Absorbable biopolymers derived from dimer fatty acids

A new class of aliphatic copolyanhydrides was synthesized from nonlinear hydrophobic dimers (FAD) of erucic acid and sebacic acid which possessed the desired physico-chemical and mechanical properties for use as a carrier for drugs. The polymers were synthesized by melt condensation to yield film-forming polymers with molecular weights of 250,000. The copolymer composition was determined by ¹H-NMR and gravimetric methods. In vitro degradation studies showed that these polymers degrade following a first-order kinetics with a rapid degradation in the first 10 days leaving a residue which is mostly the FAD comonomer. The drug release from the polymer also followed a first-order kinetics which correlates with the degradation process of the polymer. Drugs like carboplatin, methotrexate, tetracycline, and gentamicin were released in vitro for over 2 weeks and in some cases over 6 weeks. In vivo biocompatibility tests in rats and rabbits in the brain, muscle, and subcutaneously, demonstrated their toxicological inertness and biodegradability. The 1 : 1 copolymer of FAD : SA was selected as a carrier for various applications including a gentamicin-releasing implant which is now undergoing human clinical trials for the treatment of osteomyelitis. © 1993 John Wiley & Sons, Inc.     

Biodegradable hyperbranched polyesters derived from 1,1,1‐tris(hydroxymethyl)ethane

Low molar mass hyperbranched polyesters were prepared by polycondensation of 1,1,1‐tris(hydroxymethyl)ethane and various dimethyl esters of aliphatic dicarboxylic acids in bulk. The usefulness of nontoxic bismuth salts as transesterification catalysts for these polycondensations was studied. The maximum conversion increased, and the reaction time decreased in the following sequence of increasing reactivity: dimethyl sebacate < adipate < glutarate < succinate. Regardless of the monomer combination, gelation occurred at conversions > 91.5%. The hyperbranched structure was proven by ¹H NMR spectroscopy and the absence of cyclic elements by MALDI‐TOF mass spectrometry. Quantitative acylation of all CH₂OH groups was achieved with an excess of acetic anhydride or methycrylic anhydride. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 231–238, 2009     

Biodegradable polymers derived from aminoacids

Poly(amide-ester)s derived from five α-amino acid mixtures including glycine, DL-and L-alanines, DL- and L-phenylalanines, and three different diols including 1,6-hexanediol, 1,4-butanediol and trans-1,4-cyclohexanedimethanol were synthesized by interfacial, solution and melt polymerizations. All of the polymers had Tg's ranging from −6 to 50°C. The incorporation of rigid trans-1,4-cyclohexanedimethanol in the main chain significantly increased the Tg of these polymers. The degree of crystallinity depended on the type of amino acid and decreased with the size of substituent on the α-carbon in the amino acid. Biodegradation of these polymers were tested semi-quantitatively by turbidity measurements. Enzymes used included subtilisin, pronase E, α-chymotrypsin, fusarium, and lipase. The incorporation of trans-1,4-cyclohexanedimethanol unit slowed down degradation rate. Polymers containing L-amino acid generally degraded faster than the polymers containing DL-amino acids. Quantitative biodegradation testings using ninhydrin analysis, total organic analysis, and weight loss done on alanine derived polymers indicated that the degradation of the polymers by pronase E occurred at the ester bonds first and was specific against L-amino acid. The degradation was followed by slower amide bond degradation.     

Robust antimicrobial compounds and polymers derived from natural resin acids

We report novel robust resin acid-derived antimicrobial agents that exhibit excellent antimicrobial activities against a broad spectrum of bacteria (6 Gram-positive and 7 Gram-negative) with selective lysis of microbial membranes over mammalian membranes. Our results indicate that hydrophobicity and unique structures of resin acids can be determining factors in dictating the antimicrobial activity.     

Ionic solid-state dimers and polymers derived from imidazolium dicarboxylic acids

A series of imidazolium dicarboxylic acids have been prepared from the reaction of the 1,3‐bis(carboxymethyl)imidazolium zwitterion with the Brønsted acids HX (X=F, Br, Cl, ClO₄). The structures of these acids have been established in the solid state by single‐crystal X‐ray diffraction, which revealed that the cations and anions form strong hydrogen bonds through O? H???X interactions, leading to the formation of dimeric and polymeric networks. These acids react with elemental zinc and cobalt to form stable polymeric coordination complexes, some of which have also been characterised by X‐ray diffraction.     

Biomedical Investigations of Biodegradable PHAs

This work is a review of the results of biomedical studies of polymer devices (films, fibers, microparticles, 3D implants) made from resorbable PHAs synthesized by the bacterium Wautersia (Ralstonia) eutropha B5786, using the technology developed at the Institute of Biophysics of the Siberian Branch of the Russian Academy of Sciences. Two types of PHAs – polyhydroxybutyrate (PHB) and a hydroxybutyrate/hydroxyvalerate copolymer (PHB/PHV) – have been proven to be biocompatible in vitro in cultures of fibroblasts, endothelial cells, hepatocytes, and osteoblasts, and in short- and long-duration experiments on animals. Polymer films and membranes have been found to be usable as scaffolds for functioning cells and monofilament suture fibers – for stitching muscular-fascial wounds and in abdominal surgery. Ectopic bone formation assay and experiments with the model of segmental osteotomy showed that 3D PHB and PHB/HA implants can be used for reparative osteogenesis. The paper reports beneficial results of using polymers to repair bone defects in oral surgery.     

Active polycondensation: from pep tide chemistry to amino acid based biodegradable polymers

New polycondensation (PC) methods of polymer synthesis using non-traditional active derivative of dicarboxylic acids are reviewed. The new PC methods are named by general name “Active Polycondensation” (APC) to tell them from traditional low-temperature PC. The most of these methods are based on well known in peptide chemistry approaches to the activation of carboxylic groups. In the present paper the syntheses of heterochain polymers of basic classes - polyamides, polyesters, polyurethanes, polyureas, and polybenzazoles by interaction of various active diesters with di- and polyfunctional nucleophiles are discussed in brief. Special attention is given to the synthesis of non-conventional heterochain macromolecular systems, in particular poly(ester amide)s (PEAs), composed of naturally occurring α-amino acids and other non-toxic building blocks like fatty diacids and diols - synthetic analogues of naturally occurring amino acid based polymers - peptides and proteins. The synthesis and properties, biodegradation, and some practical applications of PEAs are discussed in brief.     

Proline derivatives incorporating hydrophobic long-chain derived from natural and synthetic fatty acids

The α-hydrophobic long chain-α-amino esters are prepared by α-hydroxylation of a series of fatty acid esters [derived from oleic acid (OA), linoleic acid (LA), arachidonic acid (ARA) and docosahexaenoic acid (DHA)] followed by Mitsunobu reaction and hydrazinolysis of the phthalimide. These amino esters are mixed with aldehydes and electrophilic alkenes to give very good chemical yields and diastereoselectivities of prolinate derivatives incorporating a hydrophobic long chain at the α-position. This multicomponent 1,3-dipolar cycloaddition (1,3-DC) takes place at room temperature. The synthesis of the homologue hydrophobic chain of OA is performed by its oxidation to aldehyde/racemic N-tert-butylsulfinyl imine/Neff reaction. Final 1,3-DC with benzaldehyde and N-methylmaleimide affords homologue prolinate derivative in good yield.     

Volatile fatty acids analysis from pig slurry using high-performance liquid chromatography

A simple and sensitive liquid chromatography method designed to determine the volatile fatty acids (VFA) content in pig slurry sample is proposed. The acids are isolated with a cation exchange column for carbohydrates using an isocratic phosphate eluant coupled with an ultraviolet detector in series. Centrifuged and filtered samples can be injected directly into the liquid chromatographic system. The accuracy of this new liquid-chromatographic chain using spiked solutions ranging between 20 and 5000?mg/L of VFA standard solution varied from 87 to 124%. The precision of the new procedure, expressed as variability, was between 9.2 and 0.6% for a spike solution concentration of 20 and 5000?mg/L, respectively.     

Biodegradable polymers in gene‐silencing technology

Small interfering RNAs (siRNAs) technology has shown great promise as a new class of therapeutics invention for treatment of cancer and other diseases. siRNA has been used extensively in blocking various genes and is presently being evaluated as a therapeutic for cancer and viral disease. Despite the excitement about this remarkable biological process for sequence specific gene regulation, the major limitations against the use of siRNAs‐based therapeutics are their rapid degradation by serum nuclease, poor cellular uptake, and rapid renal clearance following systemic delivery, off‐target effects, and induction of immune responses. Many researchers have tried to overcome these limitations with developing nuclease‐resistant chemically modified siRNAs and variety of synthetic and natural biodegradable lipids and polymers for siRNA delivery to enhance efficacy and safety profiles. An ideal siRNAs‐based delivery system must be clinically suitable, safe, and effective. This review discuss the recent progress of biodegradable polymers in siRNA delivery technology.     

Catalytic and anticancer activities of sawhorse-type diruthenium tetracarbonyl complexes derived from fluorinated fatty acids

The reaction of fluorinated fatty acids, perfluorobutyric acid (C₃F₇CO₂H), and perfluorododecanoic acid (C₁₁F₂₃CO₂H), with dodecacarbonyltriruthenium (Ru₃(CO)₁₂) under reflux in tetrahydrofuran, followed by addition of two-electron donors (L) such as pyridine, 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane, or triphenylphosphine, gives stable diruthenium complexes Ru₂(CO)₄(μ₂-η²-O₂CC₃F₇)₂(L)₂ (1a, L?=?C₅H₅N; 1b, L?=?PTA; 1c, L?=?PPh₃) and Ru₂(CO)₄(μ₂-η²-O₂CC₁₁F₂₃)₂(L)₂ (2a, L?=?C₅H₅N; 2b, L?=?PTA; 2c, L?=?PPh₃). The catalytic activity of the complexes for hydrogenation of styrene under supercritical carbon dioxide has been assessed and compared to the analogous triphenylphosphine complexes with non-fluorinated carboxylato groups Ru₂(CO)₄(μ₂-η²-O₂CC₃H₇)₂(PPh₃)₂ (3) and Ru₂(CO)₄(μ₂-η²-O₂CC₁₁H₂₃)₂(PPh₃)₂ (4). In addition, the cytotoxicities of the fluorinated complexes 1 were also evaluated on several human cancer cell lines (A2780, A549, Me300, HeLa). The complexes appear to be moderately cytotoxic, showing greater activity on the Me300 melanoma cells. Single-crystal X-ray structure analyses of 1a and 3 show the typical sawhorse-type arrangement of the diruthenium tetracarbonyl backbone with two bridging carboxylates and two terminal ligands occupying the axial positions.     

Release of nitric oxide from nitrated fatty acids: Insights from computational chemistry

Nitrated fatty acids (NO₂‐FAs) exhibit a variety of important biological attributes, including a nitric oxide (˙NO) donor and a cell‐signaling molecule. We investigated the mechanisms of fatty‐acid nitration, and the release of ˙NO from NO₂‐FAs. NO₂‐FAs are formed effectively by the addition of ˙NO₂, followed by either hydrogen abstraction or addition of a second NO₂. The latter reaction results in a vicinal nitronitrite ester form of FA, which isomerizes into vicinal nitrohydroxy FA via hydronium ion catalysis. The nitrohydroxy FAs exist in equilibria with NO₂‐FAs. Nitration of conjugated linoleic acid (cLA) was proved to be significantly more efficient than that of LA. In a nonaqueous environment, release of ˙NO from nitrite ester (ONO‐FA) was facilitated by ˙NO₂. Furthermore, the release of ˙NO from NO₂‐cLA is the most favorable in the nitrite ester mechanism. In an aqueous environment, the modified Nef reaction was shown to be feasible. In addition, the release of ˙NO from 10‐ and 12‐NO₂‐LA involves a larger reaction barrier and is more endergonic than those from 9‐ and 13‐NO₂‐LA.     

Novel Hydrophobic Biodegradable Ester-Polymers Obtained via Azlactone Chemistry

Biodegradable polymers having a potential for constructing resorbable therapeutical micro- and nano-containers were synthesized by interaction of bis-azlactones with bis-(L-leucine)-1,6-hexylene diester/1,6-diamino hexane either separately or as comonomers. The thermograms (DSC) all of them showed a wide endothermal peak within 55–120 °C with a maximum ranged from 86 °C to 96 °C. The peak was assigned to the melting of hydrophobic domains formed by aromatic terephthalic acid fragments in the polymeric backbones. Preliminary in vitro study showed that the ester-bonds containing polymers obtained are biodegradable – α-chymotrypsin catalyzed ester bonds hydrolysis rates ranged within 0.02–0.34 µmole/min.     

Structure–property relationships of fatty acid swollen,crosslinked natural rubber shape memory polymers

This article investigates shape memory polymers (SMPs) fabricated by swelling sulfur crosslinked natural rubber with four different molten fatty acids: lauric, myristic, palmitic, and stearic acid. As inexpensive additives, they allow commodity natural rubber to be directly converted to SMPs. The shape memory properties are investigated as a function of wt% fatty acid, the choice of fatty acid, and the applied load during shape memory programming. It is found that increasing the wt% acid improves the shape fixity up to ca. 97% at ≥50 wt% fatty acid, at which point the recovery starts to decline with increasing wt% acid due to network failure during shape programming. The shape fixity is found to depend on the yield stress and modulus of the fatty acid network, which both increase with increasing wt% acid. The choice of fatty acid also varies the trigger temperature for shape memory, which scales with the melting point of the fatty acid. Serendipitously, it is found that alignment of the fatty acid crystals during programming produces stiffer networks whose modulus increase with applied load, which counterbalances the higher elastic energy stored in the rubber network to produce lower sensitivity of the shape fixity to the applied load. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2018 , 56, 673–687     

Sequential poly(ester amide)s based on glycine,diols, and dicarboxylic acids: Thermal polyesterification versus interfacial polyamidation. Characterization of polymers containing stiff units

Sequential poly(ester amide)s derived from glycine were synthesized by a two‐step method, involving a final thermal polyesterification. Molecular weights were in general higher than those obtained with the previously reported synthesis on the basis of interfacial polyamidation. Polymers with stiff units like oxaloyl or terephthaloyl residues were thermally characterized and their degradability studied by using different types of enzymes. Polymers containing short diols are degradable in papain solutions, the degradation rate being higher for oxalic derivatives. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 4283–4293, 2001     

Aminosalicylate-based biodegradable polymers: Syntheses and in vitro characterization of poly(anhydride-ester)s and poly(anhydride-amide)s

Poly(anhydride-ester)s and poly(anhydride-amide)s derived from both 4- and 5-aminosalicylate acids (4- and 5-ASA) were synthesized and characterized by physicochemical methods. Thermal and solubility characteristics directly correlated to the polymer backbone composition; polymers based on 5-ASA had greater solubilities in organic solvents than polymers based on 4-ASA, and the poly(anhydride-ester)s thermally decomposed at temperatures nearly 100 °C higher than the corresponding poly(anhydride-amide)s. The polymers were self-contained, controlled-release systems that combine the drug and controlled-release mechanism into the polymer backbone. The erosion and degradation characteristics of the polymers were measured in physiologically relevant media. All polymer matrices fully degraded in media buffered to pH 7.4, whereas in acidic media (pH 1.2), all polymer matrices maintained greater than 50% mass over a 90-day time period. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3667–3679, 2003     

New biodegradable polymers for delivery of bioactive agents

Biodegradable, thermosensitive triblock copolymer, PLGA-PEG-PLGA, can be easily fabricated into drug-loaded microspheres or injectable in situ hydrogel system for protein or water-insoluble drugs without use of organic solvent. Aqueous-based microsphere exhibited continuous release of intact insulin in vitro for 3 weeks while the microspheres prepared using dichloromethane showed initial burst and incomplete release. Confocal miscoscopy images of microspheres corroborated the release pattern. Next study with an injectable in situ hydrogel (ReGel^TM) exhibited zero-order insulin release in vitro and sustained plasma insulin level for 2 weeks in vivo upon single subcutaneous injection in SD rats.     

New fatty acid,aromatic ester and monoterpenic benzyl glucoside from the fruits of Withania coagulans Dunal

The fruits of Withania coagulans Dunal (family: Solanaceae) are sweet, sedative, emetic, alterative and diuretic; used to treat asthma, biliousness, strangury, wounds, dyspepsia, flatulent colic, liver complaints and intestinal infections in the indigenous system of medicine. Phytochemical investigation of the methanolic extract of W. coagulans fruits led to the isolation of a new fatty acid, an aromatic ester and a monoterpenic benzyl glucoside characterised as n-octatriacont-17-enoic acid (3), geranilan-10-olyl dihydrocinnamoate (4) and geranilan-8-oic acid-10-olyl salicyloxy-2-O-β-d-glucofuranosyl-(6″→1?)-O-β-d-glucofuranosyl-6?-n-octadec-9?′,11?′-dienoate (5) along with two known fatty acids, n-dotriacont-21-enoic acid (1) and n-tetratriacontanoic acid (2). The structures of isolated phytoconstituents were established on the basis of 1D and 2D NMR, FT-IR, UV, and MS data and chemical means.