Effects of surface hydrophobicity on the structural properties of insulin

Brader, Mark L.; Millican, Rohn; Brems, David N.; Havel, Henry A.; Kriauciunas, Aidas; Chen, Victor

doi:10.1016/s1080-8914(97)80030-0

Cited by 3 publications

(3 citation statements)

References 21 publications

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“…To link insulin to CD-PEI, it was necessary to add a hydrophobic alkane side chain to the surface of insulin. It is known that palmitoylation of human insulin does not significantly alter its conformational properties (Brader et al, 1997), so a palmitate group was added to the single exposed lysine residue of insulin.…”

Section: Discussionmentioning

confidence: 99%

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Cyclodextrin–polyethylenimine conjugates for targeted in vitro gene delivery

Forrest

Gabrielson

Pack

2004

Biotech & Bioengineering

120

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Many human gene therapies will require cell-specific targeting. Though recombinant viruses are much more efficient than nonviral vectors, the latter, especially polymers, have the advantage of being targetable via conjugation of cell-specific ligands, including sugars, peptides, and antibodies, which can be covalently attached to the polymer using a variety of chemistries. Cyclodextrin, which forms inclusion complexes with small hydrophobic molecules, has been incorporated into a gene-delivery polymer and may provide a facile and versatile attachment site for targeting ligands. Polyethylenimine (PEI) was derivatized with beta-cyclodextrin on approximately 10% of the polymer's amines (termed CD-PEI). Human insulin was also derivatized with a hydrophobic palmitate group (pal-HI), which could anchor the protein to CD-PEI/DNA polyplexes. CD-PEI was essentially nontoxic to HEK293 cells at concentrations optimal for gene delivery and mediated nearly 4-fold higher gene expression than unmodified PEI, which is relatively toxic to these cells. More importantly, addition of the pal-HI to CD-PEI enhanced gene expression by more than an order of magnitude compared to unmodified PEI, either with or without the pal-HI. Because of the relative ease with which CD-binding moieties may be attached to various types of ligands, CD-PEI may be a generally useful material for testing novel cell-specific targeting compounds.

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Section: Discussionmentioning

confidence: 99%

“…Palmitate was attached to human insulin based on the procedure of Brader et al (1997). Human insulin (9.8 mg, 1.7 mmol) was dissolved in 900 AL of DMSO with 100 mM triethylamine.…”

Section: Synthesis Of Palmitoyl-lys B29 Human Insulinmentioning

confidence: 99%

Cyclodextrin–polyethylenimine conjugates for targeted in vitro gene delivery

Forrest

Gabrielson

Pack

2004

Biotech & Bioengineering

120

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“…Even though this appears to be a viable approach for a soluble insulin formulation at neutral pH, there is some question about the margin of pharmaceutical elegance due to solubility characteristics of the more lipophilic fatty acyl insulin derivatives, particularly if the concentration of the insulin derivative must be increased appreciably to accommodate a reduced potency. There is reason to believe, however, that such a molecule is possibly at least as conformationally stable as insulin [150]. Clearly, considerable research is still needed to evaluate the relation between the attractive pharmacokinetics and dynamics of acylated human insulin as a candidate to replace basal insulin and its bioavailability in humans.…”

Section: Fatty Acid Acylated Insulinsmentioning

confidence: 99%

Insulin analogues and their potential in the management of diabetes mellitus

Bolli

Marchi

Park³

et al. 1999

Diabetologia

322

211

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Hybrid insulin cocrystals for controlled release delivery

et al. 2002

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The ability to tailor the release profile of a drug by manipulating its formulation matrix offers important therapeutic advantages. We show here that human insulin can be cocrystallized at preselected ratios with the fully active lipophilically modified insulin derivative octanoyl-N(epsilon)-LysB29-human insulin (C8-HI). The cocrystal is analogous to the NPH (neutral protamine Hagedorn) crystalline complex formed with human insulin, which is commonly used as the long-acting insulin component of diabetes therapy. The in vitro and in vivo release rates of the cocrystal can be controlled by adjusting the relative proportions of the two insulin components. We identified a cocrystal composition comprising 75% C8-HI and 25% human insulin that exhibits near-ideal basal pharmacodynamics in somatostatin-treated beagle dogs. The dependence of release rate on cocrystal ratio provides a robust mechanism for modulating insulin pharmacodynamics. These findings show that a crystalline protein matrix may accommodate a chemical modification that alters the dissolution rate of the crystal in a therapeutically useful way, yet that is structurally innocuous enough to preserve the pharmaceutical integrity of the original microcrystalline entity and the pharmacological activity of the parent molecule.

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Effects of surface hydrophobicity on the structural properties of insulin

Cited by 3 publications

References 21 publications

Cyclodextrin–polyethylenimine conjugates for targeted in vitro gene delivery

Cyclodextrin–polyethylenimine conjugates for targeted in vitro gene delivery

Insulin analogues and their potential in the management of diabetes mellitus

Hybrid insulin cocrystals for controlled release delivery

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