Poly(Ethylene Glycol)-b-Poly(D,L-Lactide) Nanoparticles as Potential Carriers for Anticancer Drug Oxaliplatin

Nanoparticles based on biocompatible methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG$_{113}$-b-P(D,L)LAn) copolymers as potential vehicles for the anticancer agent oxaliplatin were prepared by a nanoprecipitation technique. It was demonstrated that an increase in the hydrophobic PLA block length from 62 to 173 monomer units leads to an increase of the size of nanoparticles from 32 to 56 nm. Small-angle X-ray scattering studies confirmed the “core-corona” structure of mPEG$_{113}$-b-P(D,L)LAn nanoparticles and oxaliplatin loading. It was suggested that hydrophilic oxaliplatin is adsorbed on the core-corona interface of the nanoparticles during the nanoprecipitation process. The oxaliplatin loading content decreased from 3.8 to 1.5% wt./wt. (with initial loading of 5% wt./wt.) with increasing PLA block length. Thus, the highest loading content of the anticancer drug oxaliplatin with its encapsulation efficiency of 76% in mPEG$_{113}$-b-P(D,L)LAn nanoparticles can be achieved for block copolymer with short hydrophobic block

Effect of Composition and Molecular Structure of Poly( l -lactic acid)/Poly(ethylene oxide) Block Copolymers on Micellar Morphology in Aqueous Solution

The effect of the hydrophobic block length in diblock (PLLA$_x$-b-PEO$_{113}$, x = 64, 166, 418) and triblock (PLLA$_y$-b-PEO$_{91}$-b-PLLA$_y$, y = 30, 52, 120) copolymers of l-lactic acid and ethylene oxide on the structure of micelles prepared by dialysis was studied by wide- and small-angle X-ray scattering in dilute aqueous solution, dynamic light scattering, transmission electron microscopy, atomic force microscopy, and force spectroscopy. It was found that the size of the crystalline PLLA core is weakly dependent on the PLLA block length. In addition to individual micelles, a number of their micellar clusters were detected with characteristic distance between adjacent micelle cores decreasing with an increase in PLLA block length. This effect was explained by the change in the conformation of PEO chains forming the micellar corona because of their overcrowding. Force spectroscopy experiments also reveal a more stretched conformation of the PEO chains for the block copolymers with a shorter PLLA block. A model describing the structure of the individual micelles and their clusters was proposed

Polymer Micelles with Hydrophobic Core and Ionic Amphiphilic Corona. 2. Starlike Distribution of Charged and Nonpolar Blocks in Corona

Mixed polymer micelles with hydrophobic polystyrene (PS) core and ionic amphiphilic poly­(4-vinylpyridine)/poly­(N-ethyl-4-vinylpyridinium bromide) corona (P4VP/PEVP) spontaneously self-assembled from mixtures of PS-<i>b</i>-PEVP and PS-<i>b</i>-P4VP macromolecules in dimethylformamide/methanol/water selective solvent. The fraction of PEVP units in corona was β = [PEVP]/([PEVP] + [P4VP]) = 0.05–1.0. Micelles were transferred into pure water via dialysis technique and pH was adjusted to 9, where P4VP blocks are insoluble. Structural characteristics of micelles as a function of corona composition β were investigated. Methods of dynamic and static light scattering, electrophoretic mobility measurements, sedimentation velocity, transmission electron microscopy, and UV spectrophotometry were applied. Spherical morphology with core (PS)–shell (P4VP)–corona (PEVP) organization was postulated. Micelles demonstrated a remarkable inflection in structural characteristics near β ∼ 0.5–0.7. Above this region, aggregation number (<i>m</i>), core and corona radii of mixed micelles coincided with those of individual PS-<i>b</i>-PEVP micelles. When β decreased below 0.5, dramatic growth of aggregation number was observed, accompanied by growth in micelle size and stretching PEVP chains. At β below 0.2, dispersions of mixed micelles were unstable and easily precipitated upon addition of NaCl. Scaling relationships between micelle characteristics and β were obtained via minimization the micelle free energy, taking into account electrostatic, osmotic, volume, and surface contributions. Theoretical estimations predicted dramatic influence of β on aggregation number, <i>m</i> ∼ β^–3. This result is in general agreement with experimental data and confirms the correctness of the core–shell–corona model. The inflection in micelle characteristics entails drastic changes in micelle dispersion stability in the presence of oppositely charged polymeric (sodium polymethacrylate) or amphiphilic (sodium dodecyl sulfate) complexing agents

Polymer Micelles with Hydrophobic Core and Ionic Amphiphilic Corona. 1. Statistical Distribution of Charged and Nonpolar Units in Corona

Polymer micelles with hydrophobic polystyrene (PS) core and ionic amphiphilic corona from charged <i>N</i>-ethyl-4-vinylpyridinium bromide (EVP) and uncharged 4-vinylpyridine (4VP) units spontaneously self-assembled from PS-<i>block</i>-poly­(4VP-<i>stat</i>-EVP) macromolecules in mixed dimethylformamide/methanol/water solvent. The fraction of statistically distributed EVP units in corona-forming block is β = [EVP]/([EVP]+[4VP]) = 0.3–1. Micelles were transferred into water via dialysis technique, and pH was adjusted to 9, where 4VP is insoluble. Structural characteristics of micelles were investigated both experimentally and theoretically as a function of corona composition β. Methods of dynamic and static light scattering, electrophoretic mobility measurements, sedimentation velocity, transmission electron microscopy, and UV spectrophotometry were applied. All micelles possessed spherical morphology. The aggregation number, structure, and electrophoretic mobility of micelles changed in a jumplike manner near β ∼ 0.6–0.75. Below and above this region, micelle characteristics were constant or insignificantly changed upon β. Theoretical dependencies for micelle aggregation number, corona dimensions, and fraction of small counterions outside corona versus β were derived via minimization the micelle free energy, taking into account surface, volume, electrostatic, and elastic contributions of chain units and translational entropy of mobile counterions. Theoretical estimations also point onto a sharp structural transition at a certain corona composition. The abrupt reorganization of micelle structure at β ∼ 0.6–0.75 entails dramatic changes in micelle dispersion stability in the presence of NaCl or in the presence of oppositely charged polymeric (sodium polymethacrylate) or amphiphilic (sodium dodecyl sulfate) complexing agents

T-Cadherin Deficiency Is Associated with Increased Blood Pressure after Physical Activity

T-cadherin is a regulator of blood vessel remodeling and angiogenesis, involved in adiponectin-mediated protective effects in the cardiovascular system and in skeletal muscles. GWAS study has previously demonstrated a SNP in the Cdh13 gene to be associated with hypertension. However, the role of T-cadherin in regulating blood pressure has not been experimentally elucidated. Herein, we generated Cdh13∆Exon3 mice lacking exon 3 in the Cdh13 gene and described their phenotype. Cdh13∆Exon3 mice exhibited normal gross morphology, life expectancy, and breeding capacity. Meanwhile, their body weight was considerably lower than of WT mice. When running on a treadmill, the time spent running and the distance covered by Cdh13∆Exon3 mice was similar to that of WT. The resting blood pressure in Cdh13∆Exon3 mice was slightly higher than in WT, however, upon intensive physical training their systolic blood pressure was significantly elevated. While adiponectin content in the myocardium of Cdh13∆Exon3 and WT mice was within the same range, adiponectin plasma level was 4.37-fold higher in Cdh13∆Exon3 mice. Moreover, intensive physical training augmented the AMPK phosphorylation in the skeletal muscles and myocardium of Cdh13∆Exon3 mice as compared to WT. Our data highlight a critically important role of T-cadherin in regulation of blood pressure and stamina in mice, and may shed light on the pathogenesis of hypertension