Pharmacokinetics of a sustained release formulation of PDGFβ-receptor directed carrier proteins to target the fibrotic liver

F. van Dijk, N. Teekamp, L. Beljaars, E. Post, J. Zuidema, R. Steendam, Y. O. Kim, H. W. Frijlink, D. Schuppand, K. Poelstra, W. L. J. Hinrichs*, P. Olinga

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

11 Citaten (Scopus)
274 Downloads (Pure)

Samenvatting

Liver fibrogenesis is associated with excessive production of extracellular matrix by myofibroblasts that often leads to cirrhosis and consequently liver dysfunction and death. Novel protein-based antifibrotic drugs show high specificity and efficacy, but their use in the treatment of fibrosis causes a high burden for patients, since repetitive and long-term parenteral administration is required as most proteins and peptides are rapidly cleared from the circulation. Therefore, we developed biodegradable polymeric microspheres for the sustained release of proteinaceous drugs. We encapsulated the drug carrier pPB-HSA, which specifically binds to the PDGF beta R that is highly upregulated on activated myofibroblasts, into microspheres composed of hydrophilic multi-block copolymers composed of poly(L-lactide) and poly ethylene glycol/poly(is an element of-caprolactone), allowing diffusion-controlled release. Firstly, we estimated in mice with acute fibrogenesis induced by a single CCl4 injection the half-life of I-125-labeled pPB-HSA at 40 min and confirmed the preferential accumulation in fibrotic tissue. Subsequently, we determined in the Mdr2-/- mouse model of advanced biliary liver fibrosis how the subcutaneously injected microspheres released pPB-HSA into both plasma and fibrotic liver at 24 h after injection, which was maintained for six days. Although the microspheres still contained protein at day seven, pPB-HSA plasma and liver concentrations were decreased. This reduction was associated with an antibody response against the human albumin-based carrier protein, which was prevented by using a mouse albumin-based equivalent (pPB-MSA). In conclusion, this study shows that our polymeric microspheres are suitable as sustained release formulation for targeted protein constructs such as pPB-HSA. These formulations could be applied for the long-term treatment of chronic diseases such as liver fibrosis.

Originele taal-2English
Pagina's (van-tot)258-265
Aantal pagina's8
TijdschriftJournal of Controlled Release
Volume269
Vroegere onlinedatum20-nov-2017
DOI's
StatusPublished - 10-jan-2018

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