Selective and Tunable Galectin Binding of Glycopolymers Synthesized by a Generalizable Conjugation Method.

Glycopolymers, conjugates of synthetic polymers with pendant carbohydrates, are becoming increasingly important to probe the role of carbohydrates in cellular processes and for applications like biosensors and drug delivery. A library of glycopolymers bearing different sugar moieties was synthesized by grafting amino-functionalized sugars to poly(acrylic acid) via DMTMM coupling. Primary amines were introduced at the anomeric (C-1) position to a number of unprotected mono-, di-, and trisaccharides using ammonium carbamate and conjugated to poly(acrylic acid) of different molecular weights, synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. This approach provides a simple and efficient route for the preparation of glycopolymers that differ only in the identity or degree of substitution of the sugar moiety on the polymer. The binding parameters (ka, kd, and KD) of these new glycopolymers to galectins-1 and -3 were quantified using surface plasmon resonance. The galectins selectively bound only to lactose-containing polymers, and the binding affinity was dependent on the galectin type, degree of sugar substitution and the molecular weight of polymer chains. Binding to both galectin-1 and -3 increased with a higher degree of sugar substitution, and higher molecular weight of the polymer backbone, reaching KD values on the order of 10-11 M.

Glucose-Responsive Polymeric Micelles via Boronic Acid-Diol Complexation for Insulin Delivery at Neutral pH.

In the present study, glucose-responsive polymeric complex micelles based on the complexation of phenylboronic-acid-based (PBA-based) block copolymer and diol-functionalized polymers are reported. The phenylboronic-acid- and diol-based block copolymers were successfully synthesized in only two reaction steps using reversible addition-fragmentation chain-transfer (RAFT) polymerization and postpolymerization modification of the obtained poly[( N-acryloylmorpholine- block-( N-acryloylmorpholine- co-pentafluorophenyl acrylate)], poly[(AMP- b-(AMP- co-PFPA)], reactive block copolymer. The self-assembly of the complex micelles was investigated under neutral conditions using dynamic light scattering (DLS) and transmission electron microscopy (TEM). The interaction of the PBA block copolymer and diol-containing polymer via boronate ester bond was investigated by 1H NMR and UV-vis spectroscopy. The complex micelles enhanced the glucose responsiveness under physiological conditions compared to simple PBA micelles. Furthermore, the successful glucose-triggered release of FITC-insulin from the polymeric micelles was investigated.

Importance of Thermally Induced Aggregation on 19F Magnetic Resonance Imaging of Perfluoropolyether-Based Comb-Shaped Poly(2-oxazoline)s.

An understanding of thermally induced aggregation and consequent 19F magnetic resonance imaging (MRI) performance is essential for improved design of thermoresponsive 19F MRI contrast agents. Herein we describe a series of novel thermoresponsive perfluoropolyether (PFPE)-based comb-shaped poly(2-oxazoline)s (POxs) with different side-chain structures (2-methyl- (MeOx), 2-ethyl- (EtOx), and 2-( n-propyl)-2-oxazoline (nPrOx)). The comb polymers were prepared through reversible addition-fragmentation chain transfer (RAFT) polymerization of the respective oligo(2-oxazoline)acrylates using a perfluoropolyether macro-RAFT agent. The fluoropolyether chain end drives aggregation of the polymers, with small aggregates forming at 300 K for both poly(OMeOx5A)9-PFPE and poly(OEtOx4A)9-PFPE. The aggregates decrease in size and display increases in 19F MRI intensity with temperature, and at 350 K the MeOx polymers are in the form of unimers in solution, similar to the oligoethylene glycol (OEG)-based PFPE polymer. Above the TCP of poly(OEtOx4A)9-PFPE, the polymer forms large aggregates, and the 19F MR imaging performance is degraded. Likewise, poly(OnPrOx4A)-PFPE is above the LCST at all temperatures studied (300-350 K), and so weak imaging intensity is obtained. This report of novel thermoresponsive POx-based PFPE polymers highlights the importance of understanding self-association of polymers in solution and provides important insights for the development of "smart" thermoresponsive 19F MRI contrast agents.

Smart pH-Sensitive Nanogels for Controlled Release in an Acidic Environment.

The encapsulation of therapeutic compounds into nanosized delivery vectors has become an important strategy to improve efficiency and reduce side effects in drug delivery applications. Here, we report the synthesis of pH-sensitive nanogels, which are based on the monomer N-[(2,2-dimethyl-1,3-dioxolane)methyl]acrylamide (DMDOMA) bearing an acid cleavable acetal group. Degradation studies revealed that these nanogels hydrolyze under acidic conditions and degrade completely, depending on the cross-linker, but are stable in physiological environment. The best performing system was further studied regarding its release kinetics using the anticancer drug doxorubicin. In vitro studies revealed a good compatibility of the unloaded nanogel and the capability of the doxorubicin loaded nanogel to mediate cytotoxic effects in a concentration and time-dependent manner with an even higher efficiency than the free drug. Based on the investigated features, the presented nanogels represent a promising and conveniently prepared alternative to existing carrier systems for drug delivery.

Harnessing the Chemical Diversity of the Natural Product Magnolol for the Synthesis of Renewable, Degradable Neolignan Thermosets with Tunable Thermomechanical Characteristics and Antioxidant Activity.

Magnolol, a neolignan natural product with antioxidant properties, contains inherent, orthogonal, phenolic, and alkenyl reactive groups that were used in both direct thermoset synthesis, as well as the stepwise synthesis of a small library of monomers, followed by transformation into thermoset materials. Each monomer from the small library was prepared via a single step functionalization reaction of the phenolic groups of magnolol. Thermoset materials were realized through solvent-free, thiol-ene reactions, and the resulting cross-linked materials were each comprised of thioether and ester linkages, with one retaining the hydrophilic phenols from magnolol, another having the phenols protected as an acetonide, and two others incorporating the phenols into additional cross-linking sites via hydrolytically labile carbonates or stable ether linkages. With this diversity of chemical compositions and structures, the thermosets displayed a range of thermomechanical properties including glass transition temperatures, Tg, 29-52 °C, onset of thermal degradation, Td, from about 290-360 °C, and ultimate strength up to 50 MPa. These tunable materials were studied in their degradation and biological properties with the aim of exploiting the antioxidant properties of the natural product. Hydrolytic degradation occurred under basic conditions (pH = 11) in all thermosets, but with kinetics that were dependent upon their chemical structures and mechanical properties: 20% mass loss was observed at 5, 7, 27, and 40 weeks for the thermosets produced from magnolol directly, acetonide-protected magnolol, bis(allyl carbonate)-functionalized magnolol, and bis(allyl ether)-functionalized magnolol, respectively. Isolated degradation products and model compounds displayed antioxidant properties similar to magnolol, as determined by both UV-vis and in vitro reactive oxygen species (ROS) assays. As these magnolol-based thermosets were found to also allow for extended cell culture, these materials may serve as promising degradable biomaterials.

Review of Stimuli-Responsive Polymers in Drug Delivery and Textile Application.

This review describes some commercially available stimuli-responsive polymers of natural and synthetic origin, and their applications in drug delivery and textiles. The polymers of natural origin such as chitosan, cellulose, albumin, and gelatin are found to show both thermo-responsive and pH-responsive properties and these features of the biopolymers impart sensitivity to act differently under different temperatures and pH conditions. The stimuli-responsive characters of these natural polymers have been discussed in the review, and their respective applications in drug delivery and textile especially for textile-based transdermal therapy have been emphasized. Some practically important thermo-responsive polymers such as pluronic F127 (PF127) and poly(N-isopropylacrylamide) (pNIPAAm) of synthetic origin have been discussed in the review and they are of great importance commercially because of their in situ gel formation capacity. Some pH-responsive synthetic polymers have been discussed depending on their surface charge, and their drug delivery and textile applications have been discussed in this review. The selected stimuli-responsive polymers of synthetic origin are commercially available. Above all, the applications of bio-based or synthetic stimuli-responsive polymers in textile-based transdermal therapy are given special regard apart from their general drug delivery applications. A special insight has been given for stimuli-responsive hydrogel drug delivery systems for textile-based transdermal therapy, which is critical for the treatment of skin disease atopic dermatitis.

Functional Polymer Systems with Aggregation-Induced Emission and Stimuli Responses.

Functional polymer systems with stimuli responses have attracted great attention over the years due to their diverse range of applications. Such polymers are capable of altering their chemical and/or physical properties, such as chemical structures, chain conformation, solubility, shape, morphologies, and optical properties, in response to single or multiple stimuli. Among various stimuli-responsive polymers, those with aggregation-induced emission (AIE) properties possess the advantages of high sensitivity, fast response, large contrast, excellent photostability, and low background noise. The changes in fluorescence signal can be conveniently detected and monitored using portable instruments. The integration of AIE and stimuli responses into one polymer system provides a feasible and effective strategy for the development of smart polymers with high sensitivity to environmental variations. Here, we review the recent advances in the design, preparation, performance, and applications of functional synthetic polymer systems with AIE and stimuli responses. Various AIE-based polymer systems with responsiveness toward single physical or chemical stimuli as well as multiple stimuli are summarized with specific examples. The current challenges and perspectives on the future development of this research area will also be discussed at the end of this review.

Synthesis and characterization of timolol maleate-loaded quaternized chitosan-based thermosensitive hydrogel: A transparent topical ocular delivery system for the treatment of glaucoma.

The chitosan-based thermosensitive hydrogel is one of the attractive in situ forming drug delivery systems that are suggested for ophthalmic applications. However, the use of this thermogel has been limited by non-transparency, relatively low solubility and prolonged gelation time. In this study, a convenient approach has been reported to develop transparent thermosensitive hydrogel with suitable cytocompatibility and gelation properties for glaucoma treatment. After obtaining the optimum quaternization conditions, the developed in-situ gelling formulation of quaternized chitosan was achieved by mixing sodium hydrogen carbonate with ß-glycerophosphate as a gelling agent. The formulation was a solution below or at room temperature and turned to a transparent hydrogel around ocular surface temperature within several minutes. The results of thermal and rheological evaluations demonstrated that adding sodium hydrogen carbonate has a synergic effect in enhancing the thermosensitivity of the hydrogel. Also, the prepared hydrogels based on quaternized chitosan presented obvious porous architectures, good swelling, and degradability. Hemolysis and cytotoxicity evaluations suggested that the developed hydrogels indicated good biocompatibility as a drug carrier. Finally, the in vitro release profile of timolol maleate as an anti-glaucoma model drug showed the initial burst release in the early hours and a steady linear release of drug from the hydrogel over 1 week. The obtained results confirmed that the developed hydrogel can be considered as an efficient drug delivery candidate for glaucoma therapy.

Stimulus-responsive polymeric nanogels as smart drug delivery systems.

Nanogels are three-dimensional nanoscale networks formed by physically or chemically cross-linking polymers. Nanogels have been explored as drug delivery systems due to their advantageous properties, such as biocompatibility, high stability, tunable particle size, drug loading capacity, and possible modification of the surface for active targeting by attaching ligands that recognize cognate receptors on the target cells or tissues. Nanogels can be designed to be stimulus responsive, and react to internal or external stimuli such as pH, temperature, light and redox, thus resulting in the controlled release of loaded drugs. This "smart" targeting ability prevents drug accumulation in non-target tissues and minimizes the side effects of the drug. This review aims to provide an introduction to nanogels, their preparation methods, and to discuss the design of various stimulus-responsive nanogels that are able to provide controlled drug release in response to particular stimuli. STATEMENT OF SIGNIFICANCE: Smart and stimulus-responsive drug delivery is a rapidly growing area of biomaterial research. The explosive rise in nanotechnology and nanomedicine, has provided a host of nanoparticles and nanovehicles which may bewilder the uninitiated reader. This review will lay out the evidence that polymeric nanogels have an important role to play in the design of innovative drug delivery vehicles that respond to internal and external stimuli such as temperature, pH, redox, and light.

High-Throughput Combinatorial Synthesis of Stimuli-Responsive Materials.

Stimuli-responsive materials find wide applications in different biological and medical settings. Traditionally, stimuli-responsive materials are synthesized and evaluated individually one-by-one. The drawback of this approach is the scarceness of possible combinations that can be practically tested for the purpose of saving time, consumables, and manpower. High-throughput methods are therefore important to accelerate the discovery of stimuli-responsive materials and to screen for biological interactions of interest in parallel. The objective of this article is to provide an overview of the successful employment of combinatorial high-throughput synthesis and screening of stimuli-responsive materials. In particular, these include thermoresponsive and hydroresponsive materials. Advantages of a combinatorial approach as well as of utilizing high-throughput methodologies in the development of stimuli-responsive materials are reviewed. Possible evolution trends of stimuli-responsive materials, advanced by high-throughput methodologies, are discussed.

High Co-loading Capacity and Stimuli-Responsive Release Based on Cascade Reaction of Self-Destructive Polymer for Improved Chemo-Photodynamic Therapy.

Photodynamic therapy (PDT) shows a promising synergy with chemotherapy in the therapeutic outcome of malignant cancers. The minimal invasiveness and nonsystemic toxicity are appealing advantages of PDT, but combination with chemotherapy brings in the nonselective toxicity. We designed a polymeric nanoparticle system that contains both a chemotherapeutic agent and a photosensitizer to seek improvement for chemo-photodynamic therapy. First, to address the challenge of efficient co-delivery, polymer-conjugated doxorubicin (PEG-PBC-TKDOX) was synthesized to load photosensitizer chlorin e6 (Ce6). Ce6 is retained with DOX by a π-π stacking interaction, with high loading (41.9 wt %) and the optimal nanoparticle size (50 nm). Second, light given in PDT treatment not only excites Ce6 to produce cytotoxic reactive oxygen species (ROS) but also spatiotemporally activates a cascade reaction to release the loaded drugs. Finally, we report a self-destructive polymeric carrier (PEG-PBC-TKDOX) that depolymerizes its backbone to facilitate drug release upon ROS stimulus. This is achieved by grafting the ROS-sensitive pendant thioketal to aliphatic polycarbonate. When DOX is covalently modified to this polymer via thioketal, target specificity is controlled by light, and off-target delivery toxicity is mostly avoided. An oral squamous cell carcinoma that is clinically relevant to PDT was used as the cancer model. We put forward a polymeric system with improved efficiency for chemo-photodynamic therapy and reduced off-target toxicity.