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(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-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 ε-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 °C, which makes them suitable as temperature-responsive gelling systems for drug delivery. Over a period of weeks at 37 °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 °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.

Cyclodextrin-based polymeric materials: synthesis, properties, and pharmaceutical/biomedical applications.

This review describes the synthesis, properties, and, in particular, biomedical and pharmaceutical applications of an upcoming class of polymeric networks and assemblies based on cyclodextrins (CDs). CDs are cyclic oligosaccharides composed of alpha-1,4-coupled d-glucose units, which contain a hydrophobic internal cavity that can act as a host for various, generally lipophilic, guest molecules. Because of this unique physicochemical property, commonly referred to as inclusion complex formation, CDs have often been used to design polymeric materials, such as hydrogels and nanoparticles. Polymeric systems based on CDs exhibit unique characteristics in terms of mechanical properties, stimuli-responsiveness, and drug release characteristics. In this contribution, first, an outline is given of covalently cross-linked polymeric networks in which CD moieties were structurally incorporated to modulate the network strength as well as the complexation and release of low molecular weight drugs. Second, physically assembled polymeric systems are discussed, of which the formation is accomplished by inclusion complexes between polymer-conjugated CDs and various guest molecule-derivatized polymers. Due to their physical nature, these polymeric systems are sensitive to external stimuli, such as temperature changes, shear forces and the presence of competing CD-binding molecules, which can be exploited to use these systems as injectable, in situ gelling devices. In recent years, many interesting CD-containing polymeric systems have been described in literature. These systems have to be optimized and extensively evaluated in preclinical studies concerning their safety and efficacy, making future clinical applications of these materials in the biomedical and pharmaceutical field feasible.

Rheological behavior of self-assembling PEG-beta-cyclodextrin/PEG-cholesterol hydrogels.

The rheological properties of a recently developed self-assembling hydrogel system composed of beta-cyclodextrin (betaCD)- and cholesterol-derivatized 8-arm star-shaped poly(ethylene glycol) (PEG8) were investigated. To understand and predict the gel rheological properties, data fitting with the Maxwell model as well as comparing the system's concentration-dependent behavior with Cates' model for reversibly breaking chains were performed. To investigate the influence of the polymer architecture, networks were also prepared by replacing the cholesterol-derivatized 8-arm star-shaped PEG by linear bifunctional PEG-cholesterol or by using 4-arm instead of 8-arm polymers. Rheological analysis showed that the 8-arm polymer-based mixtures yielded tight viscoelastic networks, but their storage and loss moduli significantly deviated from those predicted by the Maxwell model. The scaling of the plateau moduli, relaxation times, and zero-shear viscosities with concentration for gels composed of 8-arm cholesterol- and betaCD-derivatized PEG followed a power law with exponents higher than predicted by Cates' model. On the other hand, hydrogels in which linear bifunctional PEG-cholesterol was used instead of 8-arm star-shaped PEG-cholesterol or which were based on 4-arm polymers showed a substantially better fit with the Maxwell model and reduced differences between empirical and Cates' theoretical scaling exponents. Rheological analysis also showed that the hydrogels were thermoreversible. At low temperatures, the gels showed viscoelastic behavior due to slow overall relaxation of the polymer chains. At higher temperatures, however, a reduced number of betaCD/cholesterol complexes and concomitant faster chain relaxation processes eventually led to liquid-like behavior. The relationship between temperature and the relaxation time was used to determine an activation energy of 46 kJ/mol for breaking and reptation of the polymers.

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 H(1) receptor (H(1)R) and antagonists for their differences in agonists binding affinities between human and guinea pig H(1)Rs transiently expressed in African green monkey kidney (COS-7) cells. Especially, the bivalent agonist histaprodifen-histamine dimer (HP-HA) shows a higher affinity for guinea pig than for human H(1)Rs. Based on the structure of HP-HA, we have further identified VUF 4669 [7-(3-(4-(hydroxydiphenylmethyl)piperidin-1-yl)propoxy)-4-oxochroman-2-carboxylic acid] as a guinea pig-preferring H(1)R antagonist, demonstrating that the concept of species selectivity is not limited to agonists. To delineate the molecular mechanisms behind the observed species selectivity, we have created mutant human H(1)Rs in which amino acids were individually replaced by their guinea pig H(1)R counterparts. Residue Asn(84) (2.61) in transmembrane domain (TM) 2 seemed to act as a selectivity switch in the H(1)R. Molecular modeling and site-directed mutagenesis studies suggest that Asn(84) interacts with the conserved Tyr(458) (7.43) in TM7. Our data provide the first evidence that for some H(1)R ligands, the binding pocket is not only limited to TMs 3, 4, 5, and 6 but also comprises an additional pocket formed by TMs 2 and 7.