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Effects of Terminal Motif on the Self-Assembly of Dexamethasone Derivatives.

ABSTRACT: Tailoring the terminal motif of molecules including drugs might significantly affect their self-assembly tendency in aqueous solution, thus providing a rational strategy to modulate its macroscopic characteristics of supramolecular assembly. A model drug of dexamethasone (Dex) was esterified by different fatty acids [succinic acid (SA), glutaric acid (GA), and adipic acid (AA)] and aromatic acid [phthalic acid (PA)] to generate a series of Dex derivatives. Aqueous solution of Dex-SA, Dex-GA, and Dex-AA turned into hydrogel spontaneously after a period time of incubation (24, 48, and 72 h, respectively) via the auto-hydrolytic strategy, while aqueous solution of Dex-PA did not result in hydrogelation during 3 days of incubation. Aqueous solutions of Dex-SA, Dex-GA, and Dex-AA underwent apparent hydrolysis (10.73 ± 0.64%, 15.17 ± 2.24%, and 17.29 ± 1.39%, respectively), while Dex-PA exhibited a minimal hydrolysis (<1%) in a period of 28 days study, as indicated by in vitro hydrolytic test. Morphological observation showed that the hydrogel formed by Dex-SA was composed of uniform nanofibers, while hydrogels formed by Dex-GA, and Dex-AA were derived from irregular particles. The mechanical strength of hydrogel formed by Dex-SA was much bigger than that of hydrogels formed by Dex-GA and Dex-AA, as indicated by rheological test. Moreover, the acylation of Dex did not compromise its potent anti-inflammatory activity in a lipopolysaccharide (LPS)-activated RAW 264.7 macrophage.

SUBMITTER: Liu H

PROVIDER: S-EPMC7044695 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Effects of Terminal Motif on the Self-Assembly of Dexamethasone Derivatives.

Liu Hui H Yu Ailing A Dai Mali M Lin Dan D Lin Deqing D Xu Xu X Li Xingyi X Wang Yuqin Y

Frontiers in chemistry 20200220

Tailoring the terminal motif of molecules including drugs might significantly affect their self-assembly tendency in aqueous solution, thus providing a rational strategy to modulate its macroscopic characteristics of supramolecular assembly. A model drug of dexamethasone (Dex) was esterified by different fatty acids [succinic acid (SA), glutaric acid (GA), and adipic acid (AA)] and aromatic acid [phthalic acid (PA)] to generate a series of Dex derivatives. Aqueous solution of Dex-SA, Dex-GA, and ...[more]

PMID: 32154209

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Project description:Supramolecular hydrogels have emerged as a class of promising biomaterials for applications such as drug delivery and tissue engineering. Self-assembling peptides have been well studied for such applications, but low molecular weight (LMW) amino acid-derived gelators have attracted interest as low-cost alternatives with similar emergent properties. Fluorenylmethyloxycarbonyl-phenylalanine (Fmoc-Phe) is one such privileged motif often chosen due to its inherent self-assembly potential. Previously, we developed cationic Fmoc-Phe-DAP gelators that assemble into hydrogel networks in aqueous NaCl solutions of sufficient ionic strength. The chloride anions in these solutions screen the cationic charge of the gelators to enable self-assembly to occur. Herein, we report the effects of varying the anions of sodium salts on the gelation potential, nanoscale morphology, and hydrogel viscoelastic properties of Fmoc-Phe-DAP and two of its fluorinated derivatives, Fmoc-3F-Phe-DAP and Fmoc-F5-Phe-DAP. It was observed that both the anion identity and gelator structure had a significant impact on the self-assembly and gelation properties of these derivatives. Changing the anion identity resulted in significant polymorphism of the nanoscale morphology of the assembled states that was dependent on the chemical structure of the gelator. The emergent viscoelastic character of the hydrogel networks was also found to be reliant on the anion identity and gelator structure. These results demonstrate the complex interplay between the gelator and environment that have a profound and often unpredictable impact on both self-assembly properties and emergent viscoelasticity in supramolecular hydrogels formed by LMW compounds. This work also illustrates the current lack of understanding that limits the rational design of potential biomaterials that will be in contact with complex biological fluids and provides motivation for additional research to correlate the chemical structure of LMW gelators with the structure and emergent properties of the resulting supramolecular assemblies as a function of environment.

Project description:Polyphilic self-assembly leads to compartmentalization of space and development of complex structures in soft matter on different length scales, reaching from the morphologies of block copolymers to the liquid crystalline (LC) phases of small molecules. Whereas block copolymers are known to form membranes and interact with phospholipid bilayers, liquid crystals have been less investigated in this respect. Here, series of bolapolyphilic X-shaped molecules were synthesized and investigated with respect to the effect of molecular structural parameters on the formation of LC phases (part 1), and on domain formation in phospholipid bilayer membranes (part 2). The investigated bolapolyphiles are based on a rod-like π-conjugated oligo(phenylene ethynylene) (OPE) core with two glycerol groups being either directly attached or separated by additional ethylene oxide (EO) units to both ends. The X-shape is provided by two lateral alkyl chains attached at opposite sides of the OPE core, being either linear, branched, or semiperfluorinated. In this report, the focus is on the transition from polyphilic (triphilic or tetraphilic) to binary amphiphilic self-assembly. Polyphilic self-assembly, i.e., segregation of all three or four incorporated units into separate nano-compartments, leads to the formation of hexagonal columnar LC phases, representing triangular honeycombs. A continuous transition from the well-defined triangular honeycomb structures to simple hexagonal columnar phases, dominated by the arrangement of polar columns on a hexagonal lattice in a mixed continuum formed by the lipophilic chains and the OPE rods, i.e., to amphiphilic self-assembly, was observed by reducing the length and volume of the lateral alkyl chains. A similar transition was found upon increasing the length of the EO units involved in the polar groups. If the lateral alkyl chains are enlarged or replaced by semiperfluorinated chains, then the segregation of lateral chains and rod-like cores is retained, even for enlarged polar groups, i.e., the transition from polyphilic to amphiphilic self-assembly is suppressed.

Dataset Information

Effects of Terminal Motif on the Self-Assembly of Dexamethasone Derivatives.

Publications

Effects of Terminal Motif on the Self-Assembly of Dexamethasone Derivatives.

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