of vectors for delivering novel therapeutics in a targeted manner. Cell penetrating peptides (CPPs) have received a lot of attention and have been the subject of numerous developments since their identification nearly three decades ago. Known for their transduction abilities, they have generally been considered inert vectors. In this review, we present a schema for their classification, highlight what is known about their mechanism of transduction, and outline the existing literature as well as our own experience, vis a vis the intrinsic anti-inflammatory properties that certain CPPs exhibit. Given the inflammatory responses associated with viral vectors, CPPs represent a viable alternative to such vectors; furthermore, the anti-inflammatory properties of CPPs, mostly through inhibition of the NF-κB pathway, are encouraging. Much more work in relevant animal models, toxicity studies in large animal models, and ultimately human trials are needed before their potential is fully realized. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides: A Promising Tool for Drug Delivery)
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22 pages, 2922 KiB  
Review
Cell-Penetrating Peptide-Mediated Biomolecule Transportation in Artificial Lipid Vesicles and Living Cells
by Akari Miwa and Koki Kamiya
Molecules 2024, 29(14), 3339; https://doi.org/10.3390/molecules29143339 - 16 Jul 2024
Viewed by 976
Abstract
Signal transduction and homeostasis are regulated by complex protein interactions in the intracellular environment. Therefore, the transportation of impermeable macromolecules (nucleic acids, proteins, and drugs) that control protein interactions is essential for modulating cell functions and therapeutic applications. However, macromolecule transportation across the [...] Read more.
Signal transduction and homeostasis are regulated by complex protein interactions in the intracellular environment. Therefore, the transportation of impermeable macromolecules (nucleic acids, proteins, and drugs) that control protein interactions is essential for modulating cell functions and therapeutic applications. However, macromolecule transportation across the cell membrane is not easy because the cell membrane separates the intra/extracellular environments, and the types of molecular transportation are regulated by membrane proteins. Cell-penetrating peptides (CPPs) are expected to be carriers for molecular transport. CPPs can transport macromolecules into cells through endocytosis and direct translocation. The transport mechanism remains largely unclear owing to several possibilities. In this review, we describe the methods for investigating CPP conformation, translocation, and cargo transportation using artificial membranes. We also investigated biomolecular transport across living cell membranes via CPPs. Subsequently, we show not only the biochemical applications but also the synthetic biological applications of CPPs. Finally, recent progress in biomolecule and nanoparticle transportation via CPPs into specific tissues is described from the viewpoint of drug delivery. This review provides the opportunity to discuss the mechanism of biomolecule transportation through these two platforms. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides: A Promising Tool for Drug Delivery)
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16 pages, 997 KiB  
Review
Potential of Cell-Penetrating Peptide-Conjugated Antisense Oligonucleotides for the Treatment of SMA
by Jamie Leckie and Toshifumi Yokota
Molecules 2024, 29(11), 2658; https://doi.org/10.3390/molecules29112658 - 4 Jun 2024
Viewed by 1935
Abstract
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder that is caused by mutations in the survival motor neuron 1 (SMN1) gene, hindering the production of functional survival motor neuron (SMN) proteins. Antisense oligonucleotides (ASOs), a versatile DNA-like drug, are adept [...] Read more.
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder that is caused by mutations in the survival motor neuron 1 (SMN1) gene, hindering the production of functional survival motor neuron (SMN) proteins. Antisense oligonucleotides (ASOs), a versatile DNA-like drug, are adept at binding to target RNA to prevent translation or promote alternative splicing. Nusinersen is an FDA-approved ASO for the treatment of SMA. It effectively promotes alternative splicing in pre-mRNA transcribed from the SMN2 gene, an analog of the SMN1 gene, to produce a greater amount of full-length SMN protein, to compensate for the loss of functional protein translated from SMN1. Despite its efficacy in ameliorating SMA symptoms, the cellular uptake of these ASOs is suboptimal, and their inability to penetrate the CNS necessitates invasive lumbar punctures. Cell-penetrating peptides (CPPs), which can be conjugated to ASOs, represent a promising approach to improve the efficiency of these treatments for SMA and have the potential to transverse the blood–brain barrier to circumvent the need for intrusive intrathecal injections and their associated adverse effects. This review provides a comprehensive analysis of ASO therapies, their application for the treatment of SMA, and the encouraging potential of CPPs as delivery systems to improve ASO uptake and overall efficiency. Full article
(This article belongs to the Special Issue Cell-Penetrating Peptides: A Promising Tool for Drug Delivery)
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