Esterification of Alginate with Alkyl Bromides of Different Carbon Chain Lengths via the Bimolecular Nucleophilic Substitution Reaction: Synthesis, Characterization, and Controlled Release Performance.

Xiuqiong Chen,Huiqiong Yan,Chang Liu,Qiang Lin,Qingmei Zhu,Dongze Li

doi:10.3390/polym13193351

Xiuqiong Chen, Huiqiong Yan + Show 4 more

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https://doi.org/10.3390/polym13193351

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Journal: Polymers	Publication Date: Sep 30, 2021
Citations: 10	License type: CC BY 4.0

Affiliation: Hainan Normal University

Abstract

To extend the alginate applicability for the sustained release of hydrophobic medicine in drug delivery systems, the alkyl alginate ester derivative (AAD), including hexyl alginate ester derivative (HAD), octyl alginate ester derivative (OAD), decyl alginate ester derivative (DAD), and lauryl alginate ester derivative (LAD), were synthesized using the alkyl bromides with different lengths of carbon chain as the hydrophobic modifiers under homogeneous conditions via the bimolecular nucleophilic substitution (SN2) reaction. Experimental results revealed that the successful grafting of the hydrophobic alkyl groups onto the alginate molecular backbone via the SN2 reaction had weakened and destroyed the intramolecular hydrogen bonds, thus enhancing the molecular flexibility of the alginate, which endowed the AAD with a good amphiphilic property and a critical aggregation concentration (CAC) of 0.48~0.0068 g/L. Therefore, the resultant AAD could form stable spherical self-aggregated micelles with the average hydrodynamic diameter of 285.3~180.5 nm and zeta potential at approximately −44.8~−34.4 mV due to the intra or intermolecular hydrophobic associations. With the increase of the carbon chain length of the hydrophobic side groups, the AAD was more prone to self-aggregation, and therefore was able to achieve the loading and sustained release of hydrophobic ibuprofen. Additionally, the swelling and degradation of AAD microcapsules and the diffusion of the loaded drug jointly controlled the release rate of ibuprofen. Meanwhile, the AAD also displayed low cytotoxicity to the murine macrophage RAW264.7 cells. Thanks to the good amphiphilic property, colloidal interface activity, hydrophobic drug-loading performance, and cytocompatibility, the synthesized AAD exhibited a great potential for the development of hydrophobic pharmaceutical formulations.

Highlights

According to previous work [28,29], we attempted to conduct the homogeneous synthesis of alginate ester derivative (AAD) in N,N-dimethylformamide/tetrabutylammonium fluoride (DMF/TBAF), and partially esterified hexyl, octyl, decyl, and lauryl alginates were synthesized via the SN 2 reaction with the corresponding alkyl halides
With the increase of the carbon chain length of the hydrophobic side groups, the EE of AAD gradually increased for the enhancement of the hydrophobic associations
Experimental results showed that hexyl alginate ester derivative (HAD), octyl alginate ester derivative (OAD), decyl alginate ester derivative (DAD), and lauryl alginate ester derivative (LAD) was successfully synthesized, and the grafting of the hydrophobic alkyl groups onto the alginate molecular backbone had weakened and destroyed the intramolecular hydrogen bonds, enhancing the molecular flexibility of the alginate

Summary

Introduction

Synthetic amphiphilic polymers have drawn more and more attention from researchers, and their self-aggregation performance has become a research hotspots [1,2], because the amphiphilic block polymer containing the hydrophilic groups and the hydrophobic groups is able to self-aggregate into the micelle-like aggregates with 4.0/).a hydrophobic inner core and a hydrophilic outer shell in the aqueous solution, which can be applied to the medical field as a novel drug delivery system with broad prospects [3,4].Alginate, as a natural anionic heteropolysaccharide mostly derived from brown seaweed, has been extensively studied and applied to many biomedical applications owing to its excellent advantages, such as low cost, non-toxicity, immunogenicity, and good biodegradation and biocompatibility [5,6,7]. Alginate can perform mild gelation by divalent cations such as Ca2+ , and the formed hydrogel can exhibit good coating, drug-loading, and sustained release properties, making it a good candidate as a drug carrier for biomedical application [8,9,10]. Due to the abundant carboxyl and hydroxyl groups on the molecular chains, the raw alginate is very hydrophilic, which results in its poor compatibility with hydrophobic drug molecules, such as ibuprofen. The presence of these hydroxyl and carboxyl functional groups are very susceptible to forming intramolecular hydrogen bonds within the molecules, which gives rise to the highly stretched rigid structure of alginate chains that is not conducive to the loading of hydrophobic drugs [15]. The grafting of hydrophobic segments onto the backbone of alginate can improve properties such as molecular flexibility, hydrophobicity, and physicochemical and biological characteristics, which make it capable of achieving the loading of hydrophobic drugs through its self-aggregation and prolonging its stability in biological medium [13,17]

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