Kinetics of Calcite Nucleation onto Sulfated Chitosan Derivatives and Implications for Water-Polysaccharide Interactions during Crystallization of Sparingly Soluble Salts.

Anionic macromolecules are found at sites of CaCO3 biomineralization in diverse organisms, but their roles in crystallization are not well-understood. We prepared a series of sulfated chitosan derivatives with varied positions and degrees of sulfation, DS(SO3 -), and measured calcite nucleation rate onto these materials. Fitting the classical nucleation theory model to the kinetic data reveals the interfacial free energy of the calcite-polysaccharide-solution system, γnet, is lowest for nonsulfated controls and increases with DS(SO3 -). The kinetic prefactor also increases with DS(SO3 -). Simulations of Ca2+-H2O-chitosan systems show greater water structuring around sulfate groups compared to uncharged substituents, independent of sulfate location. Ca2+-SO3 - interactions are solvent-separated by distances that are inversely correlated with DS(SO3 -) of the polysaccharide. The simulations also predict SO3 - and NH3 + groups affect the solvation waters and HCO3 - ions associated with Ca2+. Integrating the experimental and computational evidence suggests sulfate groups influence nucleation by increasing the difficulty of displacing near-surface water, thereby increasing γnet. By correlating γnet and net charge per monosaccharide for diverse polysaccharides, we suggest the solvent-separated interactions of functional groups with Ca2+ influence thermodynamic and kinetic components to crystallization by similar solvent-dominated processes. The findings reiterate the importance of establishing water structure and properties at macromolecule-solution interfaces.

6-Carboxycellulose Acetate Butyrate: Effectiveness as an Amorphous Solid Dispersion Polymer.

Amorphous solid dispersion (ASD) in a polymer matrix is a powerful method for enhancing the solubility and bioavailability of otherwise crystalline, poorly water-soluble drugs. 6-Carboxycellulose acetate butyrate (CCAB) is a relatively new commercial cellulose derivative that was introduced for use in waterborne coating applications. As CCAB is an amphiphilic, carboxyl-containing, high glass transition temperature (Tg) polymer, characteristics essential to excellent ASD polymer performance, we chose to explore its ASD potential. Structurally diverse drugs quercetin, ibuprofen, ritonavir, loratadine, and clarithromycin were dispersed in CCAB matrices. We evaluated the ability of CCAB to create ASDs with these drugs and its ability to provide solubility enhancement and effective drug release. CCAB/drug dispersions prepared by spray drying were amorphous up to 25 wt % drug, with loratadine remaining amorphous up to 50% drug. CCAB formulations with 10% drug proved effective at providing in vitro solubility enhancement for the crystalline flavonoid drug quercetin as well as ritonavir, but not for the more soluble APIs ibuprofen and clarithromycin and the more hydrophobic loratadine. CCAB did provide slow and controlled release of ibuprofen, offering a simple and promising Long-duration ibuprofen formulation. Formulation with clarithromycin showed the ability of the polymer to protect against degradation of the drug at stomach pH. Furthermore, CCAB ASDs with both loratadine and ibuprofen could be improved by the addition of the water-soluble polymer poly(vinylpyrrolidone) (PVP), with which CCAB shows good miscibility. CCAB provided solubility enhancement in some cases, and the slower drug release exhibited by CCAB, especially in the stomach, could be especially beneficial, for example, in formulations containing known stomach irritants like ibuprofen.

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.

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.

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.

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.

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).

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.

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.