Synthesis, Characterization, and Retinol Stabilization of Fatty Amide-ß-cyclodextrin Conjugates.

Amphiphilic cyclodextrin (CD) has been the object of growing scientific attention because of its two recognition sites, the cavity and the apolar heart, formed by self-assembly. In the present study, mono[6-deoxy-6-(octadecanamido)]-ß-CD and mono[6-deoxy-6-(octadecenamido)]-ß-CD were successfully synthesized by reacting mono-6-amino-6-deoxy-ß-CD with N-hydroxysuccinimide esters of corresponding fatty acids in DMF. The structures were analyzed using nuclear magnetic resonance spectroscopy and mass spectrometry. The amphiphilic ß-CDs were able to form self-assembled nano-vesicles in water, and the supramolecular architectures were characterized using fluorescence spectroscopy, dynamic light scattering, and transmission electron microscopy. Using the cavity-type nano-vesicles, all-trans-retinol was efficiently encapsulated; it was then stabilized against the photo-degradation. Therefore, the present fatty amide-ß-CD conjugate will be a potential molecule for carrier systems in cosmetic and pharmaceutical applications.

Novel succinoglycan dialdehyde/aminoethylcarbamoyl-ß-cyclodextrin hydrogels for pH-responsive delivery of hydrophobic drugs.

ß-Cyclodextrin cross-linked succinoglycan dialdehyde hydrogels was prepared for hydrophobic drug delivery. Succinoglycan dialdehyde (SGDA) was synthesized from sodium periodate oxidation of succinoglycan isolated from Sinorhizobium meliloti Rm1021. Aminoethylcarbamoyl-ß-cyclodextrin (ACD) was crosslinked with SGDA to form a succinoglycan dialdehyde/aminoethylcarbamoyl-ß-cyclodextrin (SGDA/ACD) hydrogels. The SGDA/ACD hydrogels exhibited a 65.7 % improvement in storage modulus (G') and a 5.7-fold higher compressive strain than the SGDA/poly(ethylene glycol) diamine (PEG) hydrogels as controls. A hardly soluble drug, baicalein was used for the drug loading and release properties of SGDA/ACD hydrogels. Baicalein was released about 98 % within 48 h at pH 7.4, but not completely released even after 48 h at pH 2.0. In addition, at pH 7.4, only about 56 % of the baicalein loaded on the SGDA/PEG hydrogels was released within 48 h, while about 98 % of the baicalein loaded on the SGDA/ACD hydrogels was released within 48 h. It indicates that ACD significantly improved the solubilization efficacy of the baicalein. In vitro testing of cell viability using HEK-293 cells also showed that the SGDA/ACD hydrogels were suitable for the cells. In conclusion, SGDA/ACD hydrogels significantly enhance the utilization of baicalein and provide potential applications in drug delivery systems for hardly soluble drugs.

Injectable, self-healable and adhesive hydrogels using oxidized Succinoglycan/chitosan for pH-responsive drug delivery.

We prepared chitosan (CS) based multifunctional hydrogels using oxidized succinoglycan (OSG) with a semi-dissolving acidified sol-gel transition method. OSG cross-linked CS hydrogels (OSG/CS) was prepared by aldehyde-amine Schiff-base reaction. OSG/CS increased not only thermal stability but also improved mechanical strength by 5.75 times. Through the tensile and strain sweep test, OSG/CS showed excellent self-healing properties by 98.82% and 99.89%, respectively. It showed the high compressive stress of 173 kPa at 60% strain, the adhesive strength of 2763 kPa, and the antibacterial effect of 90%. Furthermore, OSG/CS showed a pH-controlled drug release pattern, where a change of pH from 7.4 to 2.0 accelerated for 5-fluorouracil release from 60% to 90%. WST-8 assay demonstrated that OSG/CS maintained 97.30% cell viability and 98.84% cell proliferation after 7 days, indicating the potential as biocompatible hydrogel materials such as wound healing, tissue engineering and drug release systems.

Bacterial Succinoglycans: Structure, Physical Properties, and Applications.

Succinoglycan is a type of bacterial anionic exopolysaccharide produced from Rhizobium, Agrobacterium, and other soil bacteria. The exact structure of succinoglycan depends in part on the type of bacterial strain, and the final production yield also depends on the medium composition, culture conditions, and genotype of each strain. Various bacterial polysaccharides, such as cellulose, xanthan, gellan, and pullulan, that can be mass-produced for biotechnology are being actively studied. However, in the case of succinoglycan, a bacterial polysaccharide, relatively few reports on production strains or chemical and structural characteristics have been published. Physical properties of succinoglycan, a non-Newtonian and shear thinning fluid, have been reported according to the ratio of substituents (pyruvyl, succinyl, acetyl group), molecular weight (Mw), and measurement conditions (concentration, temperature, pH, metal ion, etc.). Due to its unique rheological properties, succinoglycan has been mainly used as a thickener and emulsifier in the cosmetic and food industries. However, in recent reports, succinoglycan and its derivatives have been used as functional biomaterials, e.g., in stimuli-responsive drug delivery systems, therapeutics, and cell culture scaffolds. This suggests a new and expanded application of succinoglycan as promising biomaterials in biomedical fields, such as tissue engineering, regenerative medicine, and pharmaceuticals using drug delivery.

Multifunctional Oxidized Succinoglycan/Poly(N-isopropylacrylamide-co-acrylamide) Hydrogels for Drug Delivery.

We prepared the self-healing and temperature/pH-responsive hydrogels using oxidized succinoglycan (OSG) and a poly (N-isopropyl acrylamide-co-acrylamide) [P(NIPAM-AM)] copolymer. OSG was synthesized by periodate oxidation of succinoglycan (SG) isolated directly from soil microorganisms, Sinorhizobium meliloti Rm1021. The OSG/P(NIPAM-AM) hydrogels were obtained by introducing OSG into P(NIPAM-AM) networks. The chemical structure and physical properties of these hydrogels were characterized by ATR-FTIR, XRD, TGA, and FE-SEM. The OSG/P(NIPAM-AM) hydrogels showed improved elasticity, increased thermal stability, new self-healing ability, and 4-fold enhanced tensile strength compared with the P(NIPAM-AM) hydrogels. Furthermore, the 5-FU-loaded OSG/P(NIPAM-AM) hydrogels exhibited effective temperature/pH-responsive drug release. Cytotoxicity experiments showed that the OSG/P(NIPAM-AM) hydrogels were non-toxic, suggesting that OSG/P(NIPAM-AM) hydrogels could have the potential for biomedical applications, such as stimuli-responsive drug delivery systems, wound healing, smart scaffolds, and tissue engineering.

Fabrication of Flexible pH-Responsive Agarose/Succinoglycan Hydrogels for Controlled Drug Release.

Agarose/succinoglycan hydrogels were prepared as pH-responsive drug delivery systems with significantly improved flexibility, thermostability, and porosity compared to agarose gels alone. Agarose/succinoglycan hydrogels were made using agarose and succinoglycan, a polysaccharide directly isolated from Sinorhizobium meliloti. Mechanical and physical properties of agarose/succinoglycan hydrogels were investigated using various instrumental methods such as rheological measurements, attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic analysis, X-ray diffraction (XRD), and field-emission scanning electron microscopy (FE-SEM). The results showed that the agarose/succinoglycan hydrogels became flexible and stable network gels with an improved swelling pattern in basic solution compared to the hard and brittle agarose gel alone. In addition, these hydrogels showed a pH-responsive delivery of ciprofloxacin (CPFX), with a cumulative release of ~41% within 35 h at pH 1.2 and complete release at pH 7.4. Agarose/succinoglycan hydrogels also proved to be non-toxic as a result of the cell cytotoxicity test, suggesting that these hydrogels would be a potential natural biomaterial for biomedical applications such as various drug delivery system and cell culture scaffolds.

pH-Responsive Succinoglycan-Carboxymethyl Cellulose Hydrogels with Highly Improved Mechanical Strength for Controlled Drug Delivery Systems.

Carboxymethyl cellulose (CMC)-based hydrogels are generally superabsorbent and biocompatible, but their low mechanical strength limits their application. To overcome these drawbacks, we used bacterial succinoglycan (SG), a biocompatible natural polysaccharide, as a double crosslinking strategy to produce novel interpenetrating polymer network (IPN) hydrogels in a non-bead form. These new SG/CMC-based IPN hydrogels significantly increased the mechanical strength while maintaining the characteristic superabsorbent property of CMC-based hydrogels. The SG/CMC gels exhibited an 8.5-fold improvement in compressive stress and up to a 6.5-fold higher storage modulus (G') at the same strain compared to the CMC alone gels. Furthermore, SG/CMC gels not only showed pH-controlled drug release for 5-fluorouracil but also did not show any cytotoxicity to HEK-293 cells. This suggests that SG/CMC hydrogels could be used as future biomedical biomaterials for drug delivery.

Preparation of Succinoglycan Hydrogel Coordinated With Fe3+ Ions for Controlled Drug Delivery.

Hydrogel materials with a gel-sol conversion due to external environmental changes have potential applications in a wide range of fields, including controlled drug delivery. Succinoglycans are anionic extracellular polysaccharides produced by various bacteria, including Sinorhizobium species, which have diverse applications. In this study, the rheological analysis confirmed that succinoglycan produced by Sinorhizobium meliloti Rm 1021 binds weakly to various metal ions, including Fe2+ cations, to maintain a sol form, and binds strongly to Fe3+ cations to maintain a gel form. The Fe3+-coordinated succinoglycan (Fe3+-SG) hydrogel was analyzed by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, circular dichroism (CD), and field-emission scanning electron microscopy (FE-SEM). Our results revealed that the Fe3+ cations that coordinated with succinoglycan were converted to Fe2+ by a reducing agent and visible light, promoting a gel-sol conversion. The Fe3+-SG hydrogel was then successfully used for controlled drug delivery based on gel-sol conversion in the presence of reducing agents and visible light. As succinoglycan is nontoxic, it is a potential material for controlled drug delivery.

Azobenzene-grafted carboxymethyl cellulose hydrogels with photo-switchable, reduction-responsive and self-healing properties for a controlled drug release system.

In this study, multifunctional hydrogels containing host-guest complex formation between azobenzene-grafted carboxymethyl cellulose (CMC-Azo) and ß-cyclodextrin (CD) dimers connected by disulfide bonds with agarose for structural support were prepared. The obtained hydrogels exhibited self-healing properties by host-guest complexation as well as gel-sol phase transition in response to ultraviolet (UV) light and reducing agents. Photo-switchable properties of the hydrogels depend on changes in the complex formation of CD-dimers through the trans(450 nm) to cis(365 nm) photo-isomerization of azobenzene. The tensile and strain sweep tests confirmed that the hydrogel's self-healing ability was 79.44% and 81.59%, respectively. In addition, drug release from the hydrogels was controlled to accelerate to 80% in 3 h using UV light or reducing agent. Since the suggested photo-switchable, reduction-responsive, and self-healable hydrogels are non-cytotoxic, they can be potentially applied as biomedical materials in the development of hydrogel-based drug release systems.

Carboxymethyl cyclosophoraoses as a flexible pH-responsive solubilizer for pindolol.

In the present study, cyclosophoraoses (CyS) (ß-1,2 linked cyclic glucans, with glucopyranose units ranging from 17 to 23) isolated from Rhizobium leguminosarum biovar viciae VF-39 were modified with carboxymethyl (CM) groups, and the pH-sensitive complexation of CM CyS with pindolol was investigated. The solubility of pindolol increased 32-fold by its complexation with 5mM CM CyS at pH 10, whereas it shows no significant change at pH 3. Pindolol, a ß-adrenergic blocking agent, has a hydrophobic nature at non-ionized state, and CM CyS could solubilize efficiently pindolol in a high alkaline solution. The carboxymethylation of flexible CyS allows them to present a more suitable cavity for the hydrophobic pindolol at pH 10, which is differentiated from CM ß-cyclodextrin (ß-CD). It can be interpreted as that the anionic repulsion effectively modulates the flexible and distorted conformation of CyS rather than rigid annular shape of ß-CD. Resultingly, the highly solubilized CM CyS/pindolol complex was characterized by UV-vis, T1 relaxation, ROESY, DOSY NMR spectroscopy, FT-IR spectroscopy, SEM, and molecular modeling studies. The antioxidant activity of pindolol was also improved 260% in the complex compared to free pindolol. The use of flexible host molecules with pH-responsive substituents would be applied in the development of smart systems for sensing or in biomedical fields.