Cyclodextrin modulation of gallic acid in vitro antibacterial activity

The substitution of large spectrum antibiotics for natural bioactive molecules (especially polyphenolics) for the treatment of wound infections has come into prominence in the pharmaceutical industry. However, the use of such molecules depends on their stability during environmental stress and on their ability to reach the action site without losing biological properties. The application of cyclodextrins as a vehicle for polyphenolics protection has been documented and appears to enhance the properties of bioactive molecules. Therefore, the encapsulation of gallic acid, an antibacterial agent with low stability, by -cyclodextrin, (2-hydroxy) propyl--cyclodextrin and methyl--cyclodextrin, was investigated. Encapsulation by -cyclodextrin was confirmed for pH 3 and 5, with similar stability parameters. The (2-hydroxy) propyl--cyclodextrin and methyl--cyclodextrin interactions with gallic acid were only confirmed at pH 3. Among the three cyclodextrins, better gallic acid encapsulation were observed for (2-hydroxy) propyl--cyclodextrin, followed by -cyclodextrin and methyl--cyclodextrin. The effect of cyclodextrin encapsulation on the gallic acid antibacterial activity was also analysed. The antibacterial activity of the inclusion complexes was investigated here for the first time. According to the results, encapsulation of gallic acid by (2-hydroxy) propyl--cyclodextrin seems to be a viable option for the treatment of skin and soft tissue infections, since this inclusion complex has good stability and antibacterial activity.The authors are grateful for the FCT Strategic Project PEst-OE/EQB/LA0023/2013 and the Project "BioHealth-Biotechnology and Bioengineering approaches to improve health quality", Ref. NORTE-07-0124-FEDER-000027, co-funded by the "Programa Operacional Regional do Norte" (ON.2-O Novo Norte), QREN, FEDER. The authors also acknowledge the project "Consolidating Research Expertise and Resources on Cellular and Molecular Biotechnology at CEB/IBB", Ref. FCOMP-01-0124-FEDER-027462. This work is, also, funded by FEDER funds through the Operational Programme for Competitiveness Factors-COMPETE and National Funds through FCT-Foundation for Science and Technology under the project PEst-C/CTM/UI0264/2011. Additionally, the authors would like to thank the FCT for the grant for E. Pinho (SFRH/BD/62665/2009)

Self-Assembled Hydrogels Based on B-Cyclodextrin/Cholesterol Inclusion Complexes : Properties and Pharmaceutical Applications

Hydrogels, i.e. hydrophilic polymer networks that are capable of absorbing considerable quantities of water, are applied in a wide variety of biomedical and pharmaceutical applications, including soft contact lenses, drug delivery depots and tissue engineering scaffolds. Their high water content gives hydrogels a rubbery appearance, which minimizes irritation of surrounding tissue, and creates a natural environment for many encapsulated drugs (e.g. protein pharmaceuticals). In aqueous environment, hydrogels are held together by crosslinks, which are based on either covalent bonds or physical interactions between the hydrophilic polymers. The introduction of covalent bonds between the hydrophilic polymer chains requires chemical crosslinking reactions that might potentially affect the structure and biological activity of encapsulated pharmaceuticals. Furthermore, these chemical reactions often require crosslinking reagents or catalysts that are toxic towards cells. Because of these drawbacks, the use of physical crosslinks for the design of hydrogel systems is preferred. In such hydrogels the network is held together by non-permanent, reversible interactions between the polymer chains, such as ionic interactions, hydrophobic interactions, hydrogen bonds and specific biomimetic interactions. In the thesis of Frank van de Manakker, the synthesis and characterization of novel self-assembled hydrogels is described in which physical crosslinking is established by host-guest inclusion complexes between the cyclic oligosaccharide beta-cyclodextrin (betaCD) and the complementary guest molecule cholesterol. Hydrogel building blocks were prepared by end-modification of 8-arm star shaped poly(ethylene glycol) (PEG8) with either betaCD or cholesterol moieties via a hydrolytically cleavable succinyl linker. Mixing the resulting cholesterol- and betaCD-derivatized PEG8-molecules in aqueous solution led to hydrogel formation. Important gel properties, i.e. mechanical properties, gel degradation and protein release kinetics, could be tailored by a broad range of parameters, including the polymer concentration, B-?CD/cholesterol stoichiometry, PEG’s molecular weights and/or architecture, or by adding molecules that form competing inclusion complexes, e.g. adamantanecarboxylic acid and monoamino-derivatized betaCD. The physical nature of the gels did not only offer extra tools to manipulate gel properties, but also rendered the gels responsive towards external stimuli, such as temperature and mechanical stresses, which offered the opportunity to use the hydrogels as injectable, in situ gelling devices. When aqueous media (e.g. buffer and serum) were added on top of the self-assembled gels, hydrogel degradation was primarily mediated by surface erosion of dissociated PEG8 derivatives. This degradation mechanism, which is hardly observed for other hydrogel systems, also controlled protein release from the gels, which occurred at a constant rate and was nearly independent on protein size. Although at this stage, the in vivo stability of the hydrogels requires further improvement, the combination of tunable properties, high gel strengths (compared to other physically crosslinked hydrogels), the unique protein release mechanism, and easy preparation from biocompatible and well-available building blocks make these self-assembled, PEG8-based hydrogels attractive candidates for many pharmaceutical and biomedical applications, such as injectable devices for the delivery of protein pharmaceuticals

Supramolecular hydrogels formed by ß-cyclodextrin self-association and host–guest inclusion complexes

Supramolecular hydrogels are highly interesting for drug delivery and tissue engineering applications, especially those systems that display a combination of tunable properties, high mechanical strength and easy preparation from well-available and biocompatible building blocks. In the present paper, we show that the combination of free β-cyclodextrin (βCD) and 8-arm or linear cholesterol-derivatized poly(ethylene glycol) (PEG–chol) in aqueous solution resulted in the formation of almost fully elastic gels with storage moduli in the range of 10–500 kPa. X-Ray diffraction measurements demonstrated the presence of crystalline βCD domains in the hydrogel networks. Rheological experiments further proved that hydrogel formation is based on inclusion complex formation between these βCD clusters and cholesterol coupled to the terminal end of PEG. The observation that the gels were weakened by addition of the competitive βCD–guest molecule adamantanecarboxylic acid (ACA) supported the proposed gelation mechanism. The gel mechanical properties were dependent on temperature, concentration of cholesterol-derivatized PEG and/or βCD, PEG's molecular weight and its architecture. This hydrogel system can be considered as an excellent candidate for future applications in the biomedical and pharmaceutical fields

Pharmacological differences between human and guinea pig histamine H1 receptors: Asn84 (2.61) as key residue within an additional binding pocket in the H1 receptor

We tested several histamine

Effect of polymer composition on rheological and degradation properties of temperature-responsive gelling systems composed of acyl-capped PCLA-PEG-PCLA.

In this study, the ability to modulate the rheological and degradation properties of temperature-responsive gelling systems composed of acyl-capped poly(epsilon-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(epsilon-caprolactone-co-lactide) (PCLA-PEG-PCLA) triblock copolymers was investigated. Eight polymers with varying molecular weight of PCLA, caproyl/lactoyl ratio (CL/LA) and capped with either acetyl- or propionyl-groups were synthesized by ring-opening polymerization of L-lactide and epsilon-caprolactone in toluene using PEG as initiator and tin(II) 2-ethylhexanoate as catalyst, and subsequently reacted in solution with an excess of acyl chloride to yield fully acyl-capped PCLA-PEG-PCLA. The microstructure of the polymers was determined by (1)H NMR, and the thermal properties and crystallinity of the polymers in dry state and in 25 wt % aqueous systems were studied by differential scanning calorimetry and X-ray diffraction. Rheological and degradation/dissolution properties of aqueous systems composed of the polymers in 25 wt % aqueous systems were studied. (1)H NMR analysis revealed that the monomer sequence in the PCLA blocks was not fully random, resulting in relatively long CL sequences, even though transesterification was demonstrated by the enrichment with lactoyl units and the presence of PEG-OH end groups. Except the most hydrophilic polymer composed of acetyl-capped PCLA1400-PEG1500-PCLA1400 having a CL/LA molar ratio of 2.5, the polymers at 25 wt % in buffer were sols below room temperature and transformed into gels between room temperature and 37 degrees C, which makes them suitable as temperature-responsive gelling systems for drug delivery. Over a period of weeks at 37 degrees C, the systems containing polymers with long CL sequences (~8 CL) and propionyl end-groups became semicrystalline as shown by X-ray diffraction analysis. Degradation of the gels by dissolution at 37 degrees C took 100-150 days for the amorphous gels and 250-300 days for the semicrystalline gels. In conclusion, this study shows that changes in the polymer composition allow an easy but significant modulation of rheological and degradation properties