Open AccessInsulin Crystals Grown in Short-Peptide Supramolecular Hydrogels Show Enhanced Thermal Stability and Slower Release Profile
Author(s) -
Rafael ContrerasMontoya,
María Arredondo-Amador,
Guillermo EscolanoCasado,
Mari C. MañasTorres,
María Paula González,
Mayte Conejero-Muriel,
Vaibhav Bhatia,
Juan José DíazMochón,
Olga MartínezAugustin,
Fermín Sánchez de Medina,
Modesto T. López–López,
Francisco ConejeroLara,
José A. Gavira,
Luı́s Álvarez de Cienfuegos
Publication year - 2021
Publication title -
acs applied materials and interfaces
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.535
H-Index - 228
eISSN - 1944-8252
pISSN - 1944-8244
DOI - 10.1021/acsami.1c00639
Subject(s) - self healing hydrogels , agarose , materials science , in vivo , differential scanning calorimetry , insulin , dissolution , biophysics , thermal stability , composite number , peptide , drug delivery , protein crystallization , chemical engineering , combinatorial chemistry , nanotechnology , chromatography , biochemistry , chemistry , organic chemistry , crystallization , polymer chemistry , biology , physics , microbiology and biotechnology , engineering , composite material , endocrinology , thermodynamics
Protein therapeutics have a major role in medicine in that they are used to treat diverse pathologies. Their three-dimensional structures not only offer higher specificity and lower toxicity than small organic compounds but also make them less stable, limiting their in vivo half-life. Protein analogues obtained by recombinant DNA technology or by chemical modification and/or the use of drug delivery vehicles has been adopted to improve or modulate the in vivo pharmacological activity of proteins. Nevertheless, strategies to improve the shelf-life of protein pharmaceuticals have been less explored, which has challenged the preservation of their activity. Herein, we present a methodology that simultaneously increases the stability of proteins and modulates the release profile, and implement it with human insulin as a proof of concept. Two novel thermally stable insulin composite crystal formulations intended for the therapeutic treatment of diabetes are reported. These composite crystals have been obtained by crystallizing insulin in agarose and fluorenylmethoxycarbonyl-dialanine (Fmoc-AA) hydrogels. This process affords composite crystals, in which hydrogel fibers are occluded. The insulin in both crystalline formulations remains unaltered at 50 °C for 7 days. Differential scanning calorimetry, high-performance liquid chromatography, mass spectrometry, and in vivo studies have shown that insulin does not degrade after the heat treatment. The nature of the hydrogel modifies the physicochemical properties of the crystals. Crystals grown in Fmoc-AA hydrogel are more stable and have a slower dissolution rate than crystals grown in agarose. This methodology paves the way for the development of more stable protein pharmaceuticals overcoming some of the existing limitations.