Publication:
Insulin Crystals Grown in Short-Peptide Supramolecular Hydrogels Show Enhanced Thermal Stability and Slower Release Profile.

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Date

2021-02-19

Authors

Contreras-Montoya, Rafael
Arredondo-Amador, María
Escolano-Casado, Guillermo
Mañas-Torres, Mari C
Gonzalez, Mercedes
Conejero-Muriel, Mayte
Bhatia, Vaibhav
Diaz-Mochon, Juan J
Martinez-Augustin, Olga
de Medina, Fermin Sanchez

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American Chemical Society
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Abstract

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.

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MeSH Terms

Animals
Crystallization
Drug Liberation
Humans
Hydrogels
Hypoglycemic Agents
Insulin
Male
Peptides
Protein Stability
Rats, Wistar

DeCS Terms

Animales
Cristalización
Estabilidad proteica
Hidrogeles
Hipoglucemiantes
Humanos
Insulina
Liberación de fármacos
Masculino
Péptidos
Ratas Wistar

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Keywords

composite materials, drug delivery, insulin composite crystals, protein crystallization, protein therapeutics, supramolecular hydrogels

Citation

Contreras-Montoya R, Arredondo-Amador M, Escolano-Casado G, Mañas-Torres MC, González M, Conejero-Muriel M, et al. Insulin Crystals Grown in Short-Peptide Supramolecular Hydrogels Show Enhanced Thermal Stability and Slower Release Profile. ACS Appl Mater Interfaces. 2021 Mar 17;13(10):11672-11682.