Selective cross-metathesis of cellobiose derivatives with amido-functionalized olefinic structures: A model study for synthesis of cellulosic diblock copolymers.

This work describes a model study for synthesis of cellulose-based block copolymers, investigating selective coupling of peracetyl ß-d-cellobiose and perethyl ß-d-cellobiose at their reducing-ends by olefin cross-metathesis (CM). Herein we explore suitable pairs of ω-alkenamides that permit selective, quantitative coupling by CM. Condensation reactions of hepta-O-acetyl-ß-d-cellobiosylamine or hepta-O-ethyl-ß-d-cellobiosylamine with acyl chlorides afforded the corresponding N-(ß-d-cellobiosyl)-ω-alkenamide derivatives with an aromatic olefin or linear olefinic structures. Among the introduced olefinic structures, CM of the undec-10-enamide (Type I olefin) and the acrylamide (Type II olefin) gave the hetero-block tetramers, N-(hepta-O-ethyl-ß-d-cellobiosyl)-N'-(hepta-O-acetyl-ß-d-cellobiosyl)-alkene-α,ω-diamides, with >98 % selectivity. Moreover, selectivity was not influenced by the cellobiose substituents when a Type I olefin with a long alkyl tether was used. Although the amide carbonyl group could chelate the ruthenium atom and reduce CM selectivity, the results indicated that such chelation is suppressed by sterically hindered pyranose rings or the long alkyl chain between the amido group and the double bond. Based on this model study, selective end-to-end coupling of tri-O-ethyl cellulose and acetylated cellobiose was accomplished, proving the concept that this model study with cellobiose derivatives is a useful signpost for selective synthesis of polysaccharide-based block copolymers.

Synthesis and real-time characterization of self-healing, injectable, fast-gelling hydrogels based on alginate multi-reducing end polysaccharides (MREPs).

Polysaccharide-based hydrogels are promising for many biomedical applications including drug delivery, wound healing, and tissue engineering. We illustrate herein self-healing, injectable, fast-gelling hydrogels prepared from multi-reducing end polysaccharides, recently introduced by the Edgar group. Simple condensation of reducing ends from multi-reducing end alginate (M-Alg) with amines from polyethylene imine (PEI) in water affords a dynamic, hydrophilic polysaccharide network. Trace amounts of acetic acid can accelerate the gelation time from hours to seconds. The fast-gelation behavior is driven by rapid Schiff base formation and strong ionic interactions induced by acetic acid. A cantilever rheometer enables real-time monitoring of changes in viscoelastic properties during hydrogel formation. The reversible nature of these crosslinks (imine bonds, ionic interactions) provides a hydrogel with low toxicity in cell studies as well as self-healing and injectable properties. Therefore, the self-healing, injectable, and fast-gelling M-Alg/PEI hydrogel holds substantial promise for biomedical, agricultural, controlled release, and other applications.

Dextran Macroinitiator for Synthesis of Polysaccharide-b-Polypeptide Block Copolymers via NCA Ring-Opening Polymerization.

Synthesis of polysaccharide-b-polypeptide block copolymers represents an attractive goal because of their promising potential in delivery applications. Inspired by recent breakthroughs in N-carboxyanhydride (NCA) ring-opening polymerization (ROP), we present an efficient approach for preparation of a dextran-based macroinitiator and the subsequent synthesis of dextran-b-polypeptides via NCA ROP. This is an original approach to creating and employing a native polysaccharide macroinitiator for block copolymer synthesis. In this strategy, regioselective (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) oxidation of the sole primary alcohol located at the C-6 position of the monosaccharide at the nonreducing end of linear dextran results in a carboxylic acid. This motif is then transformed into a tetraalkylammonium carboxylate, thereby generating the dextran macroinitiator. This macroinitiator initiates a wide range of NCA monomers and produces dextran-b-polypeptides with a degree of polymerization (DP) of the polypeptide up to 70 in a controlled manner (D < 1.3). This strategy offers several distinct advantages, including preservation of the original dextran backbone structure, relatively rapid polymerization, and moisture tolerance. The dextran-b-polypeptides exhibit interesting self-assembly behavior. Their nanostructures have been investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM), and adjustment of the structure of block copolymers allows self-assembly of spherical micelles and worm-like micelles with varied diameters and aspect ratios, revealing a range of diameters from 60 to 160 nm. Moreover, these nanostructures exhibit diverse morphologies, including spherical micelles and worm-like micelles, enabling delivery applications.

All-polysaccharide, self-healing, pH-sensitive, in situ-forming hydrogel of carboxymethyl chitosan and aldehyde-functionalized hydroxyethyl cellulose.

In situ forming hydrogels are promising for biomedical applications, especially in drug delivery. The precursor solution can be injected at the target site, where it undergoes a sol-gel transition to afford a hydrogel. In this sense, the most significant characteristic of these hydrogels is fast gelation behavior after injection. This study describes an all-polysaccharide, rapidly in situ-forming hydrogel composed of carboxymethyl chitosan (CMCHT) and hydroxyethyl cellulose functionalized with aldehyde groups (HEC-Ald). The HEC-Ald was synthesized through acetal functionalization, followed by acid deprotection. This innovative approach avoids cleavage of pyran rings, as is inherent in the periodate oxidation approach, which is the most common method currently employed for adding aldehyde groups to polysaccharides. The resulting hydrogel exhibited fast stress relaxation, self-healing properties, and pH sensitivity, which allowed it to control the release of an encapsulated model drug in response to the medium pH. Based on the collected data, the HEC-Ald/CMCHT hydrogels show promise as pH-sensitive drug carriers.

Regioselective and controlled-density branching in amylose esters.

Herein, we report creation of methodology for one-pot synthesis of 2,3-O-acetyl-6-bromo-6-deoxy (2,3Ac-6Br) amylose with controlled degree of substitution of bromide (DS(Br)) followed by quantitative azide substitution as a route to branched polysaccharide derivatives. This methodology affords complete control of "tine" location, and strong control of degree of branching of comb-structured polymers. In this way, we achieved bromination strictly at C6 and esterification at the other hydroxy groups, where the DS(Br) at C6 was well-controlled by bromination/acylation conditions in the one-pot process. Azide displacement of all C6 bromides followed by copper-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction with the small molecule tert-butyl propargyl ether (TBPE) demonstrated the potential to create such branched structures. This synthetic method has broad potential to generate well-defined polysaccharide-based comb-like structures, with a degree of structural control that is very unusual in polysaccharide chemistry.

Threading the needle: Achieving simplicity and performance in cellulose alkanoate ω-carboxyalkanoates for amorphous solid dispersion.

Most active pharmaceutical ingredients (APIs) suffer from poor water solubility, often keeping them from reaching patients. To overcome the issues of poor drug solubility and subsequent low bioavailability, amorphous solid dispersions (ASDs) have garnered much attention. Cellulose ester derivatives are of interest for ASD applications as they are benign, sustainable-based, and successful in commercial drug delivery systems, e.g. in osmotic pump systems and as commercial ASD polymers. Synthesis of carboxy-pendant cellulose esters is a challenge, due in part to competing reactions between carboxyls and hydroxyls, forming ester crosslinks. Herein we demonstrate proof-of-concept for a scalable synthetic route to simple, yet highly promising ASD polymers by esterifying cellulose polymers through ring-opening of cyclic succinic or glutaric anhydride. We describe the complexity of such ring-opening reactions, not previously well-described, and report ways to avoid gelation. We report synthesis, characterization, and preliminary in vitro ASD evaluations of fifteen such derivatives. Synthetic routes were designed to accommodate these criteria: no protecting groups, no metal catalysts, mild conditions with standard reagents, simple purification, and one-pot synthesis. Finally, these designed ASD polymers included members that maintained fast-crystallizing felodipine in solution and release it from an ASD at rather high 20 % drug loading (DL).

Polysaccharide Aldehydes and Ketones: Synthesis and Reactivity.

Polysaccharides are biodegradable, abundant, sustainable, and often benign natural polymers. The achievement of selective modification of polysaccharides is important for targeting specific properties and structures and will benefit future development of highly functional, sustainable materials. The synthesis of polysaccharides containing aldehyde or ketone moieties is a promising tool for achieving this goal because of the rich chemistry of aldehyde or ketone groups, including Schiff base formation, nucleophilic addition, and reductive amination. The obtained polysaccharide aldehydes or ketones themselves have rich potential for making useful materials, such as self-healing hydrogels, polysaccharide-protein therapeutic conjugates, or drug delivery vehicles. Herein, we review recent advances in synthesizing polysaccharides containing aldehyde or ketone moieties and briefly introduce their reactivity and corresponding applications.

Reductive amination of oxidized hydroxypropyl cellulose with ω-aminoalkanoic acids as an efficient route to zwitterionic derivatives.

Zwitterionic polymers, with their equal amounts of cationic and anionic functional groups, have found widespread utility including as non-fouling coatings, hydrogel materials, stabilizers, antifreeze materials, and drug carriers. Polysaccharide-derived zwitterionic polymers are attractive because of their sustainable origin, potential for lower toxicity, and possible biodegradability, but previous methods for synthesis of zwitterionic polysaccharide derivatives have been limited in terms of flexibility and attainable degree of substitution (DS) of charged entities. We report herein successful design and synthesis of zwitterionic polysaccharide derivatives, in this case based on cellulose, by reductive amination of oxidized 2-hydroxypropyl cellulose (Ox-HPC) with ω-aminoalkanoic acids. Reductive amination products could be readily obtained with DS(cation) (= DS(anion)) up to 1.6. Adduct hydrophilic/hydrophobic balance (amphiphilicity) can be influenced by selecting the appropriate chain length of the ω-aminoalkanoic acid. This strategy is shown to produce a range of amphiphilic, water-soluble, moderately high glass transition temperature (Tg) polysaccharide derivatives in just a couple of efficient steps from commercially available building blocks. The adducts were evaluated as crystallization inhibitors. They are strong inhibitors of crystallization even for the challenging, poorly soluble, fast-crystallizing prostate cancer drug enzalutamide, as supported by surface tension and Flory-Huggins interaction parameter results.

Synthesis and Characterization of Multi-Reducing-End Polysaccharides.

Site-specific modification is a great challenge for polysaccharide scientists. Chemo- and regioselective modification of polysaccharide chains can provide many useful natural-based materials and help us illuminate fundamental structure-property relationships of polysaccharide derivatives. The hemiacetal reducing end of a polysaccharide is in equilibrium with its ring-opened aldehyde form, making it the most uniquely reactive site on the polysaccharide molecule, ideal for regioselective decoration such as imine formation. However, all natural polysaccharides, whether they are branched or not, have only one reducing end per chain, which means that only one aldehyde-reactive substituent can be added. We introduce a new approach to selective functionalization of polysaccharides as an entrée to useful materials, appending multiple reducing ends to each polysaccharide molecule. Herein, we reduce the approach to practice using amide formation. Amine groups on monosaccharides such as glucosamine or galactosamine can react with carboxyl groups of polysaccharides, whether natural uronic acids like alginates, or derivatives with carboxyl-containing substituents such as carboxymethyl cellulose (CMC) or carboxymethyl dextran (CMD). Amide formation is assisted using the coupling agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM). By linking the C2 amines of monosaccharides to polysaccharides in this way, a new class of polysaccharide derivatives possessing many reducing ends can be obtained. We refer to this class of derivatives as multi-reducing-end polysaccharides (MREPs). This new family of derivatives creates the potential for designing polysaccharide-based materials with many potential applications, including in hydrogels, block copolymers, prodrugs, and as reactive intermediates for other derivatives.

Chitosan as a Canvas for Studies of Macromolecular Controls on CaCO3 Biological Crystallization.

A mechanistic understanding of how macromolecules, typically as an organic matrix, nucleate and grow crystals to produce functional biomineral structures remains elusive. Advances in structural biology indicate that polysaccharides (e.g., chitin) and negatively charged proteoglycans (due to carboxyl, sulfate, and phosphate groups) are ubiquitous in biocrystallization settings and play greater roles than currently recognized. This review highlights studies of CaCO3 crystallization onto chitinous materials and demonstrates that a broader understanding of macromolecular controls on mineralization has not emerged. With recent advances in biopolymer chemistry, it is now possible to prepare chitosan-based hydrogels with tailored functional group compositions. By deploying these characterized compounds in hypothesis-based studies of nucleation rate, quantitative relationships between energy barrier to crystallization, macromolecule composition, and solvent structuring can be determined. This foundational knowledge will help researchers understand composition-structure-function controls on mineralization in living systems and tune the designs of new materials for advanced applications.

Oxidized hydroxypropyl cellulose/carboxymethyl chitosan hydrogels permit pH-responsive, targeted drug release.

Polysaccharide-based Schiff base hydrogels have promise for drug delivery, tissue engineering, and many other applications due to their reversible imine bond crosslinks. We describe herein pH-responsive, injectable, and self-healing hydrogels prepared by reacting oxidized hydroxypropyl cellulose (Ox-HPC) with carboxymethyl chitosan (CMCS). Simple combination of ketones from Ox-HPC side chains with amines from CMCS in water provides a dynamic, hydrophilic polysaccharide network. The reversible nature of these imine bonds in the presence of water provides a hydrogel with injectable and self-healing properties. Phenylalanine as a model amine-containing drug was linked by imine bonds to Ox-HPC within the hydrogel. Phenylalanine release was faster at the pH of the extracellular space around tumors (6.8) than in normal tissues (7.4), a surprising degree of pH sensitivity. Therefore, Ox-HPC/CMCS hydrogels show promise as drug carriers that may selectively target even slightly lower pH environments like the extracellular milieu around cancer cells.

Recent advances in polysaccharide-based in situ forming hydrogels.

Polysaccharides comprise an important class of natural polymers; they are abundant, diverse, polyfunctional, typically benign, and are biodegradable. Using polysaccharides to design in situ forming hydrogels is an attractive and important field of study since many polysaccharide-based hydrogels exhibit desirable characteristics including self-healing, responsiveness to environmental stimuli, and injectability. These characteristics are particularly useful for biomedical applications. This review will discuss recent discoveries in polysaccharide-based in situ forming hydrogels, including network architecture designs, curing mechanisms, physical and chemical properties, and potential applications.

Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity.

Crystallization inhibitors in amorphous solid dispersions (ASD) enable metastable supersaturated drug solutions that persist for a physiologically relevant time. Olefin cross-metathesis (CM) has successfully provided multifunctional cellulose-based derivatives as candidate ASD matrix polymers. In proof of concept studies, we prepared hydrophobic bile salt/cellulose adducts by CM with naturally occurring bile salts. We hypothesized that increased hydrophilicity would enhance the ability of these conjugates to maximize bioactive supersaturation. Their selective preparation presents a significant synthetic challenge, given polysaccharide reactivity and polysaccharide and bile salt complexity. We prepared such derivatives using a more hydrophilic hydroxypropyl cellulose (HPC) backbone, employing a pent-4-enyl tether (Pen) for appending bile acids. We probed structure-property relationships by varying the nature and degree of substitution of the bile acid substituent (lithocholic or deoxycholic acid). These conjugates are indeed synergistic inhibitors, as demonstrated with the fast-crystallizing prostate cancer drug, enzalutamide. The lithocholic acid methyl ester derivative, AcrMLC-PenHHPCPen (0.64), increased induction time 68 fold vs. drug alone.

Regioselective synthesis of polysaccharide-amino acid ester conjugates.

Site-specific conjugation of polysaccharides with proteins is very challenging. Creating the ability to control chemo- and regioselective reaction between polysaccharides and amino acid derivatives can not only create potentially useful and bioactive natural polymer constructs, but should also provide useful guidance for the principles of polysaccharide-protein conjugate synthesis. In this work, we exploited regioselective bromination of the non-reducing end primary dextran hydroxyl using N-bromosuccinimide (NBS) and triphenylphosphine (Ph3P) in the dimethylacetamide (DMAc) and lithium bromide solvent system, thereby enabling a regio- and chemoselective synthetic strategic approach to a variety of polysaccharide-amino acid ester adducts. We demonstrated selective condensation of the α-amino groups of esters of the amino acids tyrosine and proline, displacing the single, terminal C6 bromides of 6-BrDextran, as well as the 6-Br moieties of 6-BrCA320S, with high conversion (71-96%). Histidine ester side group amines were found to react with 6-BrCA320S, while those of tryptophan ester did not. These results provide useful access to polysaccharide-amino acid ester adducts of various architectures, and guide us in designing new pathways to polysaccharide-protein copolymers.

Chemical synthesis of polysaccharide-protein and polysaccharide-peptide conjugates: A review.

Polysaccharides are abundant natural polymers, which in nature are at times covalently modified with peptides and proteins. Polysaccharide-protein or polysaccharide-peptide conjugates, natural or otherwise, may have increased solubility, improved emulsion properties, prolonged circulation time, reduced immunogenicity, and enhanced selectivity for targeting specific tissues compared to native peptides and proteins. In this paper, we will review recent advances in synthetic methods for producing polysaccharide-protein conjugates and discuss their advantages with a focus on drug targeting.

A Versatile Method for Preparing Polysaccharide Conjugates via Thiol-Michael Addition.

Polysaccharide conjugates are important renewable materials. If properly designed, they may for example be able to carry drugs, be proactive (e.g., with amino acid substituents) and can carry a charge. These aspects can be particularly useful for biomedical applications. Herein, we report a simple approach to preparing polysaccharide conjugates. Thiol-Michael additions can be mild, modular, and efficient, making them useful tools for post-modification and the tailoring of polysaccharide architecture. In this study, hydroxypropyl cellulose (HPC) and dextran (Dex) were modified by methacrylation. The resulting polysaccharide, bearing α,ß-unsaturated esters with tunable DS (methacrylate), was reacted with various thiols, including 2-thioethylamine, cysteine, and thiol functional quaternary ammonium salt through thiol-Michael addition, affording functionalized conjugates. This click-like synthetic approach provided several advantages including a fast reaction rate, high conversion, and the use of water as a solvent. Among these polysaccharide conjugates, the ones bearing quaternary ammonium salts exhibited competitive antimicrobial performance, as supported by a minimum inhibitory concentration (MIC) study and tracked by SEM characterization. Overall, this methodology provides a versatile route to polysaccharide conjugates with diverse functionalities, enabling applications such as antimicrobial activity, gene or drug delivery, and biomimicry.

Preparation and properties of dual-wavelength excitable fluorescent Lyocell fibers and their applications in papermaking.

Two kinds of dual-wavelength excitable fluorescent Lyocell fibers, which can be excited by short-wavelength UV/IR or long-wavelength UV/IR radiation, were prepared by dry-jet wet spinning. These fluorescent Lyocell fibers can emit two different fluorescence wavelengths at two different excitation wavelengths, exhibiting double anti-counterfeiting functions, thereby providing higher security. SEM-EDX analysis showed the uniform phosphors distribution in Lyocell fibers. The fluorescent Lyocell fibers were mixed into pulp for papermaking. Addition of dual-wavelength excitable fluorescent Lyocell fibers had no influence on brightness and opacity of papers, and the mechanical properties of papers were similar or even higher than paper with addition of pure Lyocell fibers, although the introduction of phosphors decreased the mechanical properties of Lyocell fibers slightly. Our results proved that dual-wavelength excitable fluorescent Lyocell fibers can be used not only in textile fibers, but also in papermaking to develop various security paper products.

Interaction of Polymers with Enzalutamide Nanodroplets-Impact on Droplet Properties and Induction Times.

Amorphous solid dispersions (ASDs), which consist of a drug dispersed in a polymeric matrix, are increasingly being applied to improve the in vivo performance of poorly water-soluble drugs delivered orally. The polymer is a critical component, playing several roles including facilitating drug release from the ASD, as well as delaying crystallization from the supersaturated solution generated upon dissolution. Certain ASD formulations dissolve to produce amorphous drug-rich nanodroplets. The interaction of the polymer with these nanodroplets is poorly understood but is thought to be important for inhibiting crystallization in these systems. In this study, the impact of ionic polymers on the crystallization kinetics of enzalutamide from supersaturated solutions containing different amounts of amorphous nanodroplets was evaluated by determination of nucleation induction times. The amount of the polymer associated with the drug nanodroplets was also determined. When comparing two polymers, hydroxypropylmethyl cellulose acetate succinate (HPMCAS) and Eudragit E PO, it was found that the crystallization tendency and physical properties of the drug nanodroplets varied in the presence of these two polymers. Both polymers distributed between the aqueous phase and the drug-rich nanodroplets. A greater amount of Eudragit E PO was associated with the drug-rich nanodroplets. Despite this, Eudragit E PO was a less-effective crystallization inhibitor than HPMCAS in systems containing nanodroplets. In conclusion, in supersaturated solutions containing amorphous nanodroplets, the extent of association of a polymer with the drug nanodroplet does not solely predict crystallization inhibition.

Selective Oxidation of 2-Hydroxypropyl Ethers of Cellulose and Dextran: Simple and Efficient Introduction of Versatile Ketone Groups to Polysaccharides.

Oxidation of polysaccharides has been a useful approach to new materials. However, selectivity in oxidation of polysaccharide macromolecular polyols remains a significant challenge with few methods for the synthesis of ketone-substituted polysaccharides. We report here a selective, practical, and efficient process, beginning with 2-hydroxypropyl ethers of polysaccharides that are simple and economical to prepare. We demonstrate this approach herein using commercial 2-hydroxypropyl cellulose (HPC) and 2-hydroxypropyl dextran (HPD) that we prepared. We oxidize the terminal, secondary alcohols of the oligo(2-hydroxypropyl) substituents with sodium hypochlorite so that the product has an oligo(2-hydroxypropyl) side chains terminated by a ketone. We demonstrate the high chemo- and regioselectivity of this oxidation by analytical methods including hydrolysis to monosaccharides and mass spectrometry of the resulting mixture. We provide an initial demonstration of the potential utility of these keto-polysaccharides by reacting Ox-HPC with primary amines to form Schiff base imines, providing proactive polymers.