No abstract

Crystallization processes are in general sensitive to detailed conditions, but our present understanding of underlying mechanisms is insufficient. A crystallizable chain within a diblock copolymer assembly is expected to couple curvature to crystallization and thereby impact rigidity as well as preferred morphology, but the effects on dispersed phases have remained unclear. The hydrophobic polymer polycaprolactone (PCL) is semi-crystalline in bulk (T m = 60°C) and is shown here to generate flexible worm micelles or rigid vesicles in water from several dozen polyethyleneoxide-based diblocks (PEO-PCL). Despite the fact that `worms' have a mean curvature between that of vesicles and spherical micelles, `worms' are seen only within a narrow, process-dependent wedge of morphological phase space that is deep within the vesicle phase. Fluorescence imaging shows worms are predominantly in one of two states -either entirely flexible with dynamic thermal undulations or fully rigid; only a few worms appear rigid at room temperature (T << T m ), indicating suppression of crystallization by both curvature and PCL hydration. Worm rigidification, which depends on molecular weight, is also prevented by copolymerization of caprolactone with just 10% racemic lactide that otherwise has little impact on bulk crystallinity. In contrast to worms, vesicles of PEO-PCL are always rigid and typically leaky. Defects between crystallite domains induce dislocation-roughening with focal leakiness although select PEO-PCL -which classical surfactant arguments would predict make worms -yield vesicles that retain encapsulant and appear smooth, suggesting a gel or glassy state. Hydration in dispersion thus tends to selectively soften high curvature microphases.Keywords block copolymer; worm micelle; polymersome; crystallinity Corresponding: discher@seas.upenn.edu. Supporting Information. Molecular details of all polymers synthesized, calculation of polymer distribution in assemblies, AFM and fluorescence microscopy images, DLS and dye encapsulation studies, movies of worm micelles, persistence length measurement of worm micelles, procedure for measurement of contour lengths, and phase contrast images of OCL (2, 13.5) can be found in Supporting Information. Supporting Information is available free of charge on the internet at

The aim of this study was to develop micelle-forming poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL)-based block copolymers bearing functional side groups on the PCL block. Substituted monomer, i.e, α-benzyl carboxylate-ε-caprolactone, was synthesized by anionic activation of ε-caprolactone and further treatment with benzyl chloroformate. Successful substitution of benzyl carboxylate on ε-caprolactone monomer was evidenced by 1H NMR and mass spectroscopy. Ring-opening polymerization of α-benzyl carboxylate-ε-caprolactone with methoxy PEO (5000 g mol-1) as initiator and stannous octoate as catalyst was used to prepare PEO-b-poly(α-benzyl carboxylate ε-caprolactone) (PEO-b-PBCL). Further catalytic debenzylation of PEO-b-PBCL produced PEO-b-poly(α-carboxyl-ε-caprolactone) (PEO-b-PCCL). Ring-opening polymerization of a ε-caprolactone/α-benzyl carboxylate-ε-caprolactone mixture and further reduction of the product were also used to prepare block copolymers with various degrees of benzyl carboxylate or carboxyl group substitution. The calculated molecular weights determined by 1H NMR and gel permeation chromatography (GPC) for block copolymers were in good agreement with the theoretical values. The polydispersity of PEO-b-PBCL and PEO-b-PCCL block copolymers was 1.74 and 1.52, respectively. PEO-b-PBCL and PEO-b-PCCL block copolymers assembled to spherical micelles having average diameters of 62 and 20 nm based on dynamic light scattering (DLS) measurement, respectively. PEO-b-PBCL formed micelles at extremely low concentrations (cmc of 9.8 × 10-2 μM). The presence of carboxylic group on the PCCL block raised the cmc of PEO-b-PCCL to 1220 × 10-2 μM. For block copolymers with PCL-co-PCCL core structures, a decrease in cmc as well as an increase in size was observed as the level of PCL to PCCL was raised. Novel PEO-b-poly(ester) block copolymers with aromatic and reactive side groups on the polyester block have tremendous potential in the design of optimized carriers for the delivery of various therapeutic agents, as they can assemble to biodegradable nanoscopic micelles with chemically tailorable core structures.

‘Endothelial cells lining vascular luminal surface represent an important site of signaling and injurious effects of reactive oxygen species (ROS) produced by other cells and endothelium itself in ischemia, inflammation and other pathological conditions. Targeted delivery of ROS modulating enzymes conjugated with antibodies to endothelial surface molecules (vascular immunotargeting) provides site-specific interventions in the endothelial ROS, unattainable by other formulations including PEG-modified enzymes. Targeting of ROS generating enzymes (e.g., glucose oxidase) provides ROS- and site-specific models of endothelial oxidative stress, whereas targeting of antioxidant enzymes SOD and catalase offers site-specific quenching of superoxide anion and H2O2. These targeted antioxidant interventions help to clarify specific role of endothelial ROS in vascular and pulmonary pathologies and provide basis for design of targeted therapeutics for treatment of these pathologies. In particular, antibody/catalase conjugates alleviate acute lung ischemia/reperfusion injury, whereas antibody/SOD conjugates inhibit ROS-mediated vasoconstriction and inflammatory endothelial signaling. Encapsulation in protease-resistant, ROS-permeable carriers targeted to endothelium prolongs protective effects of antioxidant enzymes, further diversifying the means for targeted modulation of endothelial ROS.

No abstract