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This work explores for the first time the enzymatic synthesis of poly(butylene-co-e-caprolactone) (PBSCL) copolyesters in bulk using commercially available monomers (dimethyl succinate (DMS), 1,4-butanediol (BD), and e-caprolactone (CL)). A preliminary kinetic study was carried out which demonstrated the higher reactivity of DMS over CL in the condensation/ring opening polymerization reaction, catalyzed by Candida antarctica lipase B. PBSCL copolyesters were obtained with high molecular weights and a random microstructure, as determined by 13C NMR. They were thermally stable up to 300 °C, with thermal stability increasing with the content of CL in the copolyester. All of them were semicrystalline, with melting temperatures and enthalpies decreasing up to the eutectic point observed at intermediate compositions, and glass transition temperatures decreasing with the content of CL in the copolyester. The use of CALB provided copolyesters free from toxic metallic catalyst, which is very useful if the polymer is intended to be used for biomedical applications., Peer Reviewed, Objectius de Desenvolupament Sostenible::11 - Ciutats i Comunitats Sostenibles, Postprint (published version)

The synthesis, characterization, and thermal properties of partially renewable poly(butylene terephthalate) copolyesters containing alditol units are described. These copolyesters were obtained by polycondensation in solution from mixtures of 1,4-butanediol and 2,3-di-O-benzyl-L-threitol with terephthaloyl chloride. Copolyesters with weight-average molecular weights oscillating between 4 000 and 12 000 g·mol-1 and dispersities around 1.5 were obtained. All them had a random microstructure and were thermally stable well above 300°C. Copolyesters containing up to 30% of dibenzyl threitol units were found to be crystalline and to adopt the same crystal structure as the parent homopolyester poly(butylene terephthalate). The melting temperature and crystallinity were observed to decrease, and the glass transition temperature to increase, with increasing amounts of alditol units incorporated in the copolyester. Furthermore, the crystallizability was depressed by copolymerization., Peer Reviewed, Postprint (author's final draft)

Poly(gamma-glutamic acid) (gamma-PGA) is one of the few bacterial polymers in nature; as such, it possesses the added value of a “green birth” (fermentation) and “green death” (biodegradability), which is ideal for sustainable macromolecular platforms. Efficient functionalization strategies are required in order to transform the native bacterial biopolymer into a material with tailored properties for bulk scale or biomedical applications. We report on a novel approach to the facile functionalization of bacterial gamma-PGA, realized with several levels of control: (a) the modulation of the molecular weight through sonication, and the solubilization in organic solvents through counterion exchange with suitable quaternary ammonium salts, (b) the introduction of reactive functionalities through reactions in homogeneous conditions in organic solvents, to afford homo- or copolymers; (c) a second tier functionalization using copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) click chemistry., Peer Reviewed, Postprint (published version)

The enzymatic ring-opening copolymerization (eROP) of globalide (Gl) and pentadecalactone (PDL) was performed in solution from mixtures of the two macrolactones at ratios covering the whole range of comonomeric compositions. The resulting P(Glx-r-PDLy) random copolyesters were aminofunctionalized by thiol-ene reaction with aminoethanethiol. ROP of ¿-benzyl-l-glutamate N-carboxyanhydride initiated by P(Glx-r-PDLy)-NH2 provided neutral poly(¿-benzyl-L-glutamate)-grafted copolyesters, which were converted by hydrolysis into negatively charged hybrid copolymers. Both water-soluble and nonsoluble copolymers were produced depending on copolymer charge and their grafting degree, and their capacity for self-assembling in nano-objects were comparatively examined. The emulsion solvent-evaporation technique applied to the chloroform-soluble copolymers grafted with benzyl glutamate rendered well-delineated spherical nanoparticles with an average diameter of 200–300 nm. Conversely, micellar solutions in water were produced from copolyesters bearing grafted chains composed of at least 10 units of glutamic acid in the free form. The copolymer micelles were shown to be able to load doxorubicin (DOX) efficiently through electrostatic interactions and also to release the drug at a rate that was markedly pH dependent., Peer Reviewed, Postprint (published version)

In this work, we study for the first time, the isothermal crystallization behavior of isodimorphic random poly(butylene succinate)-ran-poly(e-caprolactone) copolyesters, PBS-ran-PCL, previously synthesized by us. We perform nucleation and spherulitic growth kinetics by polarized light optical microscopy (PLOM) and overall isothermal crystallization kinetics by differential scanning calorimetry (DSC). Selected samples were also studied by real-time wide angle X-ray diffraction (WAXS). Under isothermal conditions, only the PBS-rich phase or the PCL-rich phase could crystallize as long as the composition was away from the pseudo-eutectic point. In comparison with the parent homopolymers, as comonomer content increased, both PBS-rich and PCL-rich phases nucleated much faster, but their spherulitic growth rates were much slower. Therefore, the overall crystallization kinetics was a strong function of composition and supercooling. The only copolymer with the eutectic composition exhibited a remarkable behavior. By tuning the crystallization temperature, this copolyester could form either a single crystalline phase or both phases, with remarkably different thermal properties, Peer Reviewed, Postprint (published version)

Two series of partially biobased ABA triblock copolyesters were successfully prepared by ring-opening polymerization (ROP) of L-lactide initiated by two telechelic polyester polyols using an organic catalyst. B blocks were made of telechelic poly(hexamethylene terephthalate) (PHT) and poly(hexamethylene 2,5-furandicarboxylate) (PHF), respectively, with average molar masses of around 3500¿g¿mol-1 and A blocks were made of poly(lactic acid)s (PLA) of different block lengths. For each series, four copolymers with different PHT/PLA and PHF/PLA compositions were prepared by varying the feed molar ratios. The triblock structure of the obtained copolymers was ascertained by 13C NMR, which confirms that the organic catalyst employed does not promote transesterification reactions at the low temperatures used for the reaction. All copolyesters were thermally stable under inert atmosphere up to around 300¿°C. For all synthesized copolyesters, the PLA blocks were unable to crystallize, mainly due to racemization reactions taking place during L-lactide ROP. Both, PHT and PHF blocks were able to crystallize and their thermal and structural properties (Tm, Tc, Xc and lamellar thickness) were independent on PLA content until its concentration was very high and topological restrictions difficulted crystallization. According to SAXS, most copolymers were found to be miscible in the melt. Both PLA-b-PHT-b-PLA or PLA-b-PHF-b-PLA triblock copolymers showed a single Tg indicating that the components are miscible in the amorphous state, Peer Reviewed, Postprint (author's final draft)

Macrocyclic oligoesters (MCOs) derived from biomass such as those prepared from alkylene alkanedioates and 2,5-furandicarboxylates are suitable compounds for ring opening polymerization (ROP) to produce high molecular weight bio-based polyesters. The synthetic procedures that have been recently developed to obtain these MCOs in good yields, their ROP either alone or together with other cyclic compounds, and their recovery by cyclodepolymerization of the final polyesters are the main topics covered in this review. Both organometallic compounds and enzymes such as Candida antarctica lipase B are the catalytic systems used for all reactions. This synthetic approach based on ROP of MCOs derived from renewable sources opens a green pathway for a circular economy in plastics., Postprint (author's final draft)

Naturally produced peptides or proteins can be regarded as highly refined polymers. When synthetic polymers are married to proteins or peptides, the resulting bioconjugates can synergistically combine the properties of the individual components and overcome their separate limitations. This Thesis is focused on the study of hybrid copolymers based on polypeptides and polymacrolactones. Block and graft copolymers have been synthesized by making use of the ring opening polymerization method (ROP) mainly and extensively characterized including both their chemical structure and their structure in the solid state. The self-assembly properties of the new copolymers have been preliminary examined regarding their potential application as nanocarriers for pharmaceutical compounds. This Thesis initially reports the ROP of w-pentadecalactone (PDL) using different amino-ended initiators and assisted by either organic or enzymatic catalysts. This method was then extended for the ROP of PDL using bisamino-ended poly(ethylene glycol) (PEG) for the preparation of poly(w-pentadecalactone)-b-poly(ethylene glycol)-b-poly(wpentadecalactone) [PPDLx-PEG-PPDLx] triblock copolymers. These amphiphilic ABA-type copolymers were able to selfassemble in water to form nanoparticles with diameters between 100 and 200 nm. Hybrid copolymers of poly(ester-peptide) or poly(ether-ester-peptide) type exhibiting different architectures (e.g. diblock, triblock, graft or triblock/grafted) respectively, were then synthesized using as building blocks: poly(w-pentadecalactone), poly(globalide) (PGl), PEG as well as polypeptides derived from the L-glutamic acid (Glu), L-lysine (Lys), L-alanine (Ala) and L-phenylalanine (Phe) a-amino acids. The hybrid copolymers were synthesized through several stages depending on the desired architecture. The first stage in the preparation of these copolymers was the synthesis of macroinitiators from PDL or PGl containing either an amino group at the end of the chain or multip, Los polipéptidos o proteínas obtenidos de manera natural son considerados como polímeros altamente refinados. Cuando los polímeros sintéticos se unen a proteínas o polipéptidos, los sistemas bioconjugados que se obtienen pueden sinérgicamente combinar las propiedades de sus componentes individuales y mejorar las propias limitaciones que tienen por separado. La proteína o el elemento polipeptídico puede impartir propiedades bifuncionales al bioconjugado, mientras que el polímero sintético puede mejorar la estabilidad proteica, la solubilidad y la biocompatibilidad. Esta tesis está enfocada en el estudio de copolímeros híbridos basados en polipeptidos y polimacrolactonas. Copolímeros tipo bloque e injerto fueron sintetizados utilizando principalmente la polimerización por apertura de anillo y extensamente caracterizados tanto su estructura química, como su estructura en estado sólido. Las propiedades de auto-agregación de los nuevos copolímeros han sido anteriomente examinadas respecto a su potencial aplicación como nanotransportadores de compuestos farmacéuticos. Esta Tesis inicialmente reporta la homopolimerización de w-pentadecalactona (PDL) usando diferentes iniciadores aminoterminados mediante el uso de catalizadores tanto orgánicos como enzimáticos. Este se extiende a la ROP de PDL usando poli(etilén glicol) bisamino-terminado (PEG) para la preparar copolímeros tribloque poli(w-pentadecalactona)-b-poli(etilén glicol)-b-poli(w-pentadecalactona) [PPDLx-PEG-PPDLx]. Estos copolímeros de tipo ABA fueron capaces de auto-agregarse en agua para formar nanopartículas con diámetros entre 100 y 200 nm. Por otra parte, sistemas híbridos de tipo poli(éster-péptido) o poli(éter-éster-péptido) que presentan distintas arquitecturas (por ejemplo dibloque, tribloque, injerto, o tribloque-injertado) respectivamente, se sintetizaron utilizando como bloques de construcción derivados de macrolactonas (w-pentadecalactona), globalida) y a-amino ácidos (ácido L-glutámico (Glu), Llisina, Postprint (published version)

En el presente trabajo se estudia la formación y caracterización de complejos deácido poli(gamma glutámico) y etil-lauroil arginato HCl (PGGA·LAE) para la posterior evaluación de la actividad antimicrobiana frente a tres bacterias:la Listeria monocitogenesis, el Lactobacillus plantarumy la Pseudomona aeruginosa, dos hongos:elAspergillius brasilensis y elPenicillium camemberti y una levadura:la Candida albicans. Se sintetizan los complejos y se caracterizan notando que solo se ha podido lograr una de las tres composiciones objetivo, PGGA·LAE 1:1. Las pruebas antimicrobianas resultan ser prometedoras, demostrando que el complejo es activo frente a los microorganismos. Los complejos se preparan en forma de polvo y de film. Las muestras más activas para las bacterias son las de LAE puro y las del complejo en forma de polvo la superficie expuesta del agente antimicrobiano es superior. El complejo PGGA·LAE en forma de film presenta una actividad antimicrobiana más sostenida, ya que el LAE difunde más lentamente al medio acuoso y consecuentemente la concentración de LAE es inferior. El complejo PGGA·LAE presenta actividad antimicrobiana similar frente a laListeria monocytogenes y elLactobacillus plantarum consiguiendo densidades bacterianasinferiores a102UFC/mLa partir de las 6 horasde exposición. El complejo PGGA·LAE presenta menos actividad frente a la Pseudomona aeruginosallegando a 102UFC/mLa los 7 días. . En el caso de los hongos y la levadura, las pruebas con el film y el complejo en forma de polvo demuestran que el complejo es activo frente ambos microorganismosya que estos no crecen encima del complejoPGGA·LAE.

Block and graft poly(macrolactone)-poly(a-amino acid) copolymers made of l-alanine and pentadecalactone or globalide respectively, are prepared. A sequential ring-opening polymerization (ROP) copolymerization route consisting of two stages, the first devoted to the preparation of the amino-functionalized poly(macrolactone) and the second to the amino-initiated polymerization of l-alanine N-carboxyanhydride (Ala-NCA), is followed for the synthesis of both types of copolymers. Poly(l-alanine) segment lengths are accurately controlled by adjusting the macroitiator/Ala-NCA ratio used for reaction in the second stage. Block copolymers are semicrystalline with the poly(pentadecalactone) block crystallizes well in a separate phase and the poly(a-amino acid) block arranged in either the a-helical or ß-sheet structure in a ratio that is depending on composition and temperature. Graft copolymers are amorphous but with the poly(a-amino acid) side chains arranged in a more or less regular conformation. Nanoparticles with a diameter of around 300 nm and moderate positive Z-potential can be obtained from the block copolymers by self-assembling in water whereas graft copolymers are unable to render recognizable objects of nanometer-dimension under similar conditions., Peer Reviewed, Postprint (author's final draft)

Polyglobalide (PGl) with number average polymerization degree of ~20 was prepared by enzymatic ROP and then polyfunctionalized at 60% with aminothioethylene groups. The PGl20-(NH2)12 copolymer was used as macroinitiator for the ROP of NCAs of BLG (¿-benzyl L-glutamate) and ZLL (eN-carbobenzoxy-l-lysine) protected amino acids to produce neutral polypeptide-grafted polyglobalides poly[Gl20-graft-(AA)z] with z¿=¿5 and 12, which upon deprotection, afforded anionic and cationic copolymers, respectively. Both protected and deprotected graft copolymers were characterized in full detail by NMR, and their thermal properties were evaluated by TGA and DSC. The structure of these copolymers in the solid-state was examined by FTIR and XRD using synchrotron radiation. All grafted polyglobalides were amorphous but the polypeptide side chains were arranged in either alpha-helix or beta-sheet conformation, and reliable indications on the occurrence of supramolecular structures were frequently found. The capacity of poly[Gl20-graft-(AA)z] copolymers to self-assemble in aqueous medium was evidenced by the preparation of well-shaped spheroidal nanoparticles with a diversity of sizes depending on copolymer composition and charge. Loading and release of doxorubicin (DOX) from nanoparticles made of negatively charged poly[Gl20-graft-(LGA)12] as well as DNA complexation with cationic poly[Gl20-graft-(LL)5] were explored to appraise the potential of these copolymers for building drug delivery systems., Peer Reviewed, Postprint (author's final draft)

Two sets of ionically charged polypentadecalactone-polypeptide diblock copolymers (PPDLx-b-PAAy, with x= 15 or 20 and y ranging from 30 to 200), one containing alpha-L-glutamic acid (LGA) and the other containing epsilon-L-lysine (LL), were obtained from their respective precursors with the side groups of LGA and LL protected as gamma-O-benzyl and epsilon-N-carbobenzoxy, respectively. The copolymers were semicrystalline with the polyester block crystallized in the usual pseudo-rhombic lattice and the polypeptide in the alpha-helix or beta-sheet conformation depending on the amino acid and the length of the block. Copolymers with PAA blocks with y = 80 were water-soluble and they adopted the alpha-helix conformation in the aqueous medium when they are in the nonionized state. Both LGA and LL containing copolymers self-assembled in nanoparticles with a size between 150 and 180 nm in diameter. PPDL-b-PLGA nanoparticles were able to load DOX with an efficiency of ~70% whereas PPDL-b-PLL displayed a noticeable capacity for condensing DNA. In both cases hosting was based on the ionic complexation taking place between the ionized copolymer and the guest compound. Accordingly DOX release rate was found to be noticeably depending on pH., Peer Reviewed, Postprint (author's final draft)

Triblock/grafted poly(ether-ester-peptide) copolymers made or PEG, poly(globablide) and poly(L-phenylalanine) were synthesized by sequential ROP starting from diaminated PEG as first initiator. The aromatic functionality of L-phenylalanine inserted on the globalide units was utilized to impart the amphiphilicity required to drive their self-assembly in water and to provide aromaticity of potential value for the efficient loading of aromatic drugs. Depending of the method used for preparation, nanoparticles possessing diameters between 25 and 600 nm were obtained by self-assembling in aqueous medium., Postprint (author's final draft)

Diblock copolymers (PPDLx-b-pPAAy) were prepared from ¿-pentadecalactone and l-glutamic acid or l-lysine amino acids by ring opening polymerization initiated by amino groups. Telechelic amino-ended poly(¿-pentadecalactone) with a length of 15–20 repeating units was firstly synthesized by enzymatic polymerization by means of CALB and then used as macroinitiator for the polymerization of the N-carboxyanhydrides of the two a-amino acids conveniently protected as benzyl and eN-carbobenzoxy derivatives, respectively. The molecular weight of the polypeptide block was accurately controlled by adjusting the amino acid/macroinitiator ratio used in the feed. Copolymers with Mn ranging between ~5000 and ~40,000¿g·mol-1 and varying ester/peptide ratio were obtained and characterized in detail by GPC and NMR spectroscopy. The thermal properties of these copolymers were evaluated by TGA and DSC, and their structure in the solid-state including their response to heating, were examined by FTIR and XRD at variable temperature. It was shown that the polypentadecalactone segment was crystallized for all compositions and that the polypeptide counterpart adopted a two-dimensional hexagonal packing of a-helices at temperatures above melting of the polyester block. SAXS revealed the presence of a biphasic nanostructure with a repeating distance of 27¿nm for the case of glutamic-based copolymers. It was demonstrated that both glutamic and lysine-based PPDLx-b-pPAAy copolymers could self-assemble in well-shaped nanospheres with a diameter in the ~200–400¿nm range and a negative zeta-potential, Peer Reviewed, Postprint (author's final draft)

Two series of partially biobased ABA triblock copolyesters were successfully prepared by ring-opening polymerization (ROP) of L-lactide initiated by two telechelic polyester polyols using an organic catalyst. B blocks were made of telechelic poly(hexamethylene terephthalate) (PHT) and poly(hexamethylene 2,5- furandicarboxylate) (PHF), respectively, with average molar masses of around 3500 g mol-1 and A blocks were made of poly(lactic acid)s (PLA) of different block lengths. For each series, four copolymers with different PHT/PLA and PHF/PLA compositions were prepared by varying the feed molar ratios. The triblock structure of the obtained copolymers was ascertained by 13C NMR, which confirms that the organic catalyst employed does not promote transesterification reactions at the low temperatures used for the reaction. All copolyesters were thermally stable under inert atmosphere up to around 300 °C. For all synthesized copolyesters, the PLA blocks were unable to crystallize, mainly due to racemization reactions taking place during L-lactide ROP. Both, PHT and PHF blocks were able to crystallize and their thermal and structural properties (Tm, Tc, Xc and lamellar thickness) were independent on PLA content until its concentration was very high and topological restrictions difficulted crystallization. According to SAXS, most copolymers were found to be miscible in the melt. Both PLA-b-PHT-b-PLA or PLA-b-PHF-b-PLA triblock copolymers showed a single Tg indicating that the components are miscible in the amorphous state.

Poly (alpha-dodecyl-glutamate) (PAAG-12) was successfully synthesized from poly(gamma-glutamic acid) (PGGA) according to Nuclear Magnetic Resonance (NMR) analyses. PAAG-12 filmswere prepared and enriched with 5% alpha-tocopherol, with the aim of using them as novel antioxidant active packaging for food applications. Thermogravimetric Analysis (TGA) characterization determined that alpha-tocopherol improved thermal stability of films, which is beneficial for industrial processing. Polylactic Acid (PLA) films prepared with the same amount of alpha-tocopherol were used to set a comparative frame and both types of films were applied to two different food models to assess their protective action against oxidation. Water, 50% ethanol (EtOH) and 95% EtOH were used as food simulants and HPLC analyses were performed to determine difusion and partition coeficients in PLA and the novel polymer, the latter exhibiting slower release rates. Primary oxidation was measured with peroxide value, which revealed that PAAG-12 films with alpha-tocopherol protected oil-in-water (O/W) emulsions up to 29 days, complying with the Codex Alimentarius., Peer Reviewed, Postprint (published version)

Cyclic oligomers of hexamethylene furanoate and hexamethylene terephthalate were obtained from 1,6-hexanediol and the corresponding methyl esters using Candida antarctica lipase B (CALB) enzyme catalyst. HPLC, MALDI-TOF MS, and NMR analyses showed that mixtures composed from cyclic dimer up to heptamer were obtained almost quantitatively. Subsequently, these cycles were polymerized by ring opening polymerization (ROP) mediated by CALB to obtain semicrystalline polymers. In addition, we demonstrated that the polymers obtained from the ROP process could be transformed into cyclic oligomers in high yields using enzymatic cyclodepolymerization, thereby recycling the polymer in a circular biosynthetic path., Postprint (author's final draft)

Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19%- DMA31%)-(FMA5%-DEA45%)]. For the present research, three systems were validated, two of them with cross-linked cores and the other without chemical stabilization. A comparison of their loading kinetics and release profiles is discussed, with the support of additional data obtained by scanning electron microscopy and dynamic light scattering. The drug was loaded into the NPs within the first minutes; the load was dependent on the degree of cross-linking. All of the systems experienced a boost in drug release at acidic pH, ranging from 50 to 80% within the first 48 h. NPs with the highest degree (20%) of core cross-linking delivered the highest percentage of drug at fixed times. The studied systems exhibited fine-tuned sustained release features, which may provide a continuous delivery of the drug at specific acidic locations, thereby diminishing side effects and increasing therapeutic rates. Hence, the studied NPs proved to behave as smart controlled drug delivery systems capable of responding to changes in pH.

Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19%- DMA31%)-(FMA5%-DEA45%)]. For the present research, three systems were validated, two of them with cross-linked cores and the other without chemical stabilization. A comparison of their loading kinetics and release profiles is discussed, with the support of additional data obtained by scanning electron microscopy and dynamic light scattering. The drug was loaded into the NPs within the first minutes; the load was dependent on the degree of cross-linking. All of the systems experienced a boost in drug release at acidic pH, ranging from 50 to 80% within the first 48 h. NPs with the highest degree (20%) of core cross-linking delivered the highest percentage of drug at fixed times. The studied systems exhibited fine-tuned sustained release features, which may provide a continuous delivery of the drug at specific acidic locations, thereby diminishing side effects and increasing therapeutic rates. Hence, the studied NPs proved to behave as smart controlled drug delivery systems capable of responding to changes in pH.

Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19%- DMA31%)-(FMA5%-DEA45%)]. For the present research, three systems were validated, two of them with cross-linked cores and the other without chemical stabilization. A comparison of their loading kinetics and release profiles is discussed, with the support of additional data obtained by scanning electron microscopy and dynamic light scattering. The drug was loaded into the NPs within the first minutes; the load was dependent on the degree of cross-linking. All of the systems experienced a boost in drug release at acidic pH, ranging from 50 to 80% within the first 48 h. NPs with the highest degree (20%) of core cross-linking delivered the highest percentage of drug at fixed times. The studied systems exhibited fine-tuned sustained release features, which may provide a continuous delivery of the drug at specific acidic locations, thereby diminishing side effects and increasing therapeutic rates. Hence, the studied NPs proved to behave as smart controlled drug delivery systems capable of responding to changes in pH.

Aplicat embargament des de la data de defensa fins el dia 1/3/2019, In recent years, the increasing public concern about the environmental pollution caused by persistent plastic wastes has stimulated the interest in replacing synthetic polymers by biopolymers. The term biopolymer refers to polymers that are renewable or biodegradable or both. Biopolymers are capable of bio-assimilation at accelerated rates so they are biocompatible with the environment. Furthermore, their sustainability is of exceptional interest; the renewable origin of biopolymers makes them inexhaustible in contrast with the uncertain accessibility at medium-term of synthetic polymers produced from fossil sources. Nevertheless, biopolymers often have inferior properties compared to commodity polymers. Modification is a way to improve properties and achieve property combinations required for specific applications. Therefore the synthesis, characterization and property evaluation of new biopolymers derivatives are essential tasks that have to be done for the development of new materials able to replace the traditional plastics in areas such as industrial, medical, food, consumer products, and pharmaceutical applications. In the present Thesis, the chemical modification of two kinds of carboxylic biopolymers has been studied to respond to the necessity of creating new biopolymer derivatives with advanced properties at reasonable cost. Poly (gamma-glutamic acid) (PGGA) and hyaluronic acid (HyA) were the biopolymers selectedin this Thesis for their capacity to form stable ionic complexes with cationic surfactants to generate stable materials with new properties. These complexes are currently object of intensive research in our group due to their outstanding features. They are easily prepared and they tend to be selfassembled in well-ordered amphiphilic structures able to respond reversibly to thermal effects. This behaviour is of high scientific interest and also of practical relevance in the design of medical devices for thermally and chemically controlled store and, En els últims anys s’ha produït un augment de la preocupació sobre la contaminació produïda pels plàstics persistents que ha estimulat l’interès per reemplaçar els polímers sintètics pels biopolímers. El terme biopolímer es refereix als polímers que son o bé renovables o biodegradables, o ambdós. A més, és de excepcional interès la seva sostenibilitat; l’origen renovable dels biopolímers els fa inesgotables al contrari dels polímers sintètics, que al ser produïts a partir de fonts fòssils presenten una accessibilitat incerta a mig termini. No obstant, els biopolímers presenten de vegades unes propietats inferiors si se'ls comparem amb els polímers tradicionals. La modificació és una via per millorar les propietats i arribar a les combinacions de propietats requerides per a aplicacions específiques. Per tant, la síntesi, caracterització i avaluació de propietats de nous derivats de biopolímers són tasques essencials que s’han de realitzar pel des envolupament de nous materials capaços de reemplaçar els plàstics tradicionals en sectors com ara la indústria química, medicina, alimentació, productes de consum i farmàcia. En la present Tes i, s’ha estudiat la modificació química de dos tipus de biopolímers carboxílics per respondre a la necessitat de crear derivats de biopolímers amb propietats avançades i a un preu raonable. L’àcid poli(gamma-glutámic) (PGGA) i l’àcid hialurònic (HyA) van ser seleccionats per la seva capacitat per formar complexes iònics estables amb surfactants catiònics per generar materials estables amb noves propietats. Aquests complexes es preparen fàcilment i tendeixen a autoassemblar-se en estructures amfifíliques ordenades, capaços de respondre reversiblement a efectes tèrmics. Aquest comportament és d’elevat interès científic i de rellevància pràctica en el disseny de dispositius mèdics per l’emmagatzematge i alliberament de fàrmacs de manera tèrmica i químicament controlada. El principal objectiu d’aquesta Tes i es la preparació de complexes i, Postprint (published version)

Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19%- DMA31%)-(FMA5%-DEA45%)]. For the present research, three systems were validated, two of them with cross-linked cores and the other without chemical stabilization. A comparison of their loading kinetics and release profiles is discussed, with the support of additional data obtained by scanning electron microscopy and dynamic light scattering. The drug was loaded into the NPs within the first minutes; the load was dependent on the degree of cross-linking. All of the systems experienced a boost in drug release at acidic pH, ranging from 50 to 80% within the first 48 h. NPs with the highest degree (20%) of core cross-linking delivered the highest percentage of drug at fixed times. The studied systems exhibited fine-tuned sustained release features, which may provide a continuous delivery of the drug at specific acidic locations, thereby diminishing side effects and increasing therapeutic rates. Hence, the studied NPs proved to behave as smart controlled drug delivery systems capable of responding to changes in pH.

High molecular weight poly[(butylene succinate)- ran-(e-caprolactone)] copolyesters (PBS-ran-PCL) were synthesized in a wide composition range and compared with significantly lower molecular weight samples synthesized previously. DSC and WAXS showed that these copolyesters are isodimorphic (i.e., each crystalline phase contains a small amount of the second comonomer) as they able to crystallize in the entire composition range and display a pseudoeutectic point, and their unit cell dimensions are a function of composition. Copolymers close or away from the pseudoeutectic point exhibited a single crystalline phase, i.e., PBS-rich or PCL-rich crystalline phase. At the pseudoeutectic point, both phases can crystallize in double crystalline banded spherulites, as demonstrated by polarized light optical microscopy (PLOM) studies. An increase in molecular weight of the copolyester does not influence Tm and Tc significantly, as their values are determined by the randomness of the comonomer distribution. However, crystallinity values are higher for lower Mw copolymers because of their faster crystallization rate. Copolymers with higher Mw exhibited higher Tg values as expected for random copolymers that are characterized by a single phase in the amorphous regions. Therefore, changing composition and molecular weight, a remarkable separate control over Tg and Tm values can be achieved in these copolyesters. SAXS results revealed that the lamellar thickness lc decreases with composition at each side of the eutectic point. Comonomer exclusion limits the length of crystallizable sequences; as a result, the lamellar thickness values do not significantly vary with Mw in the range studied here. At the pseudoeutectic copolyester compositions, the cooling rate determines for both series of samples (low and high Mw) if one or two crystalline phases can develop: only the PCL-rich crystalline phase, only the PBS-rich crystalline phase, or both crystalline phases. This behavior was studi, Peer Reviewed, Postprint (published version)

Metal-free catalysis was successfully applied to polymerize ¿-pentadecalactone (PDL) by ring-opening polymerization (ROP) using several amino-ended initiators, namely hexylamine, allylamine and O,O'-bis(3-aminopropyl)diethylene glycol. This polymerization method was suitable to prepare telechelic polyesters carrying functional-end groups. The technique was then extended to the synthesis of block copolymers by ROP of PDL using bisamino-ended poly(ethylene glycol) (Mn¿=¿2600) as macroinitiator. PPDLx-PEG56-PPDLx triblock copolymers with Mn ranging between ~4000 and ~90,000¿g¿·mol-1 were synthesized and extensively characterized by NMR, DSC, TGA and XRD. The amphiphilic copolymers thus produced were demonstrated to be able to self-assemble in nanoparticles with average diameters of ~100–200¿nm and morphologies highly depending on blocks lengths. The described synthetic route distinguishes in providing “clean” amphiphilic copolymers, which are attractive candidates for biomedical applications., Peer Reviewed, Postprint (author's final draft)

Ethyl alpha-N-lauroyl L-arginate hydrochloride (LAE) was coupled with hyaluronic acid (HyA) 2 to form ionic complexes with LAE to HyA ratios of 1:1 and 1:2. The complexes were extensively 3 characterized by FTIR and NMR spectroscopies and their thermal properties evaluated by 4 thermogravimetry and calorimetry. Thin films prepared from these complexes by casting 5 displayed a smectic-like structure based on an ordered arrangement of LAE and HyA layers 6 with a nanometric periodicity of 3.8-3.9 nm. Films immersed in water at pH 7.4 and 5.5 7 dissociated to deliver free LAE to the environment and reaching the equilibrium in few hours. 8 The biocide activity of these films against both Gram-positive and Gram-negative bacteria was 9 preliminary assessed by the liquid medium method, and shown to be notable in both cases. The 10 antibacterial property of the complexes was found to increase with the content of LAE and to be 11 particularly efficient against Gram-negative S. enterica bacteria., Peer Reviewed, Postprint (author's final draft)

Nontoxic alkanoylcholine soaps (nACh) were synthesized from choline and fatty acids with numbers of carbons n equal to 12, 14, 16, and 18, the latter including both saturated and 9-cis unsaturated alkanoyl chains. Coupling of nACh with hyaluronic acid (HyA) rendered comblike ionic complexes nACh·HyA that were non-water-soluble. The complexes were thermally stable up to temperatures above 200 °C but readily degraded by water, in particular when hyaluronidases were present in the aqueous medium. In the solid state, these complexes were selfassembled in a biphasic layered structure in which the surfactant and the polysaccharide phases were alternating regularly with a periodicity dependent on the length of the alkanoyl chain. The paraffinic phase was found to be crystallized in saturated complexes with n = 14, but only 18ACh·HyA showed reversible melting crystallization when subjected to cyclic heating-cooling treatment. Nanoparticles with diameters in the 50-150 nm range were prepared by ionotropic gelation from unbalanced 18ACh·HyA complexes with surfactant:HyA ratios of 0.5 and 0.25. These nanoparticles were also structured in layers, swelled slowly in water, and shown to be noncytotoxic in in vitro assays against macrophages cells. It was also shown that the anticancer drug doxorubicin was efficiently encapsulated in both films and NPs of 18ACh·HyA, and its release was shown to be almost linear and complete after one day of incubation in physiological medium. The nACh·HyA complexes constitute a highly promising biocompatible/biodegradable platform for the design of systems suitable for drug transport and targeting delivery in anticancer chemotherapy., Peer Reviewed, Postprint (author's final draft)

Cyclic butylene furandicarboxylate (c(BF)n) and butylene isophthalate (c(BI)n) oligomers obtained by high dilution condensation reaction were polymerized in bulk at 200 °C with Sn(Oct)2 catalyst via ring opening polymerization to give homopolyesters and copolyesters (coPBFxIy) with weight average molar masses in the 60,000–70,000 g·mol-1 range and dispersities between 1.3 and 1.9. The composition of the copolyesters as determined by NMR was practically the same as that of the feed, and they all showed an almost random microstructure. The copolyesters were thermally stable up to 300 °C and crystalline for all compositions, and have Tg in the 40–20 °C range with values decreasing almost linearly with their content in isophthalate units in the copolyester. Both melting temperature and enthalpy of the copolyesters decreased as the content in butylene isophthalate units increased up to a composition 30/70 (BF/BI), at which the triclinic crystal phase made exclusively of butylene furanoate units changed to the crystal structure of PBI. The partial replacement of furanoate by isophthalate units decreased substantially the crystallizability of PBF., Peer Reviewed, Postprint (author's final draft)

Premi extraordinari doctorat UPC curs 2017-2018. Àmbit d’Enginyeria Industrial, In recent years, as a result of climate change, the interest in sustainable materials has increased dramatically. The replacement of compounds of petrochemical origin by bio-based has spread to all areas of chemistry. Nowadays there is a development of sustainable polymers based in 2,5-furanedicarboxylic acid (FDCA) as it may compete in performance with the ones based on terephthalic acid (PTA). On the other hand, the entropically driven ring opening polymerization (ED-ROP) is an attractive synthesis route whose interest has grown in this last decade because the reaction is athermal, no byproducts are generated and polymers of high molecular weight can be obtained in short reaction times. This Thesis reports the synthesis and characterization of cyclic oligomers of FDCA with different diols, such as 1,4-butanediol (c(BF)n), ethylene glycol (c(EF)n), resorcinol (c(RF)n) and isomannide (c(ImF)n) using different synthetic routes including high dilution condensation (HDC) and cyclodepolymerization (CD). The cyclic oligomers of butylene isophthalate (c(BI)n) and butylene terephthalate (c(BT)n) have also been synthesized by HDC. Finally, the cyclic oligomers of butylene succinate (c(BS)n) and ethylene succinate (c(ES)n) were obtained by enzymatic cyclization reaction (EC). The furanic cyclic oligomers were homopolymerized and copolymerized with the aforementioned cyclic oligoesters as well as with epsilon-caprolactone (e-CL). The polymerization reactions were catalyzed with tin octanoate (SnOct2), except in the case of homopolyesters and copolyesters with aliphatic units in which the Candida antarctica lipase B (CALB) was used. The molecular weights of the polymers obtained ranged between 25,000 and 80,000 g / mol. The copolymers presented a random microstructure with the exception of the caprolactone derivatives, which presented a blocky microstructure. Differential scanning calorimetry (DSC) studies revealed that PEF, PBF, PBT, PBI, PBS, PES, and their copolymers with l, En estos últimos años, como consecuencia del cambio climático, ha aumentado extraordinariamente el interés por materiales sostenibles. El reemplazo de los compuestos de origen petroquímico por naturales se ha extendido a todos los ámbitos de la química. Se están desarrollando polímeros sostenibles basados en ácido 2.5-furandicarboxílico (FDCA) ya que pueden competir en prestaciones con los basados en el ácido tereftálico (PTA). Por otro lado, la polimerización entrópica por apertura de anillo (ED-ROP) es una vía de síntesis atractiva cuyo interés ha crecido en esta última década debido a que la reacción es atérmica, no se generan subproductos y se puede obtener polímeros de alto peso molecular en cortos tiempos de reacción. En esta Tesis se reporta la síntesis y caracterización de oligómeros cíclicos de FDCA con diferentes dioles, tales como 1,4- butanodiol (c(BF)n), etilenglicol (c(EF)n), resorcinol (c(RF)n) e isomannide (c(ImF)n) usando diferentes rutas sintéticas incluyendo la condensación con alta dilución (HDC), la ciclodepolimerización (CD). También se han sintetizado mediante HDC los oligómeros cíclicos de butilén isoftalato (c(BI)n) y butilén tereftalato (c(BT)n). Finalmente, se han obtenido los oligómeros cíclicos de butilén succinato (c(BS)n) y etilén succinato (c(ES)n) por reacción de ciclación enzimática (EC). Los oligómeros cíclicos furánicos se homopolimerizaron y copolimerizaron con los oligoesteres cíclicos mencionados anteriormente así como con la epsilon-caprolactona (e-CL). Las reacciones de polimerización fueron catalizadas con el octanoato de estaño (SnOct2), excepto en el caso de los homopoliésteres y copoliésteres con unidades alifáticas en los que se utilizó la enzima lipasa B de Cándida antárctica (CALB). Los pesos moleculares de los polímeros obtenidos oscilaron entre 25,000 y 80,000 g/mol. Los copolímeros presentaban una microestructura al azar con la excepción de los derivados de caprolactona, los cuales presentaron una microestructura en, Award-winning, Postprint (published version)

Cyclic oligo(butylene 2,5-furandicarboxylate) and e-caprolactone were copolymerized in bulk at 130-150 ºC by enzymatic ring opening polymerization using CALB as catalyst. Copolyesters within a wide range of compositions were thus synthesized with weight-average molecular weights between 20,000 and 50,000, the highest values being obtained for equimolar or nearly equimolar contents in the two components. The copolyesters consisted of a blocky distribution of the e-oxycaproate (CL) and butylene furanoate (BF) units that could be further randomized by heating treatment. The thermal stability of these copolyesters was comparable to those of the parent homopolyesters (PBF and PCL), and they all showed crystallinity in more or less degree depending on composition. Their melting and glass-transition temperatures were ranging between those of PBF and PCL with values increasing almost linearly with the content in BF units. The ability of these copolyesters for crystallizing from the melt was evaluated by comparative isothermal crystallization and found to be favored by the presence of flexible e-oxycaproate blocks. These copolyesters are essentially insensitive to hydrolysis in neutral aqueous medium but they became noticeably, Peer Reviewed, Postprint (author's final draft)

Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19%- DMA31%)-(FMA5%-DEA45%)]. For the present research, three systems were validated, two of them with cross-linked cores and the other without chemical stabilization. A comparison of their loading kinetics and release profiles is discussed, with the support of additional data obtained by scanning electron microscopy and dynamic light scattering. The drug was loaded into the NPs within the first minutes; the load was dependent on the degree of cross-linking. All of the systems experienced a boost in drug release at acidic pH, ranging from 50 to 80% within the first 48 h. NPs with the highest degree (20%) of core cross-linking delivered the highest percentage of drug at fixed times. The studied systems exhibited fine-tuned sustained release features, which may provide a continuous delivery of the drug at specific acidic locations, thereby diminishing side effects and increasing therapeutic rates. Hence, the studied NPs proved to behave as smart controlled drug delivery systems capable of responding to changes in pH.

Ionic coupling of bacterial poly(¿-glutamic acid) (PGGA) with alkyltrimethylphosphonium surfactants is reported to render comb-like PGGA complexes with a biphasic-layered structure displaying periodicity at the nanoscopic scale. In this work, nanocomposites made of PGGA and montmorillonite, and covering a wide variety of compositions, are prepared by using either dodecyl- or eicosyl-trimethylphosphonium surfactant as a third component with a double purpose, that is, ionic complexation of PGGA and organo-modification of the nanoclay. Thermogravimetric analysis ascertains the compositions of these three-component nanocomposites and evidences their excellent thermal stability. The nanocomposite structure with PGGA and clay more or less intercalated according to composition and thermal history is evidenced by both X-ray diffraction and transmission electron microscopy. Simultaneous thermal SAXS/WAXS analysis at real time reveals extensive intermixing of the two phases that become notably enhanced by heating treatment. Thermal transition characteristics of the surfactant–PGGA complex are not significantly altered in the nanocomposites, but elastic moduli and strength to yield are found to increase proportionally to the content of clay, Peer Reviewed, Postprint (author's final draft)

Amphiphilic ionic complexes of hyaluronic acid and alkyltrimethylphosphonium soaps with alkyl chains containing even numbers of carbons from 12 to 22 have been produced. The complexes have a nearly stoichiometric composition, are non-water soluble, and are stable to heat up to temperatures above 200¿°C. These complexes are amphiphilic and able to adopt a biphasic structure with the paraffinic and polysaccharide phases ordered arranged with a periodicity ranging between 3 and 5¿nm depending on n. The paraffinic phase in complexes with n¿=¿18 was crystallized and showed melting at temperatures between 58 and 70¿°C depending on the n value. The complexes decomposed upon incubation in water under physiological conditions, and undergone extensive biodegradation by the action of hyaluronidases. Biocide assays carried out in both solid and liquid media demonstrated a high antimicrobial activity of the complexes against Gram-positive S. aureus but moderate against Gram-negative E. coli and C. albicans fungi, Postprint (updated version)

Cyclic butylene furandicarboxylate (c(BF)n) and butylene isophthalate (c(BI)n) oligomers obtained by high dilution condensation reaction were polymerized in bulk at 200 ¿C with Sn(Oct)2 catalyst via ring opening polymerization to give homopolyesters and copolyesters (coPBFxIy) with weight average molar masses in the 60,000–70,000 g·mol-1 range and dispersities between 1.3 and 1.9. The composition of the copolyesters as determined by NMR was practically the same as that of the feed, and they all showed an almost random microstructure. The copolyesters were thermally stable up to 300 ¿C and crystalline for all compositions, and have Tg in the 40–20 ¿C range with values decreasing almost linearly with their content in isophthalate units in the copolyester. Both melting temperature and enthalpy of the copolyesters decreased as the content in butylene isophthalate units increased up to a composition 30/70 (BF/BI), at which the triclinic crystal phase made exclusively of butylene furanoate units changed to the crystal structure of PBI. The partial replacement of furanoate by isophthalate units decreased substantially the crystallizability of PBF, Peer Reviewed, Postprint (published version)

Bio-based triblock copolyesters were synthesized by ring-opening polymerization of l-lactide in solution using a hydroxyl-ended polytartrate as di-functional macroinitiator. This telechelic polyester with a Mn about 3000¿g·mol-1 was obtained by non-stoichiometric melt polycondensation of dimethyl 2,3-di-O-isopropylidene-l-tartrate and 1,4-butanediol. Two symmetrical triblock copolyesters with Mn in the 5000–7000¿g·mol-1 range and differing in the length of the polylactide blocks were prepared. The protecting isopropylidene group was removed in trifluoracetic acid to generate amphiphilic triblock copolyesters bearing free hydroxyl groups in the central block. All copolyesters started to decompose approximately at 260–280¿°C, were semicrystalline, and readily degraded by hydrolysis of the main chain under both acid and basic conditions. The acetalized copolyesters had a single Tg, whereas free-hydroxyl bearing copolyesters showed two Tg indicative of blocks phase separation. All copolyesters were able to form nanoparticles with average diameters within the ~200–450¿nm range. The influence of the block lengths and protection/deprotection of the hydroxyl groups on size and ¿-potential of the nanoparticles was evaluated., Peer Reviewed, Postprint (author's final draft)

Cyclic oligomers of isomannide 2,5-furandicarboxylate were synthesized using the high dilution condensation method. A mixture of dimer, trimer, and tetramer species largely enriched in dimer was obtained. These cyclic oligomers were made to react with oligo(butylene 2,5-furandicarboxylate) in bulk at 220 °C by ring opening polymerization using Sn(Oct)2 as a catalyst. A series of random poly(butylene 2,5-furandicarboxylate) copolyesters containing isomannide in a range of 5–50 mol % and with weight-average molecular weights between 30,000 and 50,000 g·mol–1 were prepared. These copolyesters started to decompose above 300 °C, and only those containing less than 10 mol % of isomannide showed signs of crystallinity. They displayed glass-transition temperatures in the 40–100 °C range with values increasing steadily with the content in isomannide. At difference with poly(butylene 2,5-furandicarboxylate) homopolyester that is reluctant to undergo hydrolysis, the isomannide-containing copolyesters were noticeably degraded by water, much more rapidly when exposed to lipases., Peer Reviewed, Postprint (author's final draft)

In this century, the major use of synthetic polymers have been as replacements for more traditional materials, particulary in packaging. Today the packaging industry is by far the major user of plastics. Another interesting application of these materials is drug delivery systems. Polymers have played an integral role in the advancement of drug delivery technology by providing controlled release of therapeutic agents in constant doses over long periods, cyclic dosage and tunable release of both hydrophilic and hydrophobic drugs. Modern advances in drug delivery are now predicated upon the rational design of polymers tailored for specific cargo and engineered to exert distinct biological functions. Aliphatic polyesters such as poly(L-lactic acid), poly(butylene succinate), and polyhydroxyalkanoates among others, constitute primary examples of bio-based polymers that distinguish by being fully renewable and displaying partial or total biodegradability. This Ph.D. Thesis is devoted to the synthesis of aliphatic random and block polyesters from renewable resources with application for packaging and drug delivery. The main goal of this project is to develop new bio-based polymers with similar or even improved properties compared to those of conventional plastics obtained from non-renewable sources. The two cyclic acetals, 2,3-di-O-methylene-L-threitol and dimethyl 2,3-di-O-methylene-L-threarate, were used for the synthesis of two series of PBS copolyesters differing in which unit, butylene or succinate, was replaced, in addition of the corresponding parent homopolyesters. 2,4:3,5-di-O-methylene-D-glucitol was used for the synthesis of PBS copolyesters by melt polycondensation. Three series of polyalkanoates (adipates, suberates and sebacates) were synthesized using as monomers three sugar-based bicyclic diols derived from D-glucose and D-mannose. ABA triblock copolyesters were synthesized by ROP of L-lactide in solution initiated by telechelic D-glucose- and L-tartaric-ba, En este siglo, el mayor empleo que se les ha dado a los polímeros sintéticos ha sido como sustitutos de materiales más tradicionales, en particular, materiales para envase y embalaje. Hoy en día la industria de envasado es, por mucho, la mayor consumidora de plásticos. Otra aplicación interesante de estos materiales son los sistemas de administración de fármacos. Los polímeros han jugado un papel fundamental la tecnología de administración de fármacos al proporcionar un medio de liberación controlada de agentes terapéuticos en dosis constantes durante largos periodos; la dosificación cíclica y la liberación sintonizable de fármacos hidrofílicos e hidrofóbicos. Actualmente, los avances modernos en la administración de fármacos se basan en el diseño racional de polímeros para la liberación de dosis controladas que modifican distintas funciones biológicas de forma específica. Los poliésteres alifáticos tales como el poli(ácido L-láctico), el poli(succinato de butileno) y los polihidroxialcanoatos, entre otros, constituyen ejemplos primarios de polímeros de base biológica que se distinguen por ser completamente renovables y presentar biodegradabilidad parcial o total. Este trabajo de doctorado está dedicado a la síntesis de poliésteres alifáticos al azar y de bloques a partir de recursos renovables con aplicación para el envasado y la administración de fármacos. El objetivo principal de este proyecto es desarrollar nuevos polímeros biológicos con propiedades similares o incluso mejores en comparación a los plásticos convencionales obtenidos a partir de fuentes norenovables. Los dos acetales cíclicos, 2,3-di-O-metileno-L-treitol y dimetil 2,3-di-O-metileno-L-trearato, se usaron para la síntesis de dos series de copoliésteres de PBS que difieren en qué unidad, butileno o succinato, se reemplazó, además de los homopoliésteres originales correspondientes. Se usó 2,4:3,5-di-O-metileno-D-glucitol para la síntesis de copoliésteres de PBS mediante policondensación en estado fun, Postprint (published version)

In this paper, the preparation of PBS-ran-PCL copolyesters by enzymatic ring opening polymerization is presented for the first time. The copolyesters were produced in a wide composition range and free of metallic contaminants, so they may be regarded as potential biomaterials. The copolymers have been characterized by proton and carbon nuclear magnetic resonance (1H and 13C NMR), gel permeation chromatography (GPC), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), polarized light optical microscopy (PLOM) and wide angle X-ray scattering (WAXS). The PBS-ran-PCL copolyesters were able to crystallize in the entire composition range and displayed a pseudo-eutectic region. Most copolymers away from the pseudo-eutectic region exhibited a single crystalline phase (PBS-rich or PCL-rich crystalline phase), while within the pseudo-eutectic region the copolymers were double crystalline. Observations by PLOM, during isothermal crystallization showed that both nucleation density and spherulitic growth rate of the copolyesters are determined by the component that constitutes the majority phase. WAXS studies revealed that d spacings of selected crystallographic planes depend on composition. Therefore, both DSC and WAXS results suggest that the copolymers are probably isodimorphic, as the PBS-rich crystalline phase may contain small inclusions of PCL co-units, while the PCL-rich crystalline domains may also contain a minor quantity of PBS co-units inside., Peer Reviewed, Postprint (author's final draft)

Poly(ethylene succinate) (PES) with weight-average molecular weight above 60,000 g mol-1 was efficiently obtained by enzymatic ring opening polymerization of cyclic oligo(ethylene succinate)s c(ES)n, which in turn were prepared by lipase-catalysed cyclocondensation in solution of dimethyl succinate and ethylene glycol. The methodology was demonstrated to be also applicable to the synthesis of high molecular weight PES-copolyesters containing butylene succinate, e-hydroxycaproate or L-lactate units with a random distribution., Peer Reviewed, Postprint (author's final draft)

Quaternary organophosphonium salts bearing long alkyl chains are cationic surfactants of interest owing to their physical and biological properties. In the present work, the crystal structure and thermotropic behavior of the homologous series of alkyltrimethylphosphonium bromides (nATMP·Br), with the alkyl chain containing an even number (n) of carbon atoms from 12 to 22, have been examined within the 0–300 °C range of temperatures. These compounds were shown to be resistant to heat up to ~390 °C. The phases adopted at different temperatures were detected by DSC, and the structural changes involved in the phase transitions have been characterized by simultaneous WAXS and SAXS carried out in real-time, and by polarizing optical microscopy as well. Three or four phases were identified for n = 12 and 14 or n = 16, respectively, in agreement with the heat exchange peaks observed by DSC. The phase existing at room temperature (Ph-I) was found to be fully crystalline and its crystal lattice was determined by single-crystal X-ray diffraction methods. Ph-II consisted of a semicrystalline structure that can be categorized as Smectic-B with the crystallized ionic pairs hexagonally arranged in layers and the molten alkyl chain confined in the interlayer space. Ph-II of 12ATMP·Br and 14ATMP·Br directly isotropicized upon heating at ~220 °C, whereas for n = 16, it converted into a Smectic-A phase (Ph-III) that needed to be heated above ~240 °C to become isotropic (Ph-Is). The correlation existing between the thermal behavior, phase structure and length of the alkyl side chain has been demonstrated., Peer Reviewed, Postprint (published version)

A series of ionic complexes with a comb-like architecture and a nearly stoichiometric composition were prepared from bacterial poly(gamma,dl-glutamic acid) (PGGA) and alkyltrimethyl phosphonium bromides (nATMP·Br) bearing long linear alkyl chains with even numbers of carbon atoms (n) ranging from 12 to 22. The nATMP·PGGA complexes were non-water soluble but readily soluble in organic solvents, and they displayed a high thermal stability. Combined DSC and XRD studies revealed that these complexes adopted an amphiphilic layered structure with the polypeptide chain and the alkyl chain separated in two differentiated phases with a nanoperiodicity that increased steadily with the length of the alkyl chain. The paraffinic phase was found to be partially crystallized in an extent that decreased with n, so that complexes with n = 12 and 14 did not show any sign of crystallinity whereas those with n from 16 to 22 showed crystalline melting in the ~30–70 °C range. The structural transitions taking place by temperature effects were characterized by simultaneous SAXS/WAXS using synchrotron radiation at real time. In all cases, a shortening of the layer periodicity occurred upon heating with recovering of the initial structure after cooling. nATMP·PGGA with n = 16 showed strong antimicrobial activity against both E. coli and S. aureus, a property that could be related to the weak dissociation of the complexes happening upon incubation in water. The structure and properties of these complexes where comparatively discussed taking as reference their analog complexes made from PGGA and alkyltrimethylammonium bromides already studied by us., Peer Reviewed, Postprint (author's final draft)

ABA triblock copolyesters were synthesized by ring-opening polymerization (ROP) of l-lactide in solution initiated by a telechelic d-glucose-based polyester macroinitiator. The macroinitiator with a number-average molecular weight about 2500 g mol-1 was synthesized by non-stoichiometric polycondensation in the melt of 2,4:3,5-di-O-methylene-d-glucitol and dimethyl succinate. Two triblock copolyesters of Mn ranging between ~6000 and ~9000 g mol-1, and differing in the length of the polylactide blocks were prepared. These copolyesters started to decompose when heated at ~220 °C and degraded slowly upon aqueous incubation under physiological conditions. They did not display any perceivable crystallinity and showed a single glass transition temperature (Tg) around 60 °C with the higher value corresponding to the larger content in glucitol units. The copolyesters were able to form nanoparticles with average diameters of ~100–130 nm and satisfactory dispersity. The effect of the block lengths on size, ¿-potential values and physical stability of the nanoparticles was evaluated. A molecular dynamics simulation study allowed modelling the two-phase structure of the nanoparticles and evidenced the preference of the glucose-based block to be peripherally located., Peer Reviewed, Postprint (author's final draft)

En este proyecto se han sintetizado poliuretanos segmentados de 1,4-butanodiol y diisocianato de hexametileno empleando como segmento “flexible” un poliéster bicíclico derivado de la glucosa y se ha puesto de manifiesto el efecto crítico de la humedad sobre la composición y el peso molecular de los polímeros que se obtienen. La caracterización de los compuestos se realizó mediante los siguientes métodos: resonancia magnética nuclear para la determinación de la composición y la microestructura, cromatografía de permeabilidad en gel para la estimación del peso molecular, calorimetría diferencial de barrido con el fin de conocer el comportamiento térmico incluyendo la temperatura de transición vítrea, y análisis termogravimétrico para la evaluación de la estabilidad térmica y determinación de las temperaturas de descomposición. Los nuevos poliuretanos sintetizados son más sostenibles y presentan estabilidad térmica, temperatura de transición vítrea y biodegradabilidad superiores a los poliuretanos segmentados derivados de la policaprolactona. Estudios subsiguientes complementarios habrán de ratificar el potencial de estos poliuretanos como posibles alternativas a los poliuretanos convencionales empleados en la actualidad.

Two series of aliphatic-aromatic copolyesters derived from succinic and 2,5-furandicarboxylic acids, and di-O-2-(hydroxyethyl) resorcinol as diol substituent of either 1,4-butanediol or ethylene glycol, respectively, were obtained by ring opening polymerization(ROP) performed in bulk and catalyzed by Sn(Oct)2. Cyclic oligomers of furandicarboxylate of di-O-2-(hydroxyethyl) resorcinol were successfully synthesized by high-dilution condensation, and then copolymerized with cyclic oligomers of either butylene or ethylene succinate. The synthesized resorcinol-containing succinate-furanoatecopolyesters had Mw oscillating between 50,000 and 30,000 g·mol-1 depending on composition, and they all displayed a nearly random microstructure. They showed an excellent thermal stability with onset decomposition temperatures near 300 °C. They are amorphous with Tg increasing monotonically with the content in resorcinol in both series with values ranging from -30 or -13 °C for butylene and ethylene-based copolyesters, respectively, up to around 45 °C. The resorcinol-containing succinate-furanoate copolyesters showed appreciable hydrolytic degradation when incubated for a few weeks in water under physiological conditions, a behavior that was notably enhanced in the presence of lipases, Peer Reviewed, Postprint (author's final draft)

Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19%-DMA31%)-(FMA5%-DEA45%)]. For the present research, three systems were validated, two of them with cross-linked cores and the other without chemical stabilization. A comparison of their loading kinetics and release profiles is discussed, with the support of additional data obtained by scanning electron microscopy and dynamic light scattering. The drug was loaded into the NPs within the first minutes; the load was dependent on the degree of cross-linking. All of the systems experienced a boost in drug release at acidic pH, ranging from 50 to 80% within the first 48 h. NPs with the highest degree (20%) of core cross-linking delivered the highest percentage of drug at fixed times. The studied systems exhibited fine-tuned sustained release features, which may provide a continuous delivery of the drug at specific acidic locations, thereby diminishing side effects and increasing therapeutic rates. Hence, the studied NPs proved to behave as smart controlled drug delivery systems capable of responding to changes in pH., Peer Reviewed, Postprint (published version)

© 2017 by the author. The biocide agent LAE (ethyl aN-lauroyl l-arginate chloride) was coupled with poly(y-glutamic acid) (PGGA) to form stable ionic complexes with LAE:PGGA ratios of 1 and 0.5. The nanostructure adopted by these complexes and its response to thermal changes were examined in detail by Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) using synchrotron radiation in real time. A layered biphasic structure with LAE filling the space between the polypeptidic sheets was adopted in these complexes. The complexes were stable up to above 250 °C, non-water soluble, and were able to form consistent transparent films. The release of LAE from the complexes upon incubation in aqueous buffer was examined and found to depend on both pH and complex composition. The antibacterial activity of films made of these complexes against Gram-positive (L. monocytogenes and S. aureus) and Gram-negative (E. coli and S. enterica) bacteria was preliminary evaluated and was found to be very high against the formers and only moderate against the later. The bactericide activity displayed by the LAE·PGGA complexes was directly related with the amount of LAE that was released from the film to the environment, Peer Reviewed, Postprint (published version)

Poly(butylene 2,5-furandicarboxylate-co-succinate) copolyesters (coPBFxSy) have been synthesized by ring opening polymerization (ROP). Cyclic butylene 2,5-furandicarboxylate and butylene succinate oligomer mixtures, to be used as monomers for ROP, were prepared by high dilution condensation and enzymatic cyclization reactions, respectively. Two different catalytic systems, tin dioctanoate and supported Candida antarctica lipase B (CALB), were used for polymerization. Thus two series of copolyesters covering the whole range of compositions were prepared and their properties comparatively examined. In both cases, random copolyesters with compositions close to those used in their respective feeds were obtained. The influence of composition on reaction kinetics with respect to time and temperature was evaluated for the two series. Chemically catalyzed ROP rendered copolyesters with Mw in the ~50 000–65 000 g mol-1 range, whereas values between 15 000 and 45 000 g mol-1 were attained when the ROP reaction was assisted by CALB. The thermal behavior of coPBFxSy obtained by ROP was similar to that reported for such copolymers prepared by melt polycondensation. They all start to decompose above 300 °C and display melting enthalpy and temperatures that decrease with copolymerization, attaining minimum values when the comonomer contents are approximate to balance. On the contrary, the glass-transition temperature increased almost linearly with the content of butylene furandicarboxylate units, covering the whole range of values between those of the two parent homopolyesters. Small deviations in thermal properties observed between the two series could be attributed to their differences in molecular weights. Hydrolytic and enzymatic degradation studies revealed that coPBFxSy became more degradable with increasing content of succinic units, whereas the homopolyester PBF remained practically unaffected when incubated under similar conditions., Peer Reviewed, Postprint (author's final draft)

Sugar-based polyesters derived from sorbitol and isohexides were obtained via solvent-free enzymatic catalysis. Pendant hydroxyl groups, coming from the sorbitol units, were present along the polyester backbone, whereas the two isohexides, namely, isomannide and isoidide dimethyl ester monomers, were selected to introduce rigidity into the polyester chains. The feasibility of incorporating isomannide as a diol compared to the isoidide dimethyl ester as acyl-donor via lipase-catalyzed polycondensation was investigated. The presence of bicyclic units resulted in enhanced Tg with respect to the parent sorbitol-containing polyester lacking isohexides. The different capability of the two isohexides to boost the thermal properties confirmed the more flexible character provided by the isoidide diester derivative. Solvent-borne coatings were prepared by cross-linking the sugar-based polyester polyols with polyisocyanates. The increased rigidity of the obtained sugar-based polyester polyols led to an enhancement in hardness of the resulting coatings., Peer Reviewed, Postprint (author's final draft)

Renewable polyesters derived from a sugar alcohol (i.e., sorbitol) were synthesized by solvent-free polycondensation. The aim was to prepare linear polyesters with pendant hydroxyl groups along the polymer backbone. The performance of the sustainable biocatalyst SPRIN liposorb CALB [an immobilized form of Candida antarctica lipase B (CALB); SPRIN technologies] and the organo-base catalyst 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD) were compared with two metal-based catalysts: dibutyl tin oxide (DBTO) and scandium trifluoromethanesulfonate [also known as scandium triflate, Sc(OTf)3]. For the four catalytic systems, the efficiency and selectivity for the incorporation of sorbitol were studied, mainly using 13C and 31P NMR spectroscopies, whereas side reactions, such as ether formation and dehydration of sorbitol, were evaluated using MALDI-TOF-MS. Especially the biocatalyst SPRIN liposorb CALB succeeded in incorporating sorbitol in a selective way without side reactions, leading to close-to-linear polyesters. By using a renewable hydroxyl-reactive curing agent based on l-lysine, transparent and glossy poly(ester urethane) networks were successfully synthesized offering a tangible example of bio-based coatings., Peer Reviewed, Postprint (author's final draft)