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Microfluidics platform for studies of peptide - polyelectrolyte interaction
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.ORCID iD: 0000-0001-9102-956x
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering. (EMBLA)ORCID iD: 0000-0002-1264-1337
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2022 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 621, article id 121785Article in journal (Refereed) Published
Abstract [en]

Subcutaneous injection is one of the most common approaches for administering biopharmaceuticals unsuitable for oral delivery. However, there is a lack of methods to predict the behavior of biopharmaceuticals within the extracellular matrix of the subcutaneous tissue. In this work, we present a novel miniaturized microfluidic-based in vitro method able to investigate interactions between drug molecules and the polymers of the subcutaneous extracellular matrix. To validate the method, microgels consisting of, respectively, covalently cross-linked hy-aluronic acid, polyacrylic acid, and commercially available DC BeadTM, were exposed to three model substances: cytochrome C, protamine sulfate and amitriptyline hydrochloride. These components were chosen to include systems with widely different physiochemical properties (charge, size, self-assembly, etc.) The experimental results were compared with theoretical predictions from a gel model developed earlier. The results show that the method is suitable as a rapid screening method for automated, large-scale, probing of interactions between biopolymers and drug molecules, with small consumption of material.

Place, publisher, year, edition, pages
Elsevier, 2022. Vol. 621, article id 121785
Keywords [en]
Microfluidics, Microgel, Subcutaneous administration, In vitro method, Polyelectrolyte, Peptide, Protein, Drug
National Category
Pharmaceutical Sciences Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-478583DOI: 10.1016/j.ijpharm.2022.121785ISI: 000805834000005PubMedID: 35500690OAI: oai:DiVA.org:uu-478583DiVA, id: diva2:1676056
Funder
Vinnova, 2019-00048Available from: 2022-06-23 Created: 2022-06-23 Last updated: 2023-09-01Bibliographically approved
In thesis
1. Development and characterization of an in vitro method for interaction studies between polymers and pharmaceuticals: Aiding in the development of new drug delivery systems
Open this publication in new window or tab >>Development and characterization of an in vitro method for interaction studies between polymers and pharmaceuticals: Aiding in the development of new drug delivery systems
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polymers are a group of macromolecules used in formulations of pharmaceuticals, one example being the delivery system DC Bead™. Further, some of the most abundant and for drug delivery important constituents of the subcutaneous tissue are charged polymers (polyelectrolytes), e.g. collagen, hyaluronic acid, and chondroitin sulfate. The interactions between these subcutaneous polyelectrolytes and drug molecules are believed to heavily affect the transport and absorption of subcutaneously injected drugs. To increase the understanding of how the interactions between subcutaneous polymers and drug molecules affect the pharmaceutical behavior in subcutaneous tissue, we developed a new microfluidic-based platform. The platform is used to study interactions between polyelectrolytes and drug molecules, and can beyond the investigation of subcutaneous interactions be used to develop polyelectrolyte-based microgel formulations. In this thesis, the microfluidic method denoted “Microfluidic chip for interactions studies” (MIS) is presented, and the design, validation, and several examples of usage are described. The method which is based on microfluidic instrumentation, utilizes spherical microgels created using different types of polymers/polyelectrolytes. These hydrogels collapse when experiencing attractive interactions with drug molecules making it possible to investigate drug binding by studying the volume change of the microgels. We prove that the interactions are strongly affected by charges both on the gel networks and the drug molecules. Further, the aggregation behavior of drugs in a polyelectrolyte-rich environment is studied in detail. Results show that both a strong aggregation behavior and a high charge on the drugs may affect the transport through a network of polyelectrolytes. The behavior of drugs in subcutaneous polyelectrolyte-rich environments such as hyaluronic acid networks, can partly explain bioavailability and absorption rates of the drugs in vivo. Several potential drug delivery systems in the form of microgels were investigated together with both small amphiphilic molecules and larger peptides exhibiting a wide range of physicochemical properties. The results indicate a possibility of delivering large amounts of drug in low volumes of microgel suspensions but with varying release times, ranging from seconds to days. The MIS was able to provide information about the interactions in a large number of polyelectrolyte-drug systems. The studies were performed in a highly efficient and cost-effective way, with experiments being mostly automated. This makes it a suitable method for rapid screening experiments in the development of new microgel formulations, and as part of larger studies utilizing several different methods to better understand and predict the behavior and absorption profiles of potential subcutaneously administrated drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2023. p. 88
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 338
Keywords
Microgels, Subcutaneous administration, Drug delivery, Microfluidics, In vitro methodology, Method development, Biopharmaceuticals, Amphiphilic drugs, Polyelectrolytes, Hyaluronic acid, Peptides
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-509384 (URN)978-91-513-1888-2 (ISBN)
Public defence
2023-10-20, Room A1:107a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2023-09-28 Created: 2023-09-01 Last updated: 2023-09-28

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Wanselius, MarcusSearle, SeanRodler, AgnesTenje, MariaHansson, Per

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