Eric A. Appel

Ultrahigh-Water-Content Supramolecular Hydrogels Exhibiting Multistimuli Responsiveness

Hydrogels are three-dimensional networked materials that are similar to soft biological tissues and have highly variable mechanical properties, making them increasingly important in a variety of biomedical and industrial applications. Herein we report the preparation of extremely high water content hydrogels (up to 99.7% water by weight) driven by strong host-guest complexation with cucurbit[8]uril (CB[8]). Cellulosic derivatives and commodity polymers such as poly(vinyl alcohol) were modified with strongly binding guests for CB[8] ternary complex formation (K(eq) = 10(12) M(-2)). When these polymers were mixed in the presence of CB[8], whereby the overall solid content was 90% cellulosic, a lightly colored, transparent hydrogel was formed instantaneously. The supramolecular nature of these hydrogels affords them with highly tunable mechanical properties, and the dynamics of the CB[8] ternary complex cross-links allows for rapid self-healing of the materials after damage caused by deformation. Moreover, these hydrogels display responsivity to a multitude of external stimuli, including temperature, chemical potential, and competing guests. These materials are easily processed, and the simplicity of their preparation, their availability from inexpensive renewable resources, and the tunability of their properties are distinguishing features for many important water-based applications.

Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics

In vitro incubation of nanomaterials with plasma offer insights on biological interactions, but cannot fully explain the in vivo fate of nanomaterials. Here, we use a library of polymer nanoparticles to show how physicochemical characteristics influence blood circulation and early distribution. For particles with different diameters, surface hydrophilicity appears to mediate early clearance. Densities above a critical value of approximately 20 poly(ethylene glycol) chains (MW 5 kDa) per 100 nm2 prolong circulation times, irrespective of size. In knockout mice, clearance mechanisms are identified for nanoparticles with low and high steric protection. Studies in animals deficient in the C3 protein showed that complement activation could not explain differences in the clearance of nanoparticles. In nanoparticles with low poly(ethylene glycol) coverage, adsorption of apolipoproteins can prolong circulation times. In parallel, the low-density-lipoprotein receptor plays a predominant role in the clearance of nanoparticles, irrespective of poly(ethylene glycol) density. These results further our understanding of nanopharmacology.Understanding the interaction between nanoparticles and biomolecules is crucial for improving current drug-delivery systems. Here, the authors shed light on the essential role of the surface and other physicochemical properties of a library of nanoparticles on their in vivo pharmacokinetics.

Self-assembled hydrogels utilizing polymer–nanoparticle interactions

Mouldable hydrogels that flow upon applied stress and rapidly self-heal are increasingly utilised as they afford minimally invasive delivery and conformal application. Here we report a new paradigm for the fabrication of self-assembled hydrogels with shear-thinning and self-healing properties employing rationally engineered polymer-nanoparticle interactions. Biopolymer derivatives are linked together by selective adsorption to nanoparticles. The transient and reversible interactions between biopolymers and nanoparticles enable flow under applied shear stress, followed by rapid self-healing when the stress is relaxed. We develop a physical description of polymer-nanoparticle gel formation that is utilised to design biocompatible gels for minimally-invasive drug delivery. Owing to the hierarchical structure of the gel, both hydrophilic and hydrophobic drugs can be entrapped and delivered with differential release profiles, both in vitro and in vivo. The work introduces a facile and generalizable class of mouldable hydrogels amenable to a range of biomedical and industrial applications.

Triply Triggered Doxorubicin Release From Supramolecular Nanocontainers

The synthesis of a supramolecular double hydrophilic block copolymer (DHBC) held together by cucurbit[8]uril (CB[8]) ternary complexation and its subsequent self-assembly into micelles is described. This system is responsive to multiple external triggers including temperature, pH and the addition of a competitive guest. The supramolecular block copolymer assembly consists of poly(N-isopropylacrylamide) (PNIPAAm) as a thermoresponsive block and poly(dimethylaminoethylmethacrylate) (PDMAEMA) as a pH-responsive block. Moreover, encapsulation and controlled drug release was demonstrated with this system using the chemotherapeutic drug doxorubicin (DOX). This triple stimuli-responsive DHBC micelle system represents an evolution over conventional double stimuli-responsive covalent diblock copolymer systems and displayed a significant reduction in the viability of HeLa cells upon triggered release of DOX from the supramolecular micellar nanocontainers.

Formation of Single‐Chain Polymer Nanoparticles in Water through Host–Guest Interactions

The dynamic three-dimensional structures of enzymes are dictated by secondary bonding interactions and play a crucial role in both molecular recognition and allosteric regulation. Controlled crosslinking of single polymer chains in isolation, that can be seen as a mimic of the self-organization of enzymes, has previously been realized in organic solvents through crosslinking of multivalent polymer chains under highly dilute conditions. 2] In this instance, crosslinking must be specifically intramolecular to form these “self-collapsed” single-chain polymeric entities, which have been reported as discrete, spherical nanoparticulate structures. Whilst a few of the above systems are documented in the literature, where novel applications for such systems have been realized, only a small number are shown to be reversible and only one example exists in water. Moreover, the controlled folding and unfolding of a single polymer chain in water has not yet been realized. A completely reversible form of this system would be beneficial for many reasons, especially in light of one notable property of these nanoparticles (NPs), which is their ability to produce non-Einsteinian reductions in viscosity. Supramolecular crosslinking motifs exploit well-established non-covalent interactions and their incorporation into molecular constructs has led to the formation of materials with novel properties. Notable examples of such materials predominantly include gelating entities where intermolecular crosslinking leads to gel formation. This strategy has been particularly successful for systems that consist of polymeric subunits which are able to gel through multivalent functionality. Cucurbit[8]uril (CB[8]), a macrocylic host molecule capable of binding two aromatic guest molecules simultaneously, is a suitable candidate for such reversible crosslinking on account of the variety of guests available for binding. This allows for the use of guests with a range of orthogonal stimuli where guest binding can be controlled through simple external conditions (e.g. temperature, pH, light, competing guests), thus allowing for reversibility to be easily achieved. As a result, a variety of systems have already been produced bearing this reversible CB[8]-based crosslinking motif. Herein we document a CB[8]-mediated system for the preparation of metastable single-chain polymer nanoparticles. These nanoparticles are shown to form rapidly, are highly tunable and reversible and do not require protection chemistries (Figure 1).

Simple Approach to Stabilized Micelles Employing Miktoarm Terpolymers and Stereocomplexes with Application in Paclitaxel Delivery

A simple and versatile approach to miktoarm co- and terpolymers from carbonate functional oligomers is described. The key building block employed is a carboxylic acid functional cyclic carbonate, derived from 2,2-bis(methylol)propionic acid, that was readily coupled to a hydroxyl functional monomethylether poly(ethylene glycol) oligomer. Ring-opening of the cyclic carbonate using functional amines generates a carbamate linkage bearing a functional group capable of initiating either controlled radical or ring-opening polymerization, together with a primary hydroxyl group for ring-opening polymerization. Two tandem polymerization steps were possible which add the second two arms, thus generating the targeted ABC miktoarm terpolymer. The resulting amphiphilic miktoarm terpolymers containing poly(D- and L-lactide) formed polylactide stereocomplexes in the bulk. In aqueous solution, the stereocomplex mixture of Y-shaped miktoarm copolymers, poly(ethylene glycol)-poly(D-lactide)-poly(D-lactide) and poly(ethylene glycol)-poly(L-lactide)-poly(L-lactide), or the stereoblock miktoarm poly(ethylene glycol)-poly(D-lactide)-poly(L-lactide) form stabilized micelles with a significantly lower critical micelle concentration than those derived from conventional stereo regular linear or Y-shaped amphiphiles. This simple and versatile approach provides a useful synthetic route to complex macromolecular architectures that can assemble into stable micelles. These micelles provide high capacity for loading of the anticancer drug paclitaxel and possess narrow size distribution as well as unique structure, leading to sustained and near zero-ordered release of drug without significant initial burst.

Injectable Self‐Healing Glucose‐Responsive Hydrogels with pH‐Regulated Mechanical Properties

Dynamically restructuring pH-responsive hydrogels are synthesized, employing dynamic covalent chemistry between phenylboronic acid and cis-diol modified poly(ethylene glycol) macromonomers. These gels display shear-thinning behavior, followed by a rapid structural recovery (self-healing). Size-dependent in vitro controlled and glucose-responsive release of proteins from the hydrogel network, as well as the biocompatibility of the gels, are evaluated both in vitro and in vivo.

Sustained release of proteins from high water content supramolecular polymer hydrogels.

Self-assembled hydrogels with extremely high water content (up to 99.5%) and highly tunable mechanical properties were prepared from renewable cellulose derivatives. These hydrogels are easily processed and the simplicity of their preparation, their availability from inexpensive renewable resources, and the tunability of their mechanical properties are distinguishing for important biomedical applications. The protein release characteristics were investigated to determine the effect of both the protein molecular weight and polymer loadings of the hydrogels on the protein release rate. Extremely sustained release of bovine serum albumin is observed over the course of 160 days from supramolecular hydrogels containing only 1.5 wt% polymeric constituents. This sustained release far surpasses the current state of the art for protein release from a hydrogel, highlighting these materials as important potential candidates for sustained therapeutic applications.

Triggered insulin release studies of triply responsive supramolecular micelles

The synthesis of a supramolecular double hydrophilic glucose responsive block copolymer (DHBC) held together by cucurbit[8]uril (CB[8]) ternary complexation and its subsequent self-assembly into micelles is described. The supramolecular block copolymer assembly consists of poly(N-isopropylacrylamide) (PNIPAAm) and poly(acrylamidophenyl boronic acid) (PAAPBA) as temperature and glucose responsive blocks, respectively, and poly(dimethylacrylamide) (PDMAAm) as a hydrophilic block. Drug release studies of insulin-loaded micelles using three external triggers were studied with release of insulin achieved by changing temperature, glucose concentration or by adding a competitive guest for CB[8]. This system offers good control over the release of insulin under physiological conditions (pH 7.4, 37 °C). These exciting results suggest that this system could be a model for a clinically relevant drug delivery vehicle for diabetic treatment.

Bioinspired Alkenyl Amino Alcohol Ionizable Lipid Materials for Highly Potent In Vivo mRNA Delivery

Thousands of human diseases could be treated by selectively controlling the expression of specific proteins in vivo. A new series of alkenyl amino alcohol (AAA) ionizable lipid nanoparticles (LNPs) capable of delivering human mRNA with unprecedented levels of in vivo efficacy is demonstrated. This study highlights the importance of utilizing synthesis tools in tandem with biological inspiration to understand and improve nucleic acid delivery in vivo.