Schlosser, Corinna Silvia;
(2025)
Advanced delivery systems to address current challenges of polypeptide formulations.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Introduction: Advances in biotechnology and better understanding of disease mechanisms have been instrumental to the emergence of polypeptide therapeutics. However, several challenges concerning the stability of polypeptides and for many polypeptides their requirement for injections hamper their clinical application. Controlled release formulations produce an extended release of encapsulated therapeutic, reducing injection frequency and thereby improving patient adherence and treatment efficacy. Further, it has been shown that the development of solid-state formulations can offer stability advantages for polypeptides. / Methods: A solid particulate formulation for a model protein was prepared by electrospraying. The formulation composition was varied to identify parameters crucial to protein stability. From this work, the development of a controlled, pulsatile release formulation for teriparatide was explored by developing core-shell electrosprayed particles with poly(lactic-co-glycolic acid) (PLGA) as the carrier polymer as well as using thermo-responsive liposomes. Their performance was investigated by measuring the in vitro release profiles. The biological activity of the released teriparatide was assessed in a newly developed receptor-binding assay, that overexpressed teriparatide’s receptor (PTH1R) in HEK293 cells and measured intracellular cAMP levels. / Results: Initial experiments demonstrated that the polymer carrier had a significant impact on electrospraying of proteins and that the incorporation of trehalose improved storage stability. Hydrophobic ion pairing of teriparatide was shown to be advantageous for both co-axial electrospraying and entrapment of teriparatide within liposomes. The PLGA particles exhibited an extended teriparatide release over 21-days and did not achieve a pulsatile profile; however, the thermo-responsive particles showed temperature-dependent release profiles. Both PLGA particles and the liposomal formulation retained teriparatide’s biological activity as observed from the receptor-binding assay. / Conclusion: A first proof-of-concept of the suitability of thermo-responsive liposomes as pulsatile release systems was obtained. Further, hydrophobic ion pairing presents a promising approach to overcoming challenges of peptide processing.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Advanced delivery systems to address current challenges of polypeptide formulations |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | peptides, proteins, teriparatide, hydrophobic ion pairing, controlled release, thermo-responsive liposomes, stability |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10204983 |
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