Amorphous solid dispersions of amphiphilic polymer excipients and indomethacin prepared by hot melt extrusion.

Improving the solubility of poorly water-soluble drugs is essential for enhancing bioavailability, formulation flexibility and reducing patient-to-patient variability. The preparation of amorphous solid dispersions (ASDs) is an attractive strategy to formulate such drugs, leading to higher apparent water solubility and therefore higher bioavailability. For such ASDs, water-soluble polymer excipients, such as poly(vinyl pyrrolidone) (PVP) or poly(vinyl pyrrolidone-co-vinyl acetate) (P(VP-co-VA)), are employed to solubilize and stabilize the drug against crystallization.

POxload: Machine Learning Estimates Drug Loadings of Polymeric Micelles.

Block copolymers, composed of poly(2-oxazoline)s and poly(2-oxazine)s, can serve as drug delivery systems; they form micelles that carry poorly water-soluble drugs. Many recent studies have investigated the effects of structural changes of the polymer and the hydrophobic cargo on drug loading. In this work, we combine these data to establish an extended formulation database.

Perfusable Tissue Bioprinted into a 3D-Printed Tailored Bioreactor System.

Bioprinting provides a powerful tool for regenerative medicine, as it allows tissue construction with a patient's specific geometry. However, tissue culture and maturation, commonly supported by dynamic bioreactors, are needed. We designed a workflow that creates an implant-specific bioreactor system, which is easily producible and customizable and supports cell cultivation and tissue maturation.

Biomimetic Connection of Transcutaneous Implants with Skin.

Bacterial infection is a crucial complication in implant restoration, in particular in permanent skin-penetrating implants. Therein, the resulting gap between transcutaneous implant and skin represents a permanent infection risk, limiting the field of application and the duration of application. To overcome this limitation, a tight physiological connection is required to achieve a biological and mechanical welding for a long-term stable closure including self-healing probabilities.

Structural Investigation on How Guest Loading of Poly(2-oxazoline)-Based Micelles Affects the Interaction with Simulated Intestinal Fluids.

Drug loading of polymer micelles can have a profound effect on their particle size and morphology as well as their physicochemical properties. In turn, this influences performance in biological environments. For oral delivery of drugs, the intestinal environment is key, and consequently, a thorough structural understanding of what happens at this material-biology interface is required to understand in vivo performance and tailor improved delivery vehicles.

Unravel the Tangle: Atomistic Insight into Ultrahigh Curcumin-Loaded Polymer Micelles.

Amphiphilic ABA-triblock copolymers, comprised of poly(2-oxazoline) and poly(2-oxazine), can solubilize poorly water-soluble molecules in a structure-dependent manner forming micelles with exceptionally high drug loading. All-atom molecular dynamics simulations are conducted on previously experimentally characterized, curcumin-loaded micelles to dissect the structure-property relationships. Polymer-drug interactions for different levels of drug loading and variation in polymer structures of both the inner hydrophobic core and outer hydrophilic shell are investigated.

Unraveling an Alternative Mechanism in Polymer Self-Assemblies: An Order-Order Transition with Unusual Molecular Interactions between Hydrophilic and Hydrophobic Polymer Blocks.

Polymer self-assembly leading to cooling-induced hydrogel formation is relatively rare for synthetic polymers and typically relies on H-bonding between repeat units. Here, we describe a non-H-bonding mechanism for a cooling-induced reversible order-order (sphere-to-worm) transition and related thermogelation of solutions of polymer self-assemblies. A multitude of complementary analytical tools allowed us to reveal that a significant fraction of the hydrophobic and hydrophilic repeat units of the underlying block copolymer is in close proximity in the gel state.

Investigation of cationic ring-opening polymerization of 2-oxazolines in the "green" solvent dihydrolevoglucosenone.

For about the last ten years, poly(2-oxazoline)s have attracted significant attention as potential material for biomedical applications in, e.g., drug delivery systems, tissue engineering and more.

Biological Activity , Absorption, BBB Penetration, and Tolerability of Nanoformulation of BT44:RET Agonist with Disease-Modifying Potential for the Treatment of Neurodegeneration.

BT44 is a novel, second-generation glial cell line-derived neurotropic factor mimetic with improved biological activity and is a lead compound for the treatment of neurodegenerative disorders. Like many other small molecules, it suffers from intrinsic poor aqueous solubility, posing significant hurdles at various levels for its preclinical development and clinical translation. Herein, we report a poly(2-oxazoline)s (POx)-based BT44 micellar nanoformulation with an ultrahigh drug-loading capacity of 47 wt %.

Merging bioresponsive release of insulin-like growth factor I with 3D printable thermogelling hydrogels.

3D printing of biomaterials enables spatial control of drug incorporation during automated manufacturing. This study links bioresponsive release of the anabolic biologic, insulin-like growth factor-I (IGF-I) in response to matrix metalloproteinases (MMP) to 3D printing using the block copolymer of poly(2-methyl-2-oxazoline) and thermoresponsive poly(2-n-propyl-2-oxazine) (POx-b-POzi). For that, a chemo-enzymatic synthesis was deployed, ligating IGF-I enzymatically to a protease sensitive linker (PSL), which was conjugated to a POx-b-POzi copolymer.

A thermogelling organic-inorganic hybrid hydrogel with excellent printability, shape fidelity and cytocompatibility for 3D bioprinting.

Alginates are the most commonly used bioink in biofabrication, but their rheological profiles make it very challenging to perform real 3D printing. In this study, an advanced hybrid hydrogel ink was developed, a mixture of thermogelling diblock copolymer, alginate and clay i.e.

Freeform direct laser writing of versatile topological 3D scaffolds enabled by intrinsic support hydrogel.

In this study, a novel approach to create arbitrarily shaped 3D hydrogel objects is presented, wherein freeform two-photon polymerization (2PP) is enabled by the combination of a photosensitive hydrogel and an intrinsic support matrix. This way, topologies without physical contact such as a highly porous 3D network of concatenated rings were realized, which are impossible to manufacture with most current 3D printing technologies. Micro-Raman and nanoindentation measurements show the possibility to control water uptake and hence tailor the Young's modulus of the structures the light dosage, proving the versatility of the concept regarding many scaffold characteristics that makes it well suited for cell specific cell culture as demonstrated by cultivation of human induced pluripotent stem cell derived cardiomyocytes.

Concentration and composition dependent aggregation of Pluronic- and Poly-(2-oxazolin)-Efavirenz formulations in biorelevant media.

Many drugs and drug candidates are poorly water-soluble. Intestinal fluids play an important role in their solubilization. However, the interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood.

An initiator- and catalyst-free hydrogel coating process for 3D printed medical-grade poly(ε-caprolactone).

Additive manufacturing or 3D printing as an umbrella term for various materials processing methods has distinct advantages over many other processing methods, including the ability to generate highly complex shapes and designs. However, the performance of any produced part not only depends on the material used and its shape, but is also critically dependent on its surface properties. Important features, such as wetting or fouling, critically depend mainly on the immediate surface energy.

Development of polymer-based nanoparticles for zileuton delivery to the lung: PMeOx and PMeOzi surface chemistry reduces interactions with mucins.

In this paper, two amphiphilic graft copolymers were synthesized by grafting polylactic acid (PLA) as hydrophobic chain and poly(2-methyl-2-oxazoline) (PMeOx) or poly(2-methyl-2-oxazine) (PMeOzi) as hydrophilic chain, respectively, to a backbone of α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA). These original graft copolymers were used to prepare nanoparticles delivering Zileuton in inhalation therapy. Among various tested methods, direct nanoprecipitation proved to be the best technique to prepare nanoparticles with the smallest dimensions, the narrowest dimensional distribution and a spherical shape.

From Thermogelling Hydrogels toward Functional Bioinks: Controlled Modification and Cytocompatible Crosslinking.

Hydrogels are key components in bioink formulations to ensure printability and stability in biofabrication. In this study, a well-known Diels-Alder two-step post-polymerization modification approach is introduced into thermogelling diblock copolymers, comprising poly(2-methyl-2-oxazoline) and thermoresponsive poly(2-n-propyl-2-oxazine). The diblock copolymers are partially hydrolyzed and subsequently modified by acid/amine coupling with furan and maleimide moieties.

An Inverse Thermogelling Bioink Based on an ABA-Type Poly(2-oxazoline) Amphiphile.

Hydrogels are key components in several biomedical research areas such as drug delivery, tissue engineering, and biofabrication. Here, a novel ABA-type triblock copolymer comprising poly(2-methyl-2-oxazoline) as the hydrophilic A blocks and poly(2-phenethyl-2-oxazoline) as the aromatic and hydrophobic B block is introduced. Above the critical micelle concentration, the polymer self-assembles into small spherical polymer micelles with a hydrodynamic radius of approx 8-8.

Development of a 3D printable and highly stretchable ternary organic-inorganic nanocomposite hydrogel.

Hydrogels that can be processed with additive manufacturing techniques and concomitantly possess favorable mechanical properties are interesting for many advanced applications. However, the development of novel ink materials with high intrinsic 3D printing performance has been proven to be a major challenge. Herein, a novel 3D printable organic-inorganic hybrid hydrogel is developed from three components, and characterized in detail in terms of rheological property, swelling behavior and composition.

Poly(2-oxazoline)- and Poly(2-oxazine)-Based Self-Assemblies, Polyplexes, and Drug Nanoformulations-An Update.

For many decades, poly(2-oxazoline)s and poly(2-oxazine)s, two closely related families of polymers, have led the life of a rather obscure research topic with only a few research groups world-wide working with them. This has changed in the last five to ten years, presumably triggered significantly by very promising clinical trials of the first poly(2-oxazoline)-based drug conjugate. The huge chemical and structural toolbox poly(2-oxazoline)s and poly(2-oxazine)s has been extended very significantly in the last few years, but their potential still remains largely untapped.

N-H HMQC solid-state NMR as a powerful tool to study amorphous formulations - an exemplary study of paclitaxel loaded polymer micelles.

Amorphous drug-polymer formulations are complex materials and often challenging to characterize, even more so if the small molecule component itself is increasingly complex. In this work, we present N-H HMQC magic-angle spinning (MAS) NMR experiments in the solid state as a promising tool to study amorphous formulations. Poly(2-oxazoline) based polymer micelles loaded with different amounts of the cancer drug paclitaxel serve to highlight the possibilities offered by these experiments: while the dense core of these polymeric micelles prevents NMR spectroscopic analysis in solution and the very similar N chemical shifts hamper a solid-state NMR characterization based on this nucleus, N is a very versatile alternative.

A tutorial translation of the description of the historically first polymer drug conjugate and its in vivo evaluation.

Preamble Polymer-drug conjugates have been intensively investigated for several decades, and even though their clinical success still lags behind the promise many researchers have placed in them, they are a mainstay in the fields of polymer therapeutics or nanomedicine. For many in the field, the seminal perspective paper by Helmut Ringsdorf from 1975 marks the beginning of this field of research. With more than one thousand citations, this paper has indubitably affected and inspired generations of researchers in the field, including the author of this translation.

Blood-Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models.

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the family of statins have been suggested as therapeutic options in various tumors. Atorvastatin is a statin with the potential to cross the blood-brain barrier; however, the concentrations necessary for a cytotoxic effect against cancer cells exceed the concentrations achievable via oral administration, which made the development of a novel atorvastatin formulation necessary. We characterized the drug loading and basic physicochemical characteristics of micellar atorvastatin formulations and tested their cytotoxicity against a panel of different glioblastoma cell lines.