Photocleavable Polymer Cubosomes: Synthesis, Self-Assembly, and Photorelease.

Polymer cubosomes (PCs) are a recent class of self-assembled block copolymer (BCP) microparticles with an accessible periodic channel system. Most reported PCs consist of a polystyrene scaffold, which provides mechanical stability for templating but has a limited intrinsic functionality. Here, we report the synthesis of photocleavable BCPs with compositions suitable for PC formation. We analyze the self-assembly mechanism and study the model release of dyes during irradiation, where the transition of the BCPs from amphiphilic to bishydrophilic causes the rapid disassembly of the PCs. A combination of modeling and experiment shows that the evolution of PCs proceeds first via liquid-liquid phase separation into polymer-rich droplets, followed by microphase separation within this droplet confinement, and finally, membrane reorganization into high internal order. This insight may encourage exploration of alternative preparation strategies to better control the size and homogeneity of PCs.

Challenges of nanoparticle albumin bound (nab™) technology: Comparative study of Abraxane® with a newly developed albumin-stabilized itraconazole nanosuspension.

Nanoparticle albumin bound™ (nab™) technology is an established delivery platform for development of albumin stabilized nanoparticles as drug delivery systems for poorly water-soluble drugs. By using albumin for particle stabilization, nab™ technology does not require solubilizers or emulsifiers for the formulation of poorly water-soluble drugs for intravenous use. Despite the great potential, however, to date only two products based on nab™ technology have been approved by the Food and Drug Administration: Abraxane® (nab™ paclitaxel) and Fyarro® (nab™ rapamycin). In this study, the commercially available product Abraxane® was characterized in comparison to an albumin stabilized nanosuspension for the poorly water-soluble drug itraconazole. The aim of this study was to identify critical product parameters of the nanosuspensions depending on the manufacturing process in order to assess the transferability of nab™ technology to other drugs. The colloidal properties, stabilizing protein composition and particle disintegration behavior were analyzed. In addition, studies were carried out on the impact of the key process step, the high-pressure homogenization, using a design of experiments (DoE) approach. A nanosuspension comprising spherical, stable drug nanoparticles stabilized by a large fraction of dissolved albumin around the nanoparticles were identified. During the manufacturing process, the drug core was coated with a layer of albumin, which was cross-linked to a certain level. The Abraxane® and itraconazole suspensions differed in the analyzed protein fraction, with stronger cross-linking at the particle surface for Abraxane®. Both active pharmaceutical ingredients were present in the amorphous state as nanoparticles. In vitro disintegration studies performed to mimic a strong dilution during intravenous application showed the disintegration of the nanoparticles. All in all, the analysis underlined the transferability of the nab™ technology to selected other poorly water-soluble drugs with the great advantage of eliminating solubilizers and emulsifiers for intravenous applications.

Water-soluble polyphosphonate-based bottlebrush copolymers via aqueous ring-opening metathesis polymerization.

Ring-opening metathesis polymerization (ROMP) is a versatile method for synthesizing complex macromolecules from various functional monomers. In this work, we report the synthesis of water-soluble and degradable bottlebrush polymers, based on polyphosphoesters (PPEs) via ROMP. First, PPE-macromonomers were synthesized via organocatalytic anionic ring-opening polymerization of 2-ethyl-2-oxo-1,3,2-dioxaphospholane using N-(hydroxyethyl)-cis-5-norbornene-exo-2,3-dicarboximide as the initiator and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the catalyst. The resulting norbornene-based macromonomers had degrees of polymerization (DPn) ranging from 25 to 243 and narrow molar mass dispersity (D ≤ 1.10). Subsequently, these macromonomers were used in ROMP with the Grubbs 3rd-generation bispyridyl complex (Ru-G3) to produce a library of well-defined bottlebrush polymers. The ROMP was carried out either in dioxane or in aqueous conditions, resulting in well-defined and water-soluble bottlebrush PPEs. Furthermore, a two-step protocol was employed to synthesize double hydrophilic diblock bottlebrush copolymers via ROMP in water at neutral pH-values. This general protocol enabled the direct combination of PPEs with ROMP to synthesize well-defined bottlebrush polymers and block copolymers in water. Degradation of the PPE side chains was proven resulting in low molar mass degradation products only. The biocompatible and biodegradable nature of PPEs makes this pathway promising for designing novel biomedical drug carriers or viscosity modifiers, as well as many other potential applications.

Triglyceride-filled albumin-based nanocapsules: A promising new system to avoid discarding poorly water-soluble drug candidates.

Even though current drug discovery provides a variety of potential drug candidates, many of those substances are difficult to formulate due to their poor water-solubility. To overcome this obstacle a technological formulation is crucial. Albumin-based nanocarriers are a possible intravenous delivery system which is already approved and commercially available. However, no universal carrier for poorly water-soluble substances is found yet. In the present study, new preparation processes for nanocapsules consisting of a medium-chain triglyceride (MCT) core and a human serum albumin (HSA) shell were developed. The nanocarrier system exhibits desirable physicochemical properties with a hydrodynamic diameter of 150 nm and a polydispersity index of 0.1. Furthermore, the nanocapsules were stable towards the addition of electrolytes and also in basic to neutral pH range. The nanocapsules were storage stable for at least 7 months at 4 °C and could also be lyophilized to reach an even longer shelf life of at least 21 months. In addition, the nanocapsule system showed no cytotoxicity in cell culture. The developed system represents a suitable carrier for a variety of different poorly water-soluble drug substances (e.g., fenofibrate, naproxen, indomethacin) showing a high potential for a universal formulation platform for further lipophilic active pharmaceutical ingredients (APIs).

Janus nanoplates, -bowls, and -cups: controlling size and curvature via terpolymer/homopolymer blending in 3D confinement.

The synthesis and properties of Janus nanoparticles with spherical, cylindrical, and disk-like shapes are nowadays rather well understood. Other topologies such as nanorings and bowl-shaped Janus nanoparticles are believed to show distinctly different solution behavior and interaction with interfaces, but limitations in their synthesis currently prevents a proper investigation of these properties. Especially the combination of shape- and surface-anisotropy of bowl-shaped Janus nanoparticles could result in enhanced selectivity in uptake of cargo and enhanced directional diffusion. We here produce bowl-shaped Janus nanoparticles without noticeable side products through evaporation-induced confinement assembly (EICA) of triblock terpolymers blended with high molecular weight homopolymer. The triblock terpolymer phase separates from the homopolymer into spherical domes, where the terpolymer adopts a hemispherical lamella-lamella morphology (ll). Selective cross-linking, removal of the homopolymer, and disassembly of the microparticles releases the bowl-shaped Janus nanoparticles. The amount of blended homopolymer determines the size of the spherical dome, allowing to control particle curvature into flat Janus nanoplates, hemispherical Janus nanobowls, and deep Janus nanocups. The use of Shirasu Porous Glass (SPG) membranes with pore sizes in the range of dpore = 0.2-2.0 µm further provides control of particle diameter. Size and shape were analyzed with electron microscopy and the Janus character through selective surface decoration. The diffusion behavior of bowl-shaped Janus nanoparticles was investigated depending on particle curvature and anisotropy using angle-dependent dynamic light scattering.

Prismatic Block Copolymer Hexosomes.

Cubosomes and hexosomes are recent solution morphologies with an ordered porous structure and are observed for lipids and amphiphilic block copolymers (BCPs) with high hydrophobic fractions. Whereas lipid hexosomes typically exhibit a prismatic shape, BCP hexosomes have so far only been observed as closed microspheres where inner channels are not connected to the surrounding medium. Here, we describe the formation of flat, prismatic BCP hexosomes with pronounced faceting and a highly ordered lattice of hexagonally packed channels. We assemble polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP or SV) into the hexosome framework using polystyrene-block-poly(4-vinylpyridine)-block-poly(tert-butyl methacrylate) (PS-b-P4VP-b-PT or SVT) as a macromolecular surfactant in low-χ solvents. During solvent exchange, SV-rich domains form through liquid-liquid phase separation, followed by solidification and confined assembly within these domains. Since the final solvent (acetone) has a very low χ parameter toward PS and P4VP (equaling low interfacial tension), solidification of the hexosome occurs under confinement conditions that we term "supersoft". The low interfacial tension allows the stabilization of the hexagonal-prismatic shape, which originates from the hexagonal lattice of channels. Increasing the interfacial tension with polar cosolvents at some point dominates the particle shape, resulting in deformation of prismatic BCP hexosomes into spinning-top structures. The use of low-χ solvents for confined assembly of BCPs may allow the formation of unusual particle shapes simply by tuning the polymer-solvent interaction.

Confinement Assembly of Terpolymer-Based Janus Nanoparticles.

While the confinement assembly of block copolymers into functional microparticles has been extensively studied, little is known about the behavior of Janus nanoparticles (JNPs) in spherical confinement. Here, the confinement self-assembly of JNPs in drying emulsion droplets is investigated and their behavior compared to their ABC triblock terpolymer precursors. Emulsions of both materials are prepared using Shirasu Porous Glass membranes leading to narrow size distributions of the microparticles with average hydrodynamic radii in the range of Rh  = 250-500 nm (depending on the membrane pore radius, Rpore ). The internal structure of the microparticles is verified with transmission electron microscopy (TEM) on ultrathin cross sections and compared to the corresponding bulk morphologies. While the confinement assembly of terpolymers results in microparticles with ordered inner morphologies, order for JNPs diminishes when the Janus balance deviates from parity.

Morphology and Degradation of Multicompartment Microparticles Based on Semi-Crystalline Polystyrene-block-Polybutadiene-block-Poly(L-lactide) Triblock Terpolymers.

The confinement assembly of block copolymers shows great potential regarding the formation of functional microparticles with compartmentalized structure. Although a large variety of block chemistries have already been used, less is known about microdomain degradation, which could lead to mesoporous microparticles with particularly complex morphologies for ABC triblock terpolymers. Here, we report on the formation of triblock terpolymer-based, multicompartment microparticles (MMs) and the selective degradation of domains into mesoporous microparticles. A series of polystyrene-block-polybutadiene-block-poly(L-lactide) (PS-b-PB-b-PLLA, SBL) triblock terpolymers was synthesized by a combination of anionic vinyl and ring-opening polymerization, which were transformed into microparticles through evaporation-induced confinement assembly. Despite different block compositions and the presence of a crystallizable PLLA block, we mainly identified hexagonally packed cylinders with a PLLA core and PB shell embedded in a PS matrix. Emulsions were prepared with Shirasu Porous Glass (SPG) membranes leading to a narrow size distribution of the microparticles and control of the average particle diameter, d ≈ 0.4 µm-1.8 µm. The core-shell cylinders lie parallel to the surface for particle diameters d < 0.5 µm and progressively more perpendicular for larger particles d > 0.8 µm as verified with scanning and transmission electron microscopy and particle cross-sections. Finally, the selective degradation of the PLLA cylinders under basic conditions resulted in mesoporous microparticles with a pronounced surface roughness.

Biodegradable supramolecular micelles via host-guest interaction of cyclodextrin-terminated polypeptides and adamantane-terminated polycaprolactones.

Biodegradable supramolecular micelles were prepared exploiting the host-guest interaction of cyclodextrin and adamantane. Cyclodextrin-initiated polypeptides acted as the hydrophilic corona, whereas adamantane-terminated polycaprolactones served as the hydrophobic core.