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This work describes a model study for synthesis of cellulose-based block copolymers, investigating selective coupling of peracetyl β-d-cellobiose and perethyl β-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-β-d-cellobiosylamine or hepta-O-ethyl-β-d-cellobiosylamine with acyl chlorides afforded the corresponding N-(β-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-β-d-cellobiosyl)-N'-(hepta-O-acetyl-β-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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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)., Competing Interests: Declaration of competing interest The authors declare none., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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 (T g ) 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Polysaccharides are ubiquitous, generally benign in nature, and compatible with many tissues in biomedical situations, making them appealing candidates for new materials such as therapeutic agents and sensors. Fluorescent labeling can create the ability to sensitively monitor distribution and transport of polysaccharide-based materials, which can for example further illuminate drug-delivery mechanisms and therefore improve design of delivery systems. Herein, we review fluorophore selection and ways of appending polysaccharides, utility of the product fluorescent polysaccharides as new smart materials, and their stimulus-responsive nature, with focus on their biomedical applications as environment-sensitive biosensors, imaging, and as molecular rulers. Further, we discuss the advantages and disadvantages of these methods, and future prospects for creation and use of these self-reporting materials., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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 (Ph 3 P) 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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

As the most successful regenerated cellulose fiber developed in recent decades, Lyocell has attracted much attention due to its useful properties, simple manufacturing process, and recyclable solvent. However, Lyocell's lack of antibacterial properties limits its application in medical and health fields. Antibacterial modification of Lyocell fiber can be achieved by three general approaches: physical blending, chemical reaction, and post-treatment. Physical blending methods introduce antibacterial agents directly into the spinning dope. In chemical reaction methods, functional groups of the antibacterial additives are grafted or crosslinked into Lyocell fibers, thereby imparting antimicrobial properties. In post-treatment methods, antibacterial additives are deposited on Lyocell fiber surfaces by physical coating, padding, or impregnation processes. We organize our review of antibacterial modification of Lyocell fibers by these preparation methods. Some of the modified Lyocell fibers are reported to exhibit improved antimicrobial activity against various bacteria and fungi, indicating promise for application in medical or hygienic products., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Polysaccharide-based copolymers with brush-like, graft architectures have been prepared by many investigators. In contrast, it is challenging to prepare linear polysaccharide-based block copolymers. Only a few approaches have been reported for preparation of such architectures, despite the clear application potential of renewable-based, linear block copolymers. The challenging nature of regioselective polysaccharide end-group functionalization has impeded their preparation. Herein we report a different, flexible approach to linear block copolymers, demonstrated for derivatives of renewable, natural cellulose. To illustrate this approach, trimethyl cellulose-b-poly(ethylene glycol), trimethyl cellulose-b-poly(tetrahydrofuran) and trimethyl cellulose-b-poly(lactic acid) were synthesized by a coupling strategy. Trimethyl cellulose was functionalized regiospecifically at the reducing end anomeric carbon to create an ω-unsaturated alkyl acetal by solvolysis of trimethyl cellulose with an ω-unsaturated alcohol. Subsequently, mild and versatile olefin cross-metathesis was used to couple efficiently (100% conversion) the trimethyl cellulose block with a series of acrylate derivatives, including acrylated polymer blocks. The targeted block co-polymeric structures were confirmed by nuclear magnetic resonance (NMR) spectroscopy, and the degree of polymerization was relatively well-preserved during the coupling step, as shown by size exclusion chromatography (SEC). The results confirm that this new solvolysis/cross-metathesis method is a promising approach to polysaccharide-based linear AB, and likely ABC, block copolymers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Bile salts tend to form micelles in aqueous media and can thereby contribute to drug solubilization; they also exhibit crystallization inhibition properties that can stabilize supersaturated drug solutions. Herein, we explore conjugation of bile salts with polysaccharides to create new, amphiphilic polysaccharide derivatives with intriguing properties, portending broad utility in various applications. We introduce efficient conjugation of cholesterol (as a model steroid), lithocholic acid, and deoxycholic acid by mild, modular olefin cross-metathesis reactions. These small molecules were first modified with an acrylate group from the A-ring hydroxyl, then reacted with cellulose derivatives bearing olefin-terminated metathesis "handles". Successful conjugation of bile acids has demonstrated chemoselective cross-metathesis with complex, polyfunctional structures, and large multi-ring systems. It also enabled an efficient, general pathway for polysaccharide-bile salt conjugates, which promise synergy for applications such as amorphous solid dispersion (ASD)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Regioselective chlorination of cellulose is challenging due to its low reactivity, the small reactivity differences between cellulosic hydroxyl groups, and the high and diverse reactivity of most common chlorinating agents. Halogenation of cellulose affords useful precursors for subsequent nucleophilic substitution reactions, permitting incorporation of new functionality. Herein we report a simple and efficient pathway for preparation of 6-chloro-6-deoxycellulose esters and their derivatives. Cellulose acetate (degree of substitution (DS) 1.75, CA320S) can be chlorinated by essentially quantitative reaction of the primary alcohol groups with methanesulfonyl chloride (MsCl), yielding 6-chloro-6-deoxy cellulose acetate. Characterization methods including 1 H NMR, 13 C NMR, FT-IR spectroscopy, and elemental analysis, demonstrated chemo- and regioselective C-6 chlorination. We also demonstrate that chlorinated cellulose acetate is a useful intermediate for displacement reactions with nucleophiles including sodium azide, amines, and thiols to prepare functional cellulose ester derivatives., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Chemoselective modification of polysaccharides is a significant challenge, and regioselective modification is even more difficult, due to the low and similar reactivity of the various polysaccharide hydroxyl groups. Bromination of glycans that possess free 6-OH groups is exceptional in that regard, giving regiospecific, high-yield access to 6-bromo-6-deoxyglycans. Herein we report a simple and efficient pathway for synthesizing 6-ω-carboxyalkanamido-6-deoxy-containing polysaccharide derivatives in a sequence starting from 6-bromo-6-deoxycurdlan, via azide displacement, then conversion of the azide to the iminophosphorane ylide by triphenylphosphine (Ph 3 P). We take advantage of the nucleophilicity of the iminophosphorane nitrogen by subsequent regioselective ring-opening reactions of cyclic anhydrides. These reactions of the useful polysaccharide curdlan were essentially completely regio- and chemo-selective, proceeding under mild conditions in the presence of ester groups, yet preserving those groups. These interesting polysaccharide-based materials have pendant carboxyls attached through a hydrocarbon tether and hydrolytically stable amide linkage; as such they are promising for diverse application areas, including aqueous dispersions for coatings, adhesives, and other consumer products, and for amorphous solid dispersions in oral drug delivery., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The efficacy of rifapentine, an oral antibiotic used to treat tuberculosis, may be reduced due to degradation at gastric pH and low solubility at intestinal pH. We hypothesized that delivery properties would be improved in vitro by incorporating rifapentine into pH-responsive amorphous solid dispersions (ASDs) with cellulose derivatives including: hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate suberate (CASub), and 5-carboxypentyl hydroxypropyl cellulose (CHC). ASDs generally reduced rifapentine release at gastric pH, with CASub affording >31-fold decrease in area under the curve (AUC) compared to rifapentine alone. Critically, reduced gastric dissolution was accompanied by reduced degradation to 3-formylrifamycin. Certain ASDs also enhanced apparent solubility and stabilization of supersaturated solutions at intestinal pH, with HPMCAS providing nearly 4-fold increase in total AUC vs. rifapentine alone. These results suggest that rifapentine delivery via ASD with these cellulosic polymers may improve bioavailability in vivo., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Staudinger-related reactions between azides and phosphines are important in organic chemistry due to their chemoselectivity, high efficiency, and mild reaction conditions. Staudinger reduction of azides affords highly reactive iminophosphorane ylides; the reactivity of the negatively charged ylide nitrogen atom has not previously been fully explored in polysaccharide chemistry. Curdlan, a natural, biocompatible, and bioactive β-1,3-glucan with low toxicity, has remarkable potential in biomedical and pharmaceutical applications. Herein we describe a new method for preparation of regioselectively iminated/aminated curdlan derivatives via a Staudinger ylide. 6-Azido-6-deoxy-2,4-di-O-acyl-curdlan was treated with triphenylphosphine to generate the highly nucleophilic iminophosphorane intermediate which afforded: i) 6-imino curdlans by reaction with several aromatic aldehydes, and ii) 6-monoalkylamino curdlans by reductive amination using these aldehydes and NaBH 3 CN. This new chemistry combined with our previous results makes available valuable primary, secondary, and tertiary amines, quaternary ammonio derivatives, and amides, all with complete C-6 regioselectivity for the N-substitution., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cellulose-based materials are well-suited for biomedical uses, because of their abundance, renewable nature, biodegradability, and relatively low cost. However, the set of commercially available cellulose esters and ethers is limited in number and diversity, and contains no cationically charged cellulose esters. Herein we report a simple, efficient strategy for synthesizing cationic, water-soluble co-polyelectrolytes from commercial, hydrophobic, renewable-based cellulose esters. Cellulose acetate (degree of substitution (DS) 1.78, CA320S), was the exemplary starting material for preparing these cationic polyelectrolytes by a reaction sequence of phosphine-catalyzed bromination and subsequent displacement by an aromatic amine, affording high reaction conversions. We show that these modification techniques can be carried out with essentially complete regio- and chemoselectivity, proceeding in the presence of multiple ester groups, yet preserving those groups. Availability of these novel polysaccharide-based electrolytes starting from uncharged, commercial, inexpensive cellulose esters may open up multiple new application areas, including in several aspects of gene or drug delivery., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Quercetin (Q) is a bioactive flavonol with potential to benefit human health. However, Q bioavailability is relatively low, due to its poor aqueous solubility and extensive phase-II metabolism. Strategies to increase solution concentrations in the small intestinal lumen have the potential to substantially increase Q bioavailability, and by extension, efficacy. We aimed to achieve this by incorporating Q into amorphous solid dispersions (ASDs) with cellulose derivatives. Q was dispersed in matrices of cellulose esters including 6-carboxycellulose acetate butyrate (CCAB), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and cellulose acetate suberate (CASub) to afford ASDs that provided stability against crystallization, and pH-triggered release. Blends of CASub and CCAB with the hydrophilic polyvinylpyrrolidone (PVP) further enhanced dissolution. The ASD 10% Q:20% PVP:70% CASub most significantly enhanced Q solution concentration under intestinal pH conditions, increasing area under the concentration/time curve (AUC) 18-fold compared to Q alone. This novel ASD method promises to enhance Q bioavailability in vivo., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Curdlan, a bioactive β-1,3-glucan, is of intense interest for pharmaceutical and biomedical applications. Cationic derivatives of curdlan and other polysaccharides are especially attractive for their potential to interact in controlled fashion with proteins, among many other possible applications, but relatively few methods exist for their synthesis. Herein we report a regioselective method for preparation of cationic, water-soluble 6-(N,N,N-trialkylammonio)-6-deoxycurdlan salts by reaction of 6-bromo-6-deoxycurdlan and its 2,4-O-diesters with trialkylamines. Dimethyl sulfoxide was identified as the optimal solvent for this nucleophilic displacement to produce cationic curdlan derivatives (80 °C, 24h), providing maximum degree of triethylammonium substitution (DS) of 0.89, exclusively at the C-6 position. 6-Bromo-6-deoxycurdlan was also reacted with heterocyclic amines such as pyridine and imidazole, providing ammonium-substituted curdlan derivatives with substantial DS (0.66 and 0.86, respectively). The new combination of regioselective Furuhata bromination and bromine displacement under optimized conditions with tertiary amines provides access to quaternized curdlan derivatives that possess high, permanent positive charge and are readily water-soluble, properties that indicate potential application promise including for mucoadhesion, permeation enhancement, and delivery of genes and anionic drugs. Regioselectivity and DS of those curdlan ammonium derivatives were quantified by means of (1)H NMR, (13)C NMR and FTIR spectroscopic methods and by elemental analysis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Macromolecular prodrugs (MPDs) of moxifloxacin were fabricated based on hydroxypropylcellulose (HPC) and hydroxyethylcellulose (HEC). UV/Vis spectrophotometry was employed to determine covalently loaded drug content (DC) of each conjugate. The degree of substitution (DS) of moxifloxacin attained ranged from 0.27 to 0.38 (HPC) and 0.19 to 0.26 (HEC) per anhydroglucose unit (AGU), respectively. Transmission electron microscopic analyses showed that HPC-moxifloxacin conjugates self-assembled into nanowires of ∼ 30 nm diameters while HEC-moxifloxacin conjugates self-assembled into nanoparticles of 150-350 nm. In vitro drug release studies revealed that 15 and 49% moxifloxacin release occurred from the HPC-moxifloxacin conjugate after 6h at pH 1.2 and 7.4, respectively. Similarly, moxifloxacin release from HEC-moxifloxacin conjugates was 15 and 39% at pH 1.2 and 7.4, respectively. Bioavailability and pharmacokinetic studies in rabbits showed that both HPC- and HEC-conjugates exhibited significantly enhanced moxifloxacin plasma half-life, over 24h, confirming sustained release and enhanced bioavailability (AUC 2.0-2.1 times higher) of moxifloxacin., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We describe the first synthesis of hydroxy-functionalized polysaccharide esters via chemoselective olefin hydroboration-oxidation in the presence of ester groups. Cellulose esters with terminally olefinic side chains were first synthesized by esterification of commercially available cellulose esters (e.g., cellulose acetate) with undec-10-enoyl chloride or pent-4-enoyl chloride. Subsequent two-step, one-pot hydroboration-oxidation reactions of the cellulose esters were performed, using 9-borabicyclo[3.3.1]nonane as hydroboration agent, followed by oxidizing the intermediate borane to a hydroxyl group using mildly alkaline H2O2. Sodium acetate was used as a weak base to catalyze the oxidation, thereby minimizing undesired ester hydrolysis. Characterization methods including FTIR, (1)H, and (13)C NMR proved the selectivity of the hydroboration-oxidation pathway, providing a family of novel cellulose ω-hydroxyalkanoyl esters that were previously difficult to access., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cellulose esters with amide functionalities were synthesized by cross-metathesis (CM) reaction of terminally olefinic esters with different acrylamides, catalyzed by Hoveyda-Grubbs 2nd generation catalyst. Chelation by amides of the catalyst ruthenium center caused low conversions using conventional solvents. The effects of both solvent and structure of acrylamide on reaction conversion were investigated. While the inherent tendency of acrylamides to chelate Ru is governed by the acrylamide N-substituents, employing acetic acid as a solvent significantly improved the conversion of certain acrylamides, from 50% to up to 99%. Homogeneous hydrogenation using p-toluenesulfonyl hydrazide successfully eliminated the α,β-unsaturation of the CM products to give stable amide-functionalized cellulose esters. The amide-functionalized product showed higher Tg than its starting terminally olefinic counterpart, which may have resulted from strong hydrogen bonding interactions of the amide functional groups., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Water-solubility can often enhance the utility of polysaccharide derivatives, for example in pharmaceutical and biomedical applications. Synthesis of water-soluble aminopolysaccharides, particularly those bearing other sensitive functional groups, can be a challenging endeavor. Curdlan is a bioactive β-1,3-glucan with considerable promise for biomedical applications. Aminocurdlans are intriguing target molecules for study of, for example, their interactions with the proteins that form tight junctions between enterocytes. Herein we report the preparation of two water-soluble 6-aminocurdlans starting from 6-bromo-6-deoxycurdlan. The 6-bromide was first displaced by nucleophilic substitution with sodium azide in dimethyl sulfoxide. The O-2 groups were acylated with hydrophilic oligo (ethylene oxide) esters, so as to enhance aqueous solubility. The resultant 6-azido-6-deoxy-2,4-di-O-trioxadecanoylcurdlan was then treated with excess sodium borohydride to reduce the azide; unexpectedly, the water-soluble product proved to be the amide, 6-trioxadecanamido-6-deoxycurdlan. Regioselectivity and degree of substitution (DS) of those derivatives were characterized by means of (1)H NMR, (13)C NMR and FTIR-spectroscopy, elemental analysis, and titration. Alternatively, direct borohydride reduction of the parent 6-azido-6-deoxycurdlan afforded 6-amino-6-deoxycurdlan that was also water-soluble., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Tetrabutylammonium fluoride (TBAF) and tetrabutylammonium hydroxide (TBAOH) have been found to mediate regioselective deacylation of cellulose esters, with unexpected selectivity for removal of acyl groups at the more hindered secondary O-2/3 positions. This simple, efficient, one-step process triggers our investigation of TBAF/TBAOH deacylation on other glycan (amylose, curdlan, dextran, pullulan and glucomannan) esters to examine the generality of this reaction and the impact of glucan and glucomannan structure on deacylation regioselectivity. Remarkably regioselective O-2/3 deacylation was observed with amylose triesters, while moderately regioselective O-2/4 deacylation of curdlan triester occurred. No regioselectivity was observed with dextran triester, as predicted due to the lack of primary OH groups. We observed deacylation of pullulan and glucomannan triesters, but due to the complexity of the partially substituted products have not yet been able to determine the deacylation regioselectivity for these glycan esters., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Polymer design and selection are crucial to the development of amorphous solid dispersions (ASD) for solubilization of otherwise poorly water-soluble drugs. The matrix polymer is required to interact strongly at the molecular level with the drug to prevent recrystallization, but must also be able to release the drug at an adequate rate upon entering the absorptive portion of the digestive tract. Herein we report versatile syntheses of a non-ionic, water-soluble cellulosic polymer family, cellulose trioxodecanoates, containing a hydrophilic oligo(ethylene oxide) side chain. This series of cellulose derivatives is designed for both adequate stabilization of amorphous drugs with high crystallization tendency, and timely release of those drugs. Alternatively, these polymers can be rendered anionic by also appending a pH-responsive ω-carboxyalkanoate group. Detailed structural information and structure-property relationship characterization of these amphiphilic polymers are described, which will permit evaluation of these materials as ASD polymers for enhancement of drug solubility and bioavailability., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Tetraalkylammonium hydroxides have been found to mediate regioselective deacylation of cellulose esters. This deacylation surprisingly shows substantial selectivity for the removal of the acyl groups at O-2/3, affording cellulose-6-O-esters by a simple, efficient one-step process. The mechanism for this deacylation was investigated by studying the effect of tetraalkylammonium cation size upon ester deacylation selectivity. We hypothesize that coordination of the tetraalkylammonium cation by the ester oxygen atoms of the vicinal 2,3-acetate groups may drive the unexpected regioselectivity at the secondary alcohol esters. Broad scope with respect to ester type was demonstrated; regioselective O-2,3 deacylation was observed with cellulose acetate, propionate, butyrate, hexanoate and benzoate triesters. The scope of this deacylation of cellulose acetates has been investigated to understand how to carry it out most efficiently. Reaction with TBAOH in pyridine was the most effective process, providing the highest selectivity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

There has been growing interest in aminopolysaccharide synthesis over the last two decades due to the critical natural functions of aminopolysaccharides, and their potential in biomedical applications. Regioselective introduction of amino groups into polysaccharide backbones is a challenge. Natural curdlan is a linear β-(1→3)-glucan that is of interest both for its physical properties and its biomedical applications. Aminated curdlan derivatives were synthesized in three steps. First, curdlan was regioselectively brominated at the C-6 position in lithium bromide-N,N-dimethylacetamide (DMAc/LiBr). Second, the bromide of the product 6-bromo-6-deoxycurdlan was displaced by nucleophilic substitution with sodium azide (NaN3) in dimethyl sulfoxide (DMSO). Third, O-acylated 6-amido-6-deoxycurdlan was produced by a one-pot method. 6-Azido-6-deoxycurdlan was subjected to Staudinger reduction, followed by reaction in situ with excess carboxylic anhydride, without isolation of the 6-amino-6-deoxycurdlan intermediate. Regioselectivity and degree of substitution (DS) of these derivatives were confirmed by (1)H and (13)C NMR spectroscopy, FTIR spectroscopy, and elemental analysis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Hydrophobically modified polysaccharides that contain carboxyl groups possess exceptional features for drug delivery and other applications. Carboxyl groups were introduced at C-6 in the pullulan backbone by applying the well-established oxidation with TEMPO and NaOCl/NaBr. The oxidized product, 6-carboxypullulan, is even more water-soluble than pullulan. Consequently, further chemical modifications have been mainly restricted to reactions that can be performed in water or under heterogeneous conditions. We find that the TBA salt of 6-carboxypullulan is soluble in a range of organic solvents and can be reacted homogeneously with various alkyl halides in DMSO and sodium hydroxide at 40 °C to yield 6-carboxypullulan ethers. Complete substitution (DS 7 per trisaccharide repeat unit) was achieved upon reaction with iodoethane, while products from reaction with longer chain alkyl halides (propyl and butyl derivatives) achieved DS up to about 3. The amphiphilic products have impressive surfactant properties., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The use of amorphous solid dispersions (ASDs) is an effective and increasingly widely used approach for solubility enhancement of drugs and drug candidates with poor aqueous solubility. Successful molecular dispersion of drugs in polymer matrices requires new polymers that are designed to meet all ASD requirements, including drug release and prevention of drug recrystallization in storage or from solution. We describe herein design and synthesis of a new series of cellulose ω-carboxyalkanoates for ASDs, by reaction of cellulose with long-chain diacids that have been monoprotected as benzyl esters at one end, and monoactivated as acid chlorides at the other. Glass transition temperatures (Tg) of these cellulose ω-carboxyesters exceed ambient temperature by at least 50 °C, providing a sufficient ΔT to prevent drug mobility and crystallization. Cellulose acetate suberates and sebacates prepared in this way are extraordinary solution crystal growth inhibitors for the poorly soluble anti-HIV drug ritonavir. These new cellulose ω-carboxyesters have strong potential as ASD polymers for enhancement of drug solubility and bioavailability., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Alginates are (1→4) linked linear copolysaccharides composed of β-D-mannuronic acid (M) and its C-5 epimer, α-L-guluronic acid (G). Several strategies for synthesis of carboxyl modified alginate derivatives exist in the literature. Most of these however employ aqueous chemistries, such as carbodiimide coupling reactions. Based on our recently discovered method for homogeneous dissolution of tetrabutylammonium (TBA)-alginate, we now describe use of tetrabutylammonium fluoride (TBAF)-based two component solvent systems as media for synthesis of carboxyl-modified alginate esters. Partially and fully esterified benzyl, butyl, ethyl, and methyl alginates were synthesized via reaction with the corresponding alkyl halides. The newly synthesized derivatives were soluble in polar aprotic solvents without the addition of TBAF. Saponification was performed to demonstrate that alkylation was completely regioselective for carboxylate groups in preference to hydroxyl groups to form esters. We demonstrate the utility of these alginate esters to enhance aqueous solubility of the flavonoid naringenin by formation of solid dispersions., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Amorphous solid dispersions (ASD) of curcumin (Cur) in cellulose derivative matrices, hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylcellulose acetate butyrate (CMCAB), and cellulose acetate adipate propionate (CAAdP) were prepared in order to investigate the structure-property relationship and identify polymer properties necessary to effectively increase Cur aqueous solution concentration. XRD results indicated that all investigated solid dispersions were amorphous, even at a 9:1 Cur:polymer ratio. Both stability against crystallization and Cur solution concentration from these ASDs were significantly higher than those from physical mixtures and crystalline Cur. Remarkably, curcumin was also stabilized against chemical degradation in solution. Chemical stabilization was polymer-dependent, with stabilization in CAAdP>CMCAB>HPMCAS>PVP, while matrices enhanced solution concentration as PVP>HPMCAS>>CMCAB≈CAAdP. HPMCAS/Cur dispersions have useful combinations of pH-triggered release profile, chemical stabilization, and strong enhancement of Cur solution concentration., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In order to expand its utility and understand how to carry it out most efficiently, the scope of the highly regioselective, tetrabutylammonium fluoride (TBAF) catalyzed deacylation of cellulose acetates has been investigated, including the influence of key process parameters: solvent, temperature, and water content. Reactions in DMSO, THF, MEK and acetone afforded similar extents of deacylation and regioselectivity. Reaction with TBAF in DMSO at 50 °C for 18 h was the most efficient process providing regioselective deacylation at O-2/3. All results were consistent with our previous mechanistic proposals. Furthermore, we demonstrate that TBAF-catalyzed deacylation is also effective and regioselective with cellulose acetate, butyrate, and hexanoate triesters, and even with a cellulose ester devoid of alpha protons, cellulose tribenzoate. These reactions displayed regioselectivity for deacylation at O-2/3 similar to that observed earlier with cellulose acetate (DS 2.4)., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Amorphous solid dispersions (ASD) of quercetin (Que) in cellulose derivative matrices, carboxymethylcellulose acetate butyrate (CMCAB), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and cellulose acetate adipate propionate (CAAdP) were prepared with the goal of identifying an ASD that effectively increased Que aqueous solution concentration. Crystalline quercetin and Que/poly(vinylpyrrolidinone) (PVP) ASD were evaluated for comparison. Powder X-ray diffraction (XRPD) and differential scanning calorimetry (DSC) were used to examine the crystallinity of ASDs, physical mixtures (PM) and quercetin. ASDs were amorphous up to 50 wt% Que. Que stability against crystallization and solution concentrations from these ASDs were significantly higher than those observed for physical mixtures and crystalline Que. PVP stabilizes against both Que degradation and recrystallization; in contrast, these carboxylated cellulose derivatives inhibit recrystallization but release Que slowly. PVP ASDs afforded fast and complete drug release, while ASDs using these three cellulose derivatives provide slow, incomplete, pH-triggered drug release., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Structurally varied, carboxyl-containing cellulose derivatives were evaluated for their ability to form amorphous solid dispersions (ASD) with ellagic acid (EA), in order to improve the solubility of this high-melting, poorly bioavailable, but highly bioactive natural flavonoid compound. ASDs of EA with carboxymethylcellulose acetate butyrate (CMCAB), cellulose acetate adipate propionate (CAAdP), and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were prepared, and EA dissolution from these ASDs was compared with that from pure crystalline EA and from EA/poly(vinylpyrrolidinone) (PVP) solid dispersions (SD). Polymer/drug mixtures were characterized by powder X-ray diffraction (XRPD), modulated differential scanning calorimetry (MDSC), nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FT-IR). The XRPD and FT-IR results indicated that EA was amorphous in solid dispersions with EA concentration up to 25 wt%. The stability against crystallization and solution concentrations of EA from these solid dispersions were significantly higher than those observed for physical mixtures and pure crystalline EA. HPMCAS stabilized EA most effectively, among the polymers tested, against both chemical degradation and recrystallization. The relative ability to solubilize EA from ASDs at pH 6.8 was PVP>>HPMCAS>>CMCAB. EA dissolves from ASD in PVP quickly and completely (maximum 92%) at pH 6.8, but EA is also released from PVP at pH 1.2, and then crystallizes rapidly. Therefore PVP is not a practical candidate for EA ASD. In contrast, the cellulose derivative ASDs show very slow EA release at pH 1.2 (<4%) and faster but still incomplete drug release at pH 6.8 (maximum 35% for HPMCAS SD). The pH-triggered drug release from HPMCAS ASD makes HPMCAS a practical choice for EA solubility enhancement., (Copyright © 2012 Elsevier Ltd. All rights reserved.)