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Pharmaceutics
Special Issues
Quantification of Therapeutic Peptides by LC-MS
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Quantification of Therapeutic Peptides by LC-MS

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

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 6974

Special Issue Editor

Prof. Dr. Sangkyu Lee

E-Mail Website
Guest Editor
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
Interests: proteomics; drug metabolism; mass spectrometry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

The development of new drugs in the form of peptide is drawing attention worldwide, and more than 150 drugs are being developed in various fields. Although the use of an analysis method based on a mass spectrometer is required to study the pharmacokinetics of the peptide, complex pretreatment procedures and special analysis conditions are required because of the physicochemical properties and extremely low blood concentration of peptides.

This Special Issue will describe the latest findings on mass based-peptide quantification technology, including peptide extraction in the biological matrix, strategy for selection of mobile phase or column, or peptide detection based on mass spectrometry. In addition, this will include the latest research results in mass spectrometry-based pharmacokinetic/metabolism studies of bioactive peptides or new formulation of therapeutic peptide on the market etc.  As a result, it aims to propose a new analysis technology that can be used in the development of new peptide therapeutics by collecting and sharing the latest research results on peptide analysis, based on mass spectrometry technology.

In this Special Issue, we invite manuscripts in the format of a research article or a review in the field of special techniques from extraction to quantification for LC-MS analysis of peptides therapeutics.

Prof. Dr. Sangkyu Lee
Guest Editor

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

  • pharmaceutical peptides
  • therapeutic peptides
  • mass spectrometry
  • pharmacokinetics
  • peptide metabolism

Published Papers (3 papers)

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Research

11 pages, 1049 KiB  
Article
Bioanalysis of the Ex Vivo Labile PACE4 Inhibitory Peptide Ac-[d-Leu]LLLRVK-Amba in Whole Blood Using Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Quantification
by Max Sauter, Jonas Haag, Cindy Bay, Florian Leuschner, Walter E. Haefeli, Tim Christian Kuhn and Jürgen Burhenne
Pharmaceutics 2023, 15(12), 2745; https://doi.org/10.3390/pharmaceutics15122745 - 08 Dec 2023
Viewed by 731
Abstract
The calcium-dependent serine endoprotease PACE4 is evaluated as a therapeutic target for prostate cancer. The peptide Ac-[d-Leu]LLLRVK-amba inhibits PACE4 with high affinity and has shown efficacy in preclinical mice xenograft models of prostate cancer. To support in vivo examinations of the [...] Read more.
The calcium-dependent serine endoprotease PACE4 is evaluated as a therapeutic target for prostate cancer. The peptide Ac-[d-Leu]LLLRVK-amba inhibits PACE4 with high affinity and has shown efficacy in preclinical mice xenograft models of prostate cancer. To support in vivo examinations of the potential therapeutic peptide Ac-[d-Leu]LLLRVK-amba, we established a highly sensitive assay for its quantification in mouse whole blood microsamples based on UPLC-MS/MS determination. Ac-[d-Leu]LLLRVK-amba was very labile during sample processing, which was particularly pronounced in plasma. High resolution mass spectrometric investigations of the metabolism/degradation in plasma revealed that no peptide bond hydrolysis generated products were formed, leaving the cause of the observed consumption of the peptide elusive. As a consequence, whole-blood quantification was developed relying on the immediate snap-freezing of blood samples after collection and immediate sample processing after serial thawing to ensure accurate and reliable quantification. The assay was validated according to the applicable recommendations of the FDA and EMA in a range of 10–10,000 ng/mL and applied to determine the pharmacokinetics of Ac-[d-Leu]LLLRVK-amba after intravenous and intraperitoneal administration to mice. Individual pharmacokinetic profiles were assessed using four microsamplings per animal. Intraperitoneal absorption was found to be efficient, demonstrating that this well-manageable route of administration is feasible for preclinical efficacy experiments with Ac-[d-Leu]LLLRVK-amba. Full article
(This article belongs to the Special Issue Quantification of Therapeutic Peptides by LC-MS)
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16 pages, 1503 KiB  
Article
Investigating the Central Nervous System Disposition of Actinomycin D: Implementation and Evaluation of Cerebral Microdialysis and Brain Tissue Measurements Supported by UPLC-MS/MS Quantification
by Julia Benzel, Gzona Bajraktari-Sylejmani, Philipp Uhl, Abigail Davis, Sreenath Nair, Stefan M. Pfister, Walter E. Haefeli, Johanna Weiss, Jürgen Burhenne, Kristian W. Pajtler and Max Sauter
Pharmaceutics 2021, 13(9), 1498; https://doi.org/10.3390/pharmaceutics13091498 - 17 Sep 2021
Cited by 3 | Viewed by 3530
Abstract
Actinomycin D is a potent cytotoxic drug against pediatric (and other) tumors that is thought to barely cross the blood–brain barrier. To evaluate its potential applicability for the treatment of patients with central nervous system (CNS) tumors, we established a cerebral microdialysis model [...] Read more.
Actinomycin D is a potent cytotoxic drug against pediatric (and other) tumors that is thought to barely cross the blood–brain barrier. To evaluate its potential applicability for the treatment of patients with central nervous system (CNS) tumors, we established a cerebral microdialysis model in freely moving mice and investigated its CNS disposition by quantifying actinomycin D in cerebral microdialysate, brain tissue homogenate, and plasma. For this purpose, we developed and validated an ultraperformance liquid chromatography–tandem mass spectrometry assay suitable for ultra-sensitive quantification of actinomycin D in the pertinent biological matrices in micro-samples of only 20 µL, with a lower limit of quantification of 0.05 ng/mL. In parallel, we confirmed actinomycin D as a substrate of P-glycoprotein (P-gp) in in vitro experiments. Two hours after intravenous administration of 0.5 mg/kg, actinomycin D reached total brain tissue concentrations of 4.1 ± 0.7 ng/g corresponding to a brain-to-plasma ratio of 0.18 ± 0.03, while it was not detectable in intracerebral microdialysate. This tissue concentration exceeds the concentrations of actinomycin D that have been shown to be effective in in vitro experiments. Elimination of the drug from brain tissue was substantially slower than from plasma, as shown in a brain-to-plasma ratio of approximately 0.53 after 22 h. Because actinomycin D reached potentially effective concentrations in brain tissue in our experiments, the drug should be further investigated as a therapeutic agent in potentially susceptible CNS malignancies, such as ependymoma. Full article
(This article belongs to the Special Issue Quantification of Therapeutic Peptides by LC-MS)
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10 pages, 1980 KiB  
Article
Mass Spectrometric Quantification of the Antimicrobial Peptide Pep19-2.5 with Stable Isotope Labeling and Acidic Hydrolysis
by Sabrina Wohlfart, Michael Kilian, Philip Storck, Thomas Gutsmann, Klaus Brandenburg and Walter Mier
Pharmaceutics 2021, 13(9), 1342; https://doi.org/10.3390/pharmaceutics13091342 - 27 Aug 2021
Cited by 2 | Viewed by 1769
Abstract
Sepsis is the number one cause of death in intensive care units. This life-threatening condition is caused by bacterial infections and triggered by endotoxins of Gram-negative bacteria that leads to an overreaction of the immune system. The synthetic anti-lipopolysaccharide peptide Pep19-2.5 is a [...] Read more.
Sepsis is the number one cause of death in intensive care units. This life-threatening condition is caused by bacterial infections and triggered by endotoxins of Gram-negative bacteria that leads to an overreaction of the immune system. The synthetic anti-lipopolysaccharide peptide Pep19-2.5 is a promising candidate for the treatment of sepsis as it binds sepsis-inducing lipopolysaccharides and thus prevents initiation of septic shock. For clinical evaluation precise quantification of the peptide in blood and tissue is required. As the peptide is not extractable from biological samples by commonly used methods there is a need for a new analysis method that does not rely on extraction of the peptide. In order to quantify the peptide by mass spectrometry, the peptide was synthesized containing 13C9,15N1-labeled phenylalanine residues. This modification offers high stability during acidic hydrolysis. Following acidic hydrolysis of the samples, the concentration of 13C9,15N1-labeled phenylalanine determined by LC-MS could be unambiguously correlated to the content of Pep19-2.5. Further experiments validated the accuracy of the data. Moreover, the quantification of Pep19-2.5 in different tissues (as studied in Wistar rats) was shown to provide comparable results to the results obtained with radioactively-labeled (14C) Pep19-2.5- Radioactive labeling is considered as the gold standard for quantification of compounds that refrain from reliable extraction methods. This novel method represents a valuable procedure for the determination of Pep19-2.5 and sticky peptides with unpredictable extraction properties in general. Full article
(This article belongs to the Special Issue Quantification of Therapeutic Peptides by LC-MS)
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