One hundred years after the discovery of antimicrobials and antibiotics, intracellular bacterial pathogens remain a major cause of global morbidity and mortality. This is due to the complex and intricate ability of these pathogens to undergo intracellular replication while evading host cell immune defense. Bacterial agents such as Legionella pneumophila, Francisella tularensis, and Mycobacterium tuberculosis, as the causative agents of Legionnaires' disease, pulmonary tularemia, and tuberculosis (TB), respectively, contribute to this burden. Moreover, these agents are weaponizable pathogens due to their aerosolizability. TB represents a global health problem, although a potentially curative therapy has been available for approximately 50 years; this intracellular disease affects approximately 1 in 3 people worldwide, with over 10 million new cases per year and one death every three minutes. TB can usually be treated with a 6- to 9-month course of combined therapy. The necessity of using a cocktail of anti-TB drugs and the long-term treatment schedules required for conventional therapy, however, result in poor patient compliance; therefore, the risk of treatment failure and relapses is higher. Hence, improved drug delivery strategies for the existing drugs can be exploited to shorten the duration of TB...

The present PhD thesis, entitled: "Essential oil components encapsulated in mesoporous silica supports: a bioactive properties evaluation and a toxicological approach" focuses on the study of protection and controlled release of natural bioactive agents, derived from essential oil components (EOCs), encapsulated in mesoporous silica particles (MSPs). In addition, this thesis evaluatesthe silica-based supports to reduceundesirable sensorial propertiesandfor ensuring a low-health risk. The first section of the thesis shows the effect of encapsulation of EOCs in mesoporous silica supports. This study evaluates the efficiency of free and encapsulated EOCs to reduce the viability of cancer colon cell lines. This sectionalso shows the selectivity of encapsulated EOCs against cancer linesandtheir effect onnormal (non-cancer) colon cells. Results indicate that EOCs effect can be enhanced and sustained in time when EOCs are encapsulated. Moreover, EOCs' encapsulation shows promising specificity indices, reaching to double effect on colon cancer cells above normal cells. On the other hand,the encapsulation supports and their surface functionalization allows the odour masking of high volatility EOCs. Therefore, the delivery system based on MSPs represents an excellent alternative to promote controlled EOCs release, taking advance of their bioactive properties and solving the technical disadvantages related to volatility and unpleasant odours. Finally, samples used for garlic components encapsulation were immobilised in nanofibers to provide homogeneous and easy-to-handle hybrid system for controlling delivery.The developed 'composite' has potential applications on food, pharmacology, medical or engineering fields. The second sectionof the thesis evaluates the toxicity of the mesoporous silica supports through in vitro and in vivo assessments. Cell viability allows to identify the cytotoxic impact based on the kind of silica-based support, and their features (doses range, size and surface structure changes). Furthermore, the use of Caednorhabditis elegansmodel,shows the in vivo effects afterMSPs ingestion. The toxicological study confirms that size and surface structure, are decisiveMSPs' featuresfor reducing the toxicity risks for health. In summary, the present thesis evaluates the mesoporous silica-based particles as supports for EOCs encapsulation and identifies the main MSPs' features forreducingthe health-toxicity impact. Results of this thesis show that MSPs improve the EOCs activity and help to solve technical problemsof EOCs' volatility.Moreover, these results open up a suitable and safety option for oral delivery devices. / La presente tesis titulada: "Componentes de aceites esenciales encapsulados en soportes mesoporosos de sílice: una evaluación de sus propiedades bioactivas y un enfoque toxicológico" se centra enla evaluación de las propiedades funcionales y organolépticas de agentes naturales bioactivos, derivados de componentes de aceites esenciales, encapsulados en materiales mesoporosos de sílice; a la vez que evalua la toxicidad de los soportes utilizados,con el fin de proponer nuevos sistemas de liberación controlada por vía oral. La primera sección de esta tesis muestra el efecto de la encapsulación de los compuestos de aceites esenciales (EOCs, por sus siglas en inglés) en soportes mesoporosos de sílice. Por un lado, seevalúa la eficiencia de los EOCs libres y encapsulados para reducir la viabilidad en líneas celulares de cáncer de colon. Además, se evalúa la selectividad de los EOCs frente a células de colon normales (líneas no tumorales). Por otro lado, seestudia la capacidad de enmascaramiento de olor de los soportes. Los resultados obtenidos, evidencian en primer lugar, que los EOCs encapsulados mejoran su actividad frente a células de cáncer,en comparacióncon la respuesta de los compuestos sin encapsular. La encapsulación hace que el efecto de los EOCs sea sostenido en el tiempo, y muestra índices de especificidad prometedores, cuandose evalua el efecto toxico de los EOCsfrente a células de cáncer de colon y células normales. Los resultados de esta primera sección, indican que los soportes basados en partículas de sílice mesoporosa (MSPs, por sus siglas en inglés) protegen y liberan eficientemente los compuestos, sino que, a la vez que la funcionalización de la superficie de las MSPs permite enmascarar el olor de los compuestos de mayor volatilidad, y con mayores inconvenientes a nivel sensorial (p.e. compuestos derivados del ajo). Por lo tanto, el sistema de encapsulación se plantea como una excelente alternativa para (i) promover la liberación controlada de EOCs, (ii) aprovechar y mejorar el efecto de sus propiedades bioactivas en células de cáncer de colón y (iii) controlar las desventajas técnicas relacionadas con la volatilidad y limitaciones organolepticas. Por último, se ha comprobado que los soportes empleados en la encapsulación de los compuestos derivados de ajo, mantienen su funcionalidad luego der ser inmovilizados en nanofribras de nylon.Con esto, se busca desarrollar un nuevo sistema de 'composite';un material híbrido y homogéneo, fácil de manejar, que libera controladamente los compuestos encapsulados desde soportes tipo fibras (composites).Estoexpande el abanico de aplicaciones de los EOCs en laindustria alimentaria y farmacológica. La segunda sección de esta tesis, evalúa la toxicidad de los soportes de sílice mesoporosa (MSPs) mediante ensayos in vitro e in vivo. En primer lugar, la viabilidad celular permite identificar el impacto citotóxico de los MSPs sobre líneas celulares de colón. En particular, se evalúa los soportes mesoporosos de sílice, tipo MCM41, en función de (i) las dosis empleadas, (ii) la diferencia de tamaño (micro y nanopartículas) y (iii) el efecto que la funcionalización de la superficie genera en la viabilidad celular. Por otro lado, empleando el modelo Caednorhabditis elegans, yadministrando por vía oral las MSPs,se evalua la influencia de las características de laspartículas (MSPs) en función de la esperanza de vida (lifespan) y la calidad con la que viven y envejecen (healthspan) los nematodos. Los resultados de este estudio,muestran que el tamaño y la estructura de la superficie de las partículas, son parámetros determinantesal momento de diseñar soportes de bajoriesgo toxicológico. En resumen, la presente tesis ha evaluado las características de la sílice mesoporosa, micro y nanoparticulada, como soporte de encapsulación para mejorar la actividad y las aplicaciones de los compuestos de aceites esenciales, al mismo tiempo / La present tesi titulada: "Components d'olis essencials encapsulats en suports mesoporosos de sílica: una avaluació de les seves propietats bioactives i un enfocament toxicològic" se centra en estudis de protecció i alliberament controlat d'agents naturals bioactius, derivats de components d'olis essencials, encapsulats en materials mesoporosos de sílica. Els components d'olis essencials encapsulats milloren les seves propietats funcionals i redueixen els problemes sensorials per aplicacions futures, garantint, al mateix temps, la baixa toxicitat dels suports desenvolupats. La primera secció de la tesi mostra l'efecte d'encapsulació dels components d'olis essencials (EOCs, per les seves sigles en anglès) en suports mesoporosos de sílica sobre la millora de les seues propietats bioactives i el camuflament de problemes sensorials. Este estudi avalua l'eficiència dels EOCs lliures i encapsulats per a reduir la viabilitat en línies cel¿lulars de càncer còlon. A més, la selectivitat dels EOCs es va provar enfront de cèl¿lules de còlon normals (no canceroses). Els resultats han demostrat que l'efecte dels EOCs pot ser millorat i sostingut en el temps quan els EOCs estan encapsulats. Encara més, l'encapsulació dels EOCs mostra índexs d'especificitat prometedors, arribant a duplicar la toxicitat en l'efecte en les cèl¿lules de càncer de còlon amb comparacio en les cèl¿lules normals. Els resultats també mostren que els suports basats en partícules de sílice mesoporoses (MSPs, per les seves sigles en anglès) no sols protegixen i alliberen EOCs eficientment, sinó que, a més, la funcionlització en superfície de les MSPs permet emmascarar l'olor dels EOCs d'alta volatilitat, que té una aplicació limitada a causa dels seus problemes sensorials(p.e. compostos derivats de l'all). Per tant, el sistema de subministrament proposat resulta una excel¿lent alternativa per a (i) promoure l'alliberament controlat de EOCs, (ii) avançant en les seues propietats bioactives en cel¿lulas de càncer còlon i (iii) controlant els desavantatges tècnics relacionats amb la volatilitat i la disseminació desagradable de les olors. Finalmet, les mostres utilitzades per encapsulació de compostos d'all es van immobilitzar en nanofibres per a proporcionar un sistema híbrid homogeni i fàcil de manejar amb administració controlada i característiques bioactives, per aplicacions potencials en l'àrea d'alimentació, farmacologia, medicina o enginyeria. La segona secció avalua la toxicitat del suports de sílice mesoporosa per mitjà d'avaluacions in vitro e in vivo. La viabilitat cel¿lular permet identificar l'impacte citotòxic basat en el tipus de suport base de sílice i les seues característiques (rang de dosi, grandària i canvis en l'estructura superficial).A més, utilitzant el model in vivo Caednorhabditis elegants, s'ha estudiat la influència de les característiques de la sílice mesoporosa, administrant micro i nanopartícules de base sílice, no sols en l'esperança de vida, sinó també en el comportament dels nematodes durant el seu envelliment. Aquest estudi ha demostrat que la grandària i l'estructura superficial, són decisius per a reduir el risc de toxicitat dels suports de sílice mesoporosa i obrir la possibilitat d'utilitzar estos materials en aplicacions d'ingesta oral. En resum, la present tesi ha avaluat les característiques de les partícules de sílice mesoporosa, com a suports d'encapsulació per a millorar l'activitat i les aplicacions dels EOCs, alhora que es va avaluar el seu principal risc tòxicologic. En conseqüència, els resultats obrin una opció adequada i de seguretat per als dispositius d'administració oral. / Acosta Romero, C. (2017). Essential oil components encapsulated in mesoporous silica supports: a bioactive properties evaluation and toxicological approach [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/90653 / TESIS

Les leucémies sont une famille de cancers issus de la prolifération maligne des cellules hématopoïétiques. La leucémie myéloïde aigüe (AML) représente 30% des leucémies chez les adultes et menace surtout les personnes âgées de 64 ans et plus. Actuellement, la chimiothérapie est la méthode principale de prise en charge de l’AML, mais celle-ci comporte des effets secondaires importants ainsi qu’un risque de récidive qui freinent son développement. Le redéploiement de molécules déjà utilisées pour d’autres maladies est une stratégie émergente dans le traitement du cancer. Par exemple, la chlorpromazine (CPZ), un antipsychotique, démontre une activité contre les lignées cellulaires issues d’AML, mais son activité au niveau du système nerveux central entraine des effets indésirables. Compte tenu de l’activité de CPZ contre les cellules leucémiques, nous avons mis au point un système de vectorisation des médicaments original pour le traitement de l’AML. La CPZ est d’abord incluse dans une cyclodextrine (CD) : molécule cage à base de glucose et ce complexe est ensuite encapsulé dans un liposome : vésicules à contenu aqueux délimitées par une ou plusieurs bicouches phospholipidiques. Ce système de “drug-in-CD-in-liposomes” (DCL) est conçu pour circuler longtemps dans le sang après injection intraveineuse mais ne pas passer la barrière hémato-encéphalique (BHE).Il a été nécessaire d’optimiser la formulation avec ses trois composants principaux : CD, CPZ et phospholipides. Ainsi, une évaluation physico-chimique approfondie a été réalisée pour les interactions CD/CPZ, CD/phospholipides et CPZ/phospholipides. La calorimétrie de titration isotherme (ITC) a permis de déterminer la stœchiométrie et la constante d’association pour les complexes d’inclusion CD/CPZ, démontrant les associations les plus importantes avec la Sugammadex ou la SBE-β-CD. La spectroscopie RMN 2D ROESY a mis en évidence des géométries d’inclusion différentes selon la taille et le type de substitution des CDs. Par ailleurs, l’inclusion de la CPZ dans les CDs accélère légèrement la photodégradation de l’antipsychotique. Quant à l’interaction CD/phospholipides, la SBE-Et-β-CD déstabilise les liposomes multilamellaires (MLVs) composés de palmitoylstearoylphosphatidylcholine (PSPC) pour des concentrations supérieures à 25 mM, tandis que les autres CDs sont sans effet. En outre, des études de turbidité ont démontré que les liposomes unilamellaires (SUV) ne sont pas perturbés en présence de la plupart des CDs. Une étude de l’interaction entre CPZ et PSPC a démontré que la quantité maximale qu’il est possible d’encapsuler était égale à 3,75 mol%. Par la suite, des DCL contenant CPZ ont été préparés par la méthode « dehydration-rehydration vesicles » (DRV) mais le pourcentage du principe actif encapsulé (EE) s’avérait faible (environ 10%). Ainsi la méthode DRV combinée à l’utilisation d’un gradient de concentration de sulfate d’ammonium a été mise en œuvre, ce qui a permis d’augmenter l’EE à 27% tout en gardant une taille compatible avec l’administration IV. Par la suite, la cytotoxicité de ces formulations a été évaluée sur 4 lignées cellulaires humaines issues d’AML (HL-60, MOLM13, MV4-11 and OCI-AML). Les liposomes contenant la CPZ ont tous démontré un effet cytotoxique tandis que les liposomes vides avaient tendance à stimuler la croissance cellulaire et les CD seules étaient sans effet. Pourtant, l’activité des DRVs avec CD était inférieure à celle des DRV/CPZ, selon l’ordre suivant : DRV-SGM/CPZ < DRV-SBE-β-CD/CPZ < DRV-HP-γ-CD/CPZ. L’activité était inversement proportionnelle à la constante d’affinité, suggérant une libération retardée. Cette hypothèse a été confortée par le fait que l’activité des DRV CD/CPZ était plus importante après une exposition de 72h qu’après 24h.Ces résultats sont prometteurs pour la mise au point de systèmes à libération contrôlée de CPZ pour le traitement d’AML. / Leukemia is a group of cancers caused by malignant clonal proliferation of hematopoietic stem cells. Accounting for 30% of all leukemias in adults, acute myeloid leukemia (AML) is especially a threat for older people with a median age of 64 years. Presently, chemotherapy is the main therapeutic method for AML but severe side-effects and possibility of relapse have hampered its development. “Repurposing” of drugs used in other diseases is a current trend for the treatment of cancer. For example, chlorpromazine (CPZ), a widely used anti-psychotic drug, shows effective activity in AML cell lines, but can also cause side effects in the central nervous system.Basing on the inhibiting capability of CPZ against leukemia-related cell lines, we have designed and developed a novel nanometric drug delivery system for AML treatment. CPZ is first entrapped in the hydrophobic internal cavity and forms inclusion complexes with cyclodextrin (CD), a cask-like molecule composed of glucose units, then the CD/CPZ inclusion complexes are encapsulated in liposomes, phospholipid vesicles consisting of a series of lipid bilayers enclosing aqueous compartments. The “drug-in-CD-in-liposomes” (DCL) system provides a promising strategy which is capable of achieving long circulation time in the blood after intravenous administration while circumventing the blood-brain barrier (BBB). It was necessary to optimize the formulation for its three main components: CD, CPZ and phospholipid. Therefore, a comprehensive physicochemical investigation of the interaction between CD/CPZ, CD/lipid and CPZ/lipid was performed. Isothermal titration calorimetry (ITC) was used to obtain the stoichiometry and association constant of the CPZ-CD inclusion complexes, showing that sugammadex and SBE-β-CD has the highest complexation ratio. 2D ROESY NMR revealed different inclusion processes depending on the size and chemical modification of CDs. Photodegradation experiments indicated that CDs can slightly accelerate CPZ's photodegradation. As far as liposome stability was concerned, SBE-Et-β-CD was found to have an obvious interaction with palmitoyl stearoyl phosphatidylcholine (PSPC) multilamellar liposomes (MLVs) above 25 mM, while the other CDs were without effect. However, turbidity measurements indicated that small unilamellar liposomes (SUVs) remain intact in presence of CDs. A study of the interaction between CPZ and PSPC showed that the maximum proportion of CPZ that could be incorporated into the lipid membrane was 3.75 mol%. Subsequently, DCL systems containing CPZ was prepared by the dehydration-rehydration vesicles (DRV) method. However, low drug encapsulation efficiency (EE) was obtained (about 10% of added drug). Therefore, an active loading strategy, the ammonium sulphate gradient method, was used in combination with the DRV method. As a result, the EE of CPZ increased to about 27% and yielded liposomal formulations with suitable size for IV administration.Finally, the cytotoxicity of CPZ, CDs, empty liposomes and liposomes containing CD/CPZ complexes was evaluated against a panel of leukemia cell lines. CPZ was found to show a growth-inhibiting effect on the human leukemia cell lines (HL-60, MOLM13, MV4-11 and OCI-AML), while empty liposomes were observed to slightly promote their growth and CDs alone had no significant cytotoxicity. However, a difference in activity was observed with the DRV containing CD/CPZ complexes, which were less active than DRV containing free CPZ, with the order: DRV-SGM/CPZ < DRV-SBE-β-CD/CPZ < DRV-HP-γ-CD/CPZ. The activity was inversely proportional to the formation constant of CD/CPZ complexes obtained by ITC, suggesting a delayed release from the complexes. This was confirmed by varying the exposure time; the activity of DRV CD/CPZ being relatively higher in a longer incubation.These results suggest that the DCL system could provide controlled release of CPZ for the treatment of AML.

There is growing interest in the development of biomimetic matrices that are simultaneously cell-friendly, allow rapid vascularization, exhibit enough mechanical integrity to be comfortably handled and resist mechanical stresses when implanted in the site of interest. Meeting all these requirements with a single component material has proved to be very challenging. The hypothesis underlying this work was that hybrid materials obtained by combining scaffolds with bioactive hydrogels would result in a synergy of their best properties: a construct with good mechanical properties, easily handled and stable thanks to the scaffold; but also, because of the gel, cell-friendly and with enhanced oxygen and nutrients diffusion, and promoter of cell colonization. Moreover, such a composite material would also be useful as a controlled release system because of the gel’s incorporation. Poly (ethyl acrylate) (PEA) scaffolds prepared with two different morphologies were envisaged to provide the mechanical integrity to the system. Both types of scaffolds were physicochemically characterized and the effect of the scaffolds production process on the PEA properties was examined. The scaffolds preparation methods affected the PEA properties; nevertheless, the modifications induced were not detrimental for the PEA biological performance. Two different bioactive gels were studied as fillers of the scaffolds’ pores: hyaluronan (HA), which is a natural polysaccharide, and a synthetic self-assembling peptide, RAD16-I. HA is ubiquitously present in the body and its degradation products have been reported to be angiogenic. RAD16-I is a synthetic polypeptide that mimics the extracellular matrix providing a favourable substrate for cell growth and proliferation. Given the hydrophobic nature of poly(ethyl acrylate), the combination of PEA scaffolds with aqueous gels raised a number of problems regarding the methods to combine such different elements, the ways to gel them inside the pores, and the procedures to seed cells in the new composite materials. Different alternatives to solve these questions were thoroughly studied and yielded protocols to reliably obtain these complex structures and their biohybrids. An extensive physico-chemical characterization of the components’ interaction and the combined systems was undertaken. As these materials were intended for cardiac tissue engineering applications, the mechanical properties and the effect of the fatigue on them were studied. The different composite systems here developed were homogeneously filled or coated with the hydrogels, were easy to manipulate, and displayed appropriate mechanical properties. Interestingly, these materials exhibited a very good performance under fatigue. The use of the composite systems as a controlled release device was based on the possibility of incorporating active soluble molecules in the hydrogel within the pores. A release study of bovine serum albumin (BSA), intended as a model protein, was performed, which served as a proof of concept. The biological performance of the hybrid scaffolds was first evaluated with fibroblasts to discard the materials cytotoxicity and to optimize the cell seeding procedure. Subsequently, human umbilical vein endothelial cells (HUVECs) cultures were performed for their interest in angiogenic and vascularization processes. Finally, co-cultures of HUVECs with adipose-tissue derived mesenchymal cells (MSCs) were carried out. These last cells are believed to play an important role for clinical regenerative medicine, and their cross-talk with the endothelial cells enhances the viability and phenotypic development of HUVECs. Through the different experiments undertaken, hybrid scaffolds exceeded the outcome achieved by bare PEA scaffolds. / Arnal Pastor, MP. (2014). New scaffolding materials for the regeneration of infarcted myocardium [Tesis doctoral]. Editorial Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/46129 / TESIS / Premios Extraordinarios de tesis doctorales

Plants require N to complete their life cycle. Without adequate concentration of N, crops will not produce their potential yields. For turfgrass systems, N fertilizer application allows for the maintenance of functional, aesthetic, and recreational properties. However, fertilizer mismanagement is common and leads to N pollution in the environment. Controlled-release and slow-release fertilizers can enhance nitrogen (N)-use efficiency, reduce N pollution, minimize the need for repeated fertilizer applications, and reduce turfgrass shoot growth and associated costs. In order to evaluate the effectiveness of these fertilizers in the Intermountain West, research is needed. The timing of N release was evaluated for seven urea fertilizers: uncoated, sulfur coated (SCU), polymer-sulfur coated (PSCU), and four polymer-coated (PCU) with release timings of 45, 75, 120, and 180 d estimated release. These products were placed on bare soil, a Kentucky bluegrass (Poa pratensis L.) thatch layer, and incorporated into soil. These three placement treatments were replicated to allow for enough samples to be placed in two locations. The first was outside in a field to represent field conditions with diurnal fluctuating temperatures and the second was placed in a storage facility to replicate laboratory conditions with static diurnal temperatures. The PCU prills incorporated into soil under field conditions generally released N over the estimated release period. However, when applied to bare soil or thatch, N from PCU had 80% or greater N release by 35 d after application regardless of expected release time. Fertilizers under laboratory conditions had minimal N release despite having similar average daily temperatures, suggesting that fluctuating temperatures impact N release. The PSCU and SCU treatments were no different from uncoated urea, showing no slow release properties for this particular product. Spring-applied N fertilizer trials were conducted over two years to determine the optimal N rate for Kentucky bluegrass. Similar PCU120 products were applied at 50, 75, and 100% of the recommended full rate, while also being compared to an unfertilized control and urea applied either all at once or split monthly. Spring-applied PCU showed minimal initial N response while urea applied all at once resulted in an initial spike of N uptake. Once PCU began to release N, there was minimal difference for all rates compared to urea split monthly for biomass growth, verdure, and shoot tissue N. Although at the 50% rate, there were a few sampling dates with slower growth and lower verdure. The decrease in verdure at this low rate was slight, and it is recommended that PCU could be applied effectively at a reduced rate between 50 and 75%. Although for better results, additional quick release N is required to compensate for early season lag in N release.

Controlled release of drugs to the lungs is an interesting and evolving field of research. The influence of physicochemical properties of nanoparticles on the controlled release of ciprofloxacin and in-vivo pharmacokinetics following pulmonary administration was evaluated. The physicochemical properties had an effect on encapsulation efficiency and surface charge, but no significant effect on particle size. The in-vitro release profiles of ciprofloxacin in phosphate buffered saline showed small differences over the range of physicochemical properties evaluated. The physicochemical properties of ciprofloxacin nanoparticles resulted in variable and unreliable nebulizer output using a vibrating mesh nebulizer whereas the impact on the aerosol properties of a jet nebulizer was negligible. Addition of mucoadhesive polymers in the nanoparticles had a three-fold increase in apparent half-life in rats by releasing ciprofloxacin over an extended release period on the surfaces of the lungs.

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This research is the first systematic investigation of solid-state orientation as a novel method for controlling drug release from biodegradable polymers. The effect of various degrees of polymer orientation was studied in oriented Poly (L-lactic acid) (PLA) films containing curcumin and theophylline as model drugs. Additionally, direction specific drug release was studied from oriented PLA rods containing paracetamol. The films oriented to 2X uniaxial constant width (UCW) or 2X2Y biaxial draw ratio showed retardation of drug release, when their nematic structure was stabilised by the presence of crystalline theophylline. Contrarily, the same films when contained solid solution of curcumin, shrunk in the release medium and exhibited a release profile similar to the un-oriented films. All films oriented to the UCW draw ratio ≥ 3X contained α crystalline form of PLA and showed acceleration of drug release proportionate to the draw ratio. According to the proposed mechanism augmented formation of water filled channels in these films was responsible for faster drug release. Similarly, the paracetamol loaded PLA rods die-drawn to uniaxial draw ratios ≥ 3X exhibited enhancement of drug release. Importantly, the amount of drug released along the oriented chain axis was significantly larger than that in the perpendicular direction. Drug release from the die-drawn rods was accelerated by a greater degree than that observed from the oriented films. This can be correlated to the differences in their size, geometry and the crystalline form of PLA. In conclusion, the current study provided substantial evidence that solid-state orientation can offer a control over drug release from PLA.