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Self-regulated glycosylated insulin delivery

1990; Elsevier BV; Volume: 11; Issue: 1-3 Linguagem: Inglês

10.1016/0168-3659(90)90132-d

1873-4995

Sung Wan Kim, Chaul Min Paii, Makino Kimiko, Leah A. Seminoff, David L. Holmberg, Jeremy M. Gleeson, Dana E. Wilson, Eric J. Mack,

RNA Interference and Gene Delivery

A self-regulating insulin delivery system, based on the concept of competitive binding between synthetic glycosylated insulin (G-insulin) and glucose to concanavalin A (Con A) ligand substrate, has been designed. The competitive binding of the two ligands for the substrate regulates G-insulin release in relation to the outside glucose concentration, while a polymeric membrane, serving as a peritoneal implant pouch containing G-insulin and Con A, is used to control the permeability of glucose influx and G-insulin efflux. Mono-, di- and tri-sugar substituted insulins have been characterized. The nonimmunogenicity, bioactivity and pharmacodynamic activity of succinyl amidophenyl glucopyranoside insulin (SAPG-insulin) and succinyl amidophenyl mannopyranoside insulin (SAPM-insulin) were found to be comparable to unsubstituted bovine insulin. Initial systems were based on SAPG- or SAPM-insulin with water soluble Con A tetramer contained in pouches of porous ρ-HEMA or cellulose acetate. A second system was designed with Con A immobilized beads (to prevent Con A leakage) and cellulose acetate or Nucleopore® membranes. A new system was designed by crosslinking the Con A molecules to create a gel and enclosing the insulin and gel in a pouch of Durapore® membrane (heat sealable and having comparable permeability to G-insulins andglucose). The fabricated pouch in vitro showed a short lag time in response to glucose with no leakage of Con A molecules. An alternative system of Con A and SAPG-insulin loaded into microcapsules demonstrated a short lag time for insulin release due to the large surface area of the microcapsules.