University of Groningen
Delivery of biologicals van Dijk, Fransien
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Publication date: 2018
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van Dijk, F. (2018). Delivery of biologicals: Sustained release of cell-specific proteins in fibrosis. Rijksuniversiteit Groningen.
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Chapter 1
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Introduction
Many new molecular entities currently developed and introduced to the market are biological, protein-based therapeutics1,2. These therapeutic proteins are increasingly used in the treatment of a broad spectrum of disorders, including chronic conditions varying from cancer and diabetes to rheumatoid arthritis3. A severe, chronic condition that cannot be fully treated yet, and was therefore the focus of this thesis, is fibrosis, characterized by an excessive production of extracellular matrix (ECM) proteins by activated fibroblasts4. Therapeutic proteins are particularly interesting candidates for future therapies, because they often have highly specific and complex functions that cannot be easily mimicked by small-molecule drugs, and are generally well tolerated1. Clinical application of many experimental compounds is however often still limited despite these promising characteristics, mostly related to low exposure to target cells and induction of severe side effects due to ubiquitous receptor expressions3. An approach to overcome these limitations is to increase their local concentration at the target cells via cell-selective delivery to disease-specific receptors. It is widely known that upon activation, fibroblasts highly and specifically express the platelet-derived growth factor receptor beta (PDGFβR). This receptor provides an excellent target for the delivery of potential antifibrotic proteins5,6.
Not only the low exposure to target cells impedes the clinical application of many biologicals, but also the administration route is considered a challenge. Generally, protein therapeutics are administered parenterally, leading to unfavorable high fluctuations in the plasma concentration7. Subcutaneously injectable sustained release drug delivery systems assuring the gradual and prolonged release of a protein therapeutic following a single injection are a patient-friendly alternative8,9. One such delivery system is a polymeric microsphere formulation, that allows flexible dosing of the drug9. These microspheres are particularly attractive as they provide physical protection of the drug from surrounding cells and tissues9. The in this thesis applied polymers provide diffusion-controlled release of encapsulated therapeutic proteins, instead of degradation-mediated release, which results in a less harsh environment for these proteins10. This is important for complex protein constructs like the cell-specific drug carriers applied in the present thesis.
Introduction and aim of the thesis
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Aim of the thesis
The aim of this thesis is to evaluate the different PDGFβ-receptor directed constructs that were developed in the past years, and to gain more insight in the uptake and signaling mechanism at the cellular level of our most promising lead compound: the PDGFβ-receptor targeted antifibrotic cytokine interferon gamma (Fibroferon). Additionally, we aim to develop a sustained release formulation for PDGFβ-receptor targeted therapeutic proteins. Chapter 2 outlines the onset of this thesis regarding the cell-specific delivery of therapeutic proteins. It provides a review of recent protein-based strategies to deliver compounds to the PDGFβ-receptor. In the studies described in chapter 3 the signaling pathway of the potent compound Fibroferon is examined. In an attempt to bring the clinical application of such biologicals one step closer, we performed the studies described in chapter 4. In these studies, we developed and tested a sustained release formulation based on polymeric microspheres for our model protein pPB-HSA, which is a highly versatile PDGFβ-receptor targeted drug carrier composed of multiple PDGFβR-recognizing peptides (pPB) coupled to human serum albumin (HSA). The concept of combining cell-specific constructs with a sophisticated polymeric microsphere formulation was further explored in vitro and in vivo in studies described in chapter 5. In particular, the in vivo pharmacokinetic release profile of pPB-HSA loaded microspheres was studied. Finally, the antifibrotic effectivity of microspheres containing the drug carrier coupled to the active antifibrotic compound Y27632, suitable for use in mice, was tested in studies described in chapter 6. Chapter 7 provides a summary and a general discussion of the results described in this thesis, as well as future directions for protein-based drugs and an appropriate sustained release formulation.
Chapter 1
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References
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2. Kinch MS. An overview of FDA-approved biologics medicines. Drug Discov Today. 2015;20(4):393-398.
3. Pisal DS, Kosloski MP, Balu-Iyer SV. Delivery of therapeutic proteins. J Pharm Sci. 2010;99(6):2557-2575.
4. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134(6):1655-1669.
5. Borkham-Kamphorst E, Kovalenko E, van Roeyen CR, et al. Platelet-derived growth factor isoform expression in carbon tetrachloride-induced chronic liver injury. Lab Invest. 2008;88(10):1090-1100.
6. van Dijk F, Olinga P, Poelstra K, Beljaars L. Targeted therapies in liver fibrosis: Combining the best parts of platelet-derived growth factor BB and interferon gamma. Front Med
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7. Wu F, Jin T. Polymer-based sustained-release dosage forms for protein drugs, challenges, and recent advances. AAPS PharmSciTech. 2008;9(4):1218-1229.
8. Prajapati VD, Jani GK, Kapadia JR. Current knowledge on biodegradable microspheres in drug delivery. Expert Opin Drug Deliv. 2015;12(8):1283-1299.
9. Vaishya R, Khurana V, Patel S, Mitra AK. Long-term delivery of protein therapeutics.
Expert Opin Drug Deliv. 2015;12(3):415-440.
10. Teekamp N, Van Dijk F, Broesder A, et al. Polymeric microspheres for the sustained release of a protein-based drug carrier targeting the PDGFbeta-receptor in the fibrotic kidney. Int J Pharm. 2017;534(1-2):229-236.
