title: Kinetic simulation model of protein secretion and accumulation in the cell microcapsules.
abstract: BACKGROUND
  In cell therapy, microencapsulated cells secrete therapeutic protein, which is further released from the microcapsules. In principle, some secreted, but unreleased, protein may accumulate in the microcapsules. The kinetic simulation model was built to simulate the potential accumulation of the protein in the microcapsules.
  
  
  METHODS
  The alginate microcapsules were cross-linked with divalent cations to encapsulate either flourescein isothiocyanate (FITC)-dextrans (molecular weights = 4.3, 10.5, 43 kDa) or retinal pigment epithelial cells (ARPE-19). The cells were genetically engineered to produce secreted alkaline phosphatase (SEAP). SEAP production from the cells was quantified with and without microcapsulation and, finally, the cells were killed with toxin to quantify the secreted but yet unreleased SEAP from the microcapsules. The empirical three-compartment kinetic model was constructed based on the release of FITC-dextrans of different molecular weights from the alginate microcapsules with different pore sizes. Protein secretion from the cells into the microcapsules was added to the model. The impact of the microcapsule wall permeability on the steady-state amounts of secreted protein in the microcapsules and in the hypothetical target compartment in the body was simulated. The simulations were compared to the experimental data from the microencapsulated SEAP secreting ARPE-19 cells.
  
  
  RESULTS
  The model and the data show that substantial amounts (10-15 daily doses) of protein may accumulate in the microcapsules with poor wall permeability. At high permeability, the accumulation was insignificant. The pharmacokinetic simulations show that even a 1.5-fold increase in the wall permeability may result in a substantial peak in the drug amount in the target compartment, especially if the elimination rate of the protein is high.
  
  
  CONCLUSIONS
  The kinetic simulation model for protein secretion from microcapsulated cells is a useful tool for the early kinetic prediction and risk assessment of cell therapy.
authors.affiliation: Drug Discovery and Development Technology Center, University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Wikström
authors.forename: H
authors.initials: H
authors.lastname: Syväjärvi
authors.forename: A
authors.initials: A
authors.lastname: Urtti
authors.forename: M
authors.initials: M
authors.lastname: Yliperttula
mesh_terms: D000464:Alginates; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002214:Capsules / Q000737:chemistry* / Q000627:therapeutic use; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D003911:Dextrans; D004847:Epithelial Cells / Q000378:metabolism; D020723:Glucuronic Acid; D006603:Hexuronic Acids; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D010539:Permeability; D011506:Proteins / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D000464:Alginates; D002214:Capsules; D003911:Dextrans; D006603:Hexuronic Acids; D011506:Proteins; D020723:Glucuronic Acid; D000469:Alkaline Phosphatase