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Pharmaceutics
Special Issues
Advances in Delivering Protein and Peptide Therapeutics
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Advances in Delivering Protein and Peptide Therapeutics

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (10 December 2021) | Viewed by 29871

Special Issue Editors

Dr. Evgenia G. Korzhikova-Vlakh

E-Mail Website
Guest Editor
1. Institute of Macromolecular Compounds, Russian Academy of Sciences, 199004 Saint-Petersburg, Russia
2. Institute of Chemistry, Saint-Petersburg State University, Universitetsky pr. 26, 198504 St. Petersburg, Russia
Interests: amphiphilic polymers; self-assembling; nanoparticles; biodegradation; drug delivery systems; proteins; peptides; DNA/RNA
Special Issues, Collections and Topics in MDPI journals
Dr. Ivan Guryanov

E-Mail Website
Guest Editor
1. Fresenius Kabi iPSUM, 23 Via San Leonardo, 45010 Villadose, RO, Italy
2. Institute of Chemistry, Saint-Petersburg State University, 26 Universitetsky Pr., 198504 St. Petersburg, Russia
Interests: synthesis of peptides and polyaminoacids for physicochemical and biomedical applications; gold nanoparticle functionalization; nanoparticle based drug delivery systems
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent achievements in peptide and protein synthesis and large-scale production have revealed the high potential of these compounds as selective and efficient drugs for the treatment of a number of diseases. Currently, proteins and peptides are widely considered as prospective biopharmaceutics or vaccines, and many of them are already available in clinics as oral, intravenous, subcutaneous, transdermal, and intranasal formulations. In spite of the many advantages of peptides and proteins as drugs, their wide application is limited because of some crucial obstacles. Among these, opsonization and proteolytic degradation severely affect their therapeutic efficiency. In turn, more frequent administration may cause many complications and undesirable side-effects. Moreover, the intracellular action of some peptide and protein drugs can be limited because of their poor penetration into the cell. The abovementioned problems can be overcome by different approaches such as conjugation of peptides/proteins with polymers, encapsulation/entrapment of biopharmaceutics into polymer particles, as well as application of special systems or/and vectors for intracellular delivery.

As Guest Editors, we invite researchers to submit to this Special Issue their valuable results and findings focused on conjugation, encapsulation, entrapment, preparation of novel formulations or other modifications to enhance stability of peptides/proteins and improve their therapeutic efficacy or intracellular delivery. Articles prepared as research papers, reviews or short communications are welcomed for publication.

Dr. Evgenia G. Korzhikova-Vlakh
Dr. Ivan Guryanov
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • peptides
  • proteins
  • delivery systems
  • conjugation
  • encapsulation
  • entrapment
  • novel formulations
  • intracellular delivery
  • oral delivery
  • parenteral delivery
  • nasal delivery
  • transdermal delivery
  • ocular delivery

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Published Papers (8 papers)

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Research

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14 pages, 3226 KiB  
Article
A New Approach to Supramolecular Structure Determination in Pharmaceutical Preparation of Self-Assembling Peptides: A Case Study of Lanreotide Autogel
by Manuela Grimaldi, Angelo Santoro, Michela Buonocore, Claudio Crivaro, Nicola Funicello, Matilde Sublimi Saponetti, Cristina Ripoli, Manuela Rodriquez, Salvatore De Pasquale, Fabrizio Bobba, Lucia Ferrazzano, Walter Cabri, Anna Maria D’Ursi and Antonio Ricci
Pharmaceutics 2022, 14(3), 681; https://doi.org/10.3390/pharmaceutics14030681 - 20 Mar 2022
Cited by 5 | Viewed by 3962
Abstract
The supramolecular structure in peptides’ prolonged-released gel formulations is the most critical parameter for the determination of the pharmaceutical profile of the drug. Here, we report our investigation on lanreotide Autogel as a case study. For the first time, we describe the use [...] Read more.
The supramolecular structure in peptides’ prolonged-released gel formulations is the most critical parameter for the determination of the pharmaceutical profile of the drug. Here, we report our investigation on lanreotide Autogel as a case study. For the first time, we describe the use of the pulsed field gradient (PFG) diffusion-ordered spectroscopy (DOSY) magic-angle spinning NMR to characterize the supramolecular self-assembly and molecular mobility of different samples of lanreotide Autogel formulations prepared according to different formulation protocols. The diffusion coefficient was used to calculate the hydrodynamic radii of supramolecular assemblies and build relative molecular models. DOSY data were integrated with NMR imaging (MRI) measurements and atomic force microscopy (AFM) imaging. Full article
(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics)
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16 pages, 5184 KiB  
Article
The Cysteine-Containing Cell-Penetrating Peptide AP Enables Efficient Macromolecule Delivery to T Cells and Controls Autoimmune Encephalomyelitis
by Won-Ju Kim, Gil-Ran Kim, Hyun-Jung Cho and Je-Min Choi
Pharmaceutics 2021, 13(8), 1134; https://doi.org/10.3390/pharmaceutics13081134 - 25 Jul 2021
Cited by 8 | Viewed by 2865
Abstract
T cells are key immune cells involved in the pathogenesis of several diseases, rendering them important therapeutic targets. Although drug delivery to T cells is the subject of continuous research, it remains challenging to deliver drugs to primary T cells. Here, we used [...] Read more.
T cells are key immune cells involved in the pathogenesis of several diseases, rendering them important therapeutic targets. Although drug delivery to T cells is the subject of continuous research, it remains challenging to deliver drugs to primary T cells. Here, we used a peptide-based drug delivery system, AP, which was previously developed as a transdermal delivery peptide, to modulate T cell function. We first identified that AP-conjugated enhanced green fluorescent protein (EGFP) was efficiently delivered to non-phagocytic human T cells. We also confirmed that a nine-amino acid sequence with one cysteine residue was the optimal sequence for protein delivery to T cells. Next, we identified the biodistribution of AP-dTomato protein in vivo after systemic administration, and transduced it to various tissues, such as the spleen, liver, intestines, and even to the brain across the blood–brain barrier. Next, to confirm AP-based T cell regulation, we synthesized the AP-conjugated cytoplasmic domain of CTLA-4, AP-ctCTLA-4 peptide. AP-ctCTLA-4 reduced IL-17A expression under Th17 differentiation conditions in vitro and ameliorated experimental autoimmune encephalomyelitis, with decreased numbers of pathogenic IL-17A+GM-CSF+ CD4 T cells. These results collectively suggest the AP peptide can be used for the successful intracellular regulation of T cell function, especially in the CNS. Full article
(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics)
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15 pages, 2941 KiB  
Article
Polyacrylate-GnRH Peptide Conjugate as an Oral Contraceptive Vaccine Candidate
by Mohammad O. Faruck, Prashamsa Koirala, Jieru Yang, Michael J. D’Occhio, Mariusz Skwarczynski and Istvan Toth
Pharmaceutics 2021, 13(7), 1081; https://doi.org/10.3390/pharmaceutics13071081 - 15 Jul 2021
Cited by 10 | Viewed by 4021
Abstract
Contraceptive vaccines are designed to elicit immune responses against major components of animal reproductive systems. These vaccines, which are most commonly administered via injection, typically target gonadotropin-releasing hormone (GnRH). However, the need to restrain animals for treatment limits the field applications of injectable [...] Read more.
Contraceptive vaccines are designed to elicit immune responses against major components of animal reproductive systems. These vaccines, which are most commonly administered via injection, typically target gonadotropin-releasing hormone (GnRH). However, the need to restrain animals for treatment limits the field applications of injectable vaccines. Oral administration would broaden vaccine applicability. We explored contraceptive vaccine candidates composed of GnRH peptide hormone, universal T helper PADRE (P), and a poly(methylacrylate) (PMA)-based delivery system. When self-assembled into nanoparticles, PMA-P-GnRH induced the production of high IgG titers after subcutaneous and oral administration in mice. PADRE was then replaced with pig T helper derived from the swine flu virus, and the vaccine was tested in pigs. High levels of systemic antibodies were produced in pigs after both injection and oral administration of the vaccine. In conclusion, we developed a simple peptide–polymer conjugate that shows promise as an effective, adjuvant-free, oral GnRH-based contraceptive vaccine. Full article
(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics)
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18 pages, 6064 KiB  
Article
Polymer Particles Bearing Recombinant LEL CD81 as Trapping Systems for Hepatitis C Virus
by Dmitry Polyakov, Ekaterina Sinitsyna, Natalia Grudinina, Mariia Antipchik, Rodion Sakhabeev, Viktor Korzhikov-Vlakh, Mikhail Shavlovsky, Evgenia Korzhikova-Vlakh and Tatiana Tennikova
Pharmaceutics 2021, 13(5), 672; https://doi.org/10.3390/pharmaceutics13050672 - 7 May 2021
Cited by 8 | Viewed by 2099
Abstract
Hepatitis C is one of the most common social diseases in the world. The improvements in both the early diagnostics of the hepatitis C and the treatment of acute viremia caused by hepatitis C virus are undoubtedly an urgent task. In present work, [...] Read more.
Hepatitis C is one of the most common social diseases in the world. The improvements in both the early diagnostics of the hepatitis C and the treatment of acute viremia caused by hepatitis C virus are undoubtedly an urgent task. In present work, we offered the micro- and nanotraps for the capturing of HCV. As a capturing moiety, we designed and synthesized in E. coli a fusion protein consisting of large extracellular loop of CD81 receptor and streptavidin as spacing part. The obtained protein has been immobilized on the surface of PLA-based micro- and nanoparticles. The developed trapping systems were characterized in terms of their physico-chemical properties. In order to illustrate the ability of developed micro- and nanotraps to bind HCV, E2 core protein of HCV was synthesized as a fusion protein with GFP. Interaction of E2 protein and hepatitis C virus-mimicking particles with the developed trapping systems were testified by several methods. Full article
(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics)
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18 pages, 3980 KiB  
Article
Synthesis and In Vivo Evaluation of Insulin-Loaded Whey Beads as an Oral Peptide Delivery System
by Joanne Heade, Fiona McCartney, Miguel Chenlo, Olga Moreno Marro, Maja Severic, Robert Kent, Sinead B. Bleiel, Clara V. Alvarez, Brendan T. Griffin and David J. Brayden
Pharmaceutics 2021, 13(5), 656; https://doi.org/10.3390/pharmaceutics13050656 - 4 May 2021
Cited by 4 | Viewed by 3266
Abstract
For many diabetics, daily, lifelong insulin injections are required to effectively manage blood glucose levels and the complications associated with the disease. This can be a burden and reduces patient quality of life. Our goal was to develop a more convenient oral delivery [...] Read more.
For many diabetics, daily, lifelong insulin injections are required to effectively manage blood glucose levels and the complications associated with the disease. This can be a burden and reduces patient quality of life. Our goal was to develop a more convenient oral delivery system that may be suitable for insulin and other peptides. Insulin was entrapped in 1.5-mm beads made from denatured whey protein isolate (dWPI) using gelation. Beads were then air-dried with fumed silica, Aerosil®. The encapsulation efficiency was ~61% and the insulin loading was ~25 µg/mg. Dissolution in simulated gastric-, and simulated intestinal fluids (SGF, SIF) showed that ~50% of the insulin was released from beads in SGF, followed by an additional ~10% release in SIF. The omission of Aerosil® allowed greater insulin release, suggesting that it formed a barrier on the bead surface. Circular dichroism analysis of bead-released insulin revealed an unaltered secondary structure, and insulin bioactivity was retained in HepG2 cells transfected to assess activation of the endogenous insulin receptors. Insulin-entrapped beads were found to provide partial protection against pancreatin for at least 60 min. A prototype bead construct was then synthesised using an encapsulator system and tested in vivo using a rat intestinal instillation bioassay. It was found that 50 IU/kg of entrapped insulin reduced plasma glucose levels by 55% in 60 min, similar to that induced by subcutaneously (s.c.)-administered insulin (1 IU/kg). The instilled insulin-entrapped beads produced a relative bioavailability of 2.2%. In conclusion, when optimised, dWPI-based beads may have potential as an oral peptide delivery system. Full article
(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics)
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20 pages, 4997 KiB  
Article
Polypeptide Self-Assembled Nanoparticles as Delivery Systems for Polymyxins B and E
by Dmitrii Iudin, Natalia Zashikhina, Elena Demyanova, Viktor Korzhikov-Vlakh, Elena Shcherbakova, Roman Boroznjak, Irina Tarasenko, Natalya Zakharova, Antonina Lavrentieva, Yury Skorik and Evgenia Korzhikova-Vlakh
Pharmaceutics 2020, 12(9), 868; https://doi.org/10.3390/pharmaceutics12090868 - 11 Sep 2020
Cited by 23 | Viewed by 3979
Abstract
Polymyxins are peptide antibiotics that are highly efficient against many multidrug resistant pathogens. However, the poor stability of polymyxins in the bloodstream requires the administration of high drug doses that, in turn, can lead to polymyxin toxicity. Consequently, different delivery systems have been [...] Read more.
Polymyxins are peptide antibiotics that are highly efficient against many multidrug resistant pathogens. However, the poor stability of polymyxins in the bloodstream requires the administration of high drug doses that, in turn, can lead to polymyxin toxicity. Consequently, different delivery systems have been considered for polymyxins to overcome these obstacles. In this work, we report the development of polymyxin delivery systems based on nanoparticles obtained from the self-assembly of amphiphilic random poly(l-glutamic acid-co-d-phenylalanine). These P(Glu-co-dPhe) nanoparticles were characterized in terms of their size, surface charge, stability, cytotoxicity, and uptake by macrophages. The encapsulation efficiency and drug loading into P(Glu-co-dPhe) nanoparticles were determined for both polymyxin B and E. The release kinetics of polymyxins B and E from nanoformulations was studied and compared in buffer solution and human blood plasma. The release mechanisms were analyzed using a number of mathematical models. The minimal inhibitory concentrations of the nanoformulations were established and compared with those determined for the free antibiotics. Full article
(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics)
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Review

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22 pages, 20222 KiB  
Review
Bacteria from Infectious Particles to Cell Based Anticancer Targeted Drug Delivery Systems
by Mounir M. Salem-Bekhit, Abdullah M. E. Youssof, Fars K. Alanazi, Fadilah Sfouq Aleanizy, Alsuwyeh Abdulaziz, Ehab I. Taha and Amro Abd Al Fattah Amara
Pharmaceutics 2021, 13(12), 1984; https://doi.org/10.3390/pharmaceutics13121984 - 23 Nov 2021
Cited by 8 | Viewed by 3615
Abstract
Bacterial ghosts (BGs) are empty cell envelopes of nonliving evacuated bacterial cells. They are free from their cytoplasmic contents; however, they sustain their cellular 3D morphology and antigenic structures, counting on bioadhesive properties. Lately, they have been tested as an advanced drug delivery [...] Read more.
Bacterial ghosts (BGs) are empty cell envelopes of nonliving evacuated bacterial cells. They are free from their cytoplasmic contents; however, they sustain their cellular 3D morphology and antigenic structures, counting on bioadhesive properties. Lately, they have been tested as an advanced drug delivery system (DDS) for different materials like DNA, peptides, or drugs, either single components or combinations. Different studies have revealed that, BG DDS were paid the greatest attention in recent years. The current review explores the impact of BGs on the field of drug delivery and drug targeting. BGs have a varied area of applications, including vaccine and tumor therapy. Moreover, the use of BGs, their synthesis, their uniqueness as a delivery system and application principles in cancer are discussed. Furthermore, the safety issues of BGs and stability aspects of using ghost bacteria as delivery systems are discussed. Future perspective efforts that must be followed for this important system to continue to grow are important and promising. Full article
(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics)
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16 pages, 4948 KiB  
Review
Peptide Inhibitors of Vascular Endothelial Growth Factor A: Current Situation and Perspectives
by Ivan Guryanov, Tatiana Tennikova and Arto Urtti
Pharmaceutics 2021, 13(9), 1337; https://doi.org/10.3390/pharmaceutics13091337 - 26 Aug 2021
Cited by 16 | Viewed by 3636
Abstract
Vascular endothelial growth factors (VEGFs) are the family of extracellular signaling proteins involved in the processes of angiogenesis. VEGFA overexpression and altered regulation of VEGFA signaling pathways lead to pathological angiogenesis, which contributes to the progression of various diseases, such as age-related macular [...] Read more.
Vascular endothelial growth factors (VEGFs) are the family of extracellular signaling proteins involved in the processes of angiogenesis. VEGFA overexpression and altered regulation of VEGFA signaling pathways lead to pathological angiogenesis, which contributes to the progression of various diseases, such as age-related macular degeneration and cancer. Monoclonal antibodies and decoy receptors have been extensively used in the anti-angiogenic therapies for the neutralization of VEGFA. However, multiple side effects, solubility and aggregation issues, and the involvement of compensatory VEGFA-independent pro-angiogenic mechanisms limit the use of the existing VEGFA inhibitors. Short chemically synthesized VEGFA binding peptides are a promising alternative to these full-length proteins. In this review, we summarize anti-VEGFA peptides identified so far and discuss the molecular basis of their inhibitory activity to highlight their pharmacological potential as anti-angiogenic drugs. Full article
(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics)
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