Cancer remains one of the most dreaded diseases due to inevitable suffering and possible fatality. Only cardiac disease has caused more deaths than cancer. Present day cancer treatment involves radiation, surgery or chemotherapy. In chemotherapy, an anti-tumoral drug is used to treat the tumor either by killing or stalling the growth of the tumor cells. In certain types of cancer, for e.g. metastatic breast cancer, the first line of therapy is often chemotherapy. But the inability of current clinically approved drugs to selectively target tumor cells, ultimately results in side effects. To reduce these side effects, prodrug therapies have been developed. A prodrug is defined as a drug molecule inactivated by a temporary cap or carrier, subsequently removed by an external intra or extracellular stimulus. Several prodrug strategies such as ADEPT (Antibody–Directed Enzyme Prodrug Therapy) have been tested in clinical trials but have thus far met with limited success. In the wake of these limitations, development of photo-activatable prodrugs may be particularly desirable for minimizing the adverse side effects associated with current cancer chemotherapeutics. Photodynamic therapy (PDT) is a light dependent tumor treatment modality that has existed for many years. PDT involves a photosensitizer which is administered to the patient and later activated using the light of wavelengths between 650-800 nm. The activated photosensitizer creates singlet oxygen, which acts as cytotoxic agent to the tumor cells. But this approach has several drawbacks including slow uptake of the photosensitizer by the tumor cells and the dependence on molecular oxygen that is not always present at even moderate levels in the tumor tissues. To address these limitations of PDT, we developed a new prodrug concept called ‘Photocaged Permeability’ in our first project, and demonstrated drug delivery using this approach. The basis of this concept is that, by attaching a hydrophilic molecule to the drug via a photosensitive linker, the permeability of the drug could be restrained. But the drug could be released at the site of the tumor after irradiating with UV light. To achieve this goal, we designed and synthesized a photosensitive drug conjugate that was comprised of doxorubicin attached to a negatively charged, cell impermeable molecule, EDANS (5-((2-Aminoethyl) amino) naphthalein-1-sulfonic acid) via a photosensitive nitroveratryl linker. Later, we performed MTT (cell viability) assays using esophageal adenocarcinoma (JH-EsoAd1) cells to determine the efficiency of our drug conjugate to induce cell death. As expected our drug conjugate was able to induce cell death, but only in presence of light. But in the dark, the cells remained unaffected. Also, we did several control studies to substantiate the fact that the cell death was actually due to drug release but not due to light or other entities. Further, we performed FACS (Fluorescence Assisted Cell Sorting) and confocal assays to show that in dark, the drug conjugate did not permeate cells. But upon irradiation with UV light, the drug was released from the conjugate, permeated the cells and induced cell death. A weakness of the above mentioned approach is that the drug is “decaged” or photo-released from the conjugates only under UV light; which cannot be translated to physiological conditions. This is because the UV light cannot penetrate deeper than 5 mm into the human skin. As a result, tumor cells that are deeply embedded in the human body cannot be treated using these approaches. To address this problem, Near Infrared (NIR) light could be used as it penetrates deeper than UV. Recently, several groups have reported using Upconverting Nanoparticles (UCNP) for the purpose of drug activation. The basis of this phenomenon is that the incidence of NIR light on these particles initiates multi-photon processes, eventually emitting UV/VIS wavelengths. The advantage of the NIR is that it deeply penetrates into the human skin. In our latest project, we have designed a drug conjugate that would be attached to UCNPs. We envision that after grafting the drug conjugate onto the nanoparticles and irradiating it with NIR drug release will occur as a result of upconversion. The above two systems describes novel methodologies for controlled release of the drug. To further improve the efficacy of the drug action, we designed new photosensitive systems based on the concept of targeted drug delivery. Targeted drug delivery is a treatment methodology in which the modified chemotherapeutic drug with higher tumor affinity could be concentrated in the tumor tissues. In certain cases, the receptors of tumor cells are targeted for the purpose of therapy. Receptors are cell surface proteins that are expressed on their plasma membrane. A select few of them such as Folic Acid Receptor (FAR) and PSMA (Prostate Specific Membrane Antigen) are overexpressed in malignant cells. In our new designs, we attached folic acid and urea based (DUPA) ligand, which were previously reported to bind to FAR and PSMA receptors respectively. Cell studies are currently underway to determine the specificity of these drug conjugates in targeting tumor cells. Once we demonstrate the above drug delivery strategies in vitro and later in vivo, we will have established novel drug delivery systems that could potentially be applied towards chemotherapeutic treatment.

[EN] The doctoral thesis presented under the title "Hybrid inorganic-organic materials for the optical recognition of neutral and anionic species" has had as its main objective the synthesis and characterization of organic-inorganic hybrid materials based on the combination of the principles of Supramolecular Chemistry and Materials Science. Recent studies confirm that cooperation between these two areas of Chemistry allow the simulation of what natural living beings have been doing for millions of years in a natural way. At cellular level, many vital functions are related to the ability of a particular receptor to recognize a particular species, giving a specific answer. But what is more interesting is that in living organisms, most of these systems do not exist as dissolved molecules, but are bounded to a (bio)organic skeleton with more or less flexibility. When we imitated these systems bearing in mind the supramolecular and analytical chemistry, we find that we need a sensory molecule able to join with the specie that we want to detect and at the same time, this union must produce a change in its physico-chemical properties giving as a result a signal. But moreover, if we take advantatge of the fact that siliceous nanostructured materials present a high physical and chemical stability and that they have cavities where the sensor system can be incorporated into, we have the synthetic hybrid organic-inorganic combination similar to the natural one. In order to develop this idea, we have used sensor systems widely studied in molecular recognition processes in aqueous media and we have applied them to the inorganic-organic hydrid materials. Therefore, the present work thesis has been structured in two parts: on the one hand, the synthesis and characterization of the functionalized inorganic porous solid materials by the study and detection of amines using the "chemodosimeter" approach. On the other hand, we have made the synthesis and characterization of the organic functionalized inorganic porous solid materials for the study and detection of anionic species through the displacement assays approach. / [ES] La tesis doctoral que se presenta bajo el título "Hybrid inorganic-organic materials for the optical recognition of neutral and anionic species" ha tenido como objetivo principal la síntesis y caracterización de materiales híbridos orgánico-inorgànicos basados en la combinación de los principios de la Química Supramolecular y la Ciencia de los Materiales. Recientes estudios corroboran que la cooperación entre estas dos áreas de la Química permite simular lo que ya hace millones de años realizan de forma natural los organismos vivos. A nivel celular, muchas de las funciones vitales están relacionadas con la habilidad de un receptor concreto para reconocer una determinada especie, dando una respuesta específica. Pero lo que resulta más interesante, es que en los organismos vivos, la mayoría de estos sistemas no existen en forma de moléculas disueltas, sino que están unidos con mayor o menor flexibilidad a un esqueleto bio(in)orgánico. Cuando imitamos estos sistemas teniendo en cuenta la química supramolecular y analítica, nos encontramos que necesitamos de una molécula indicadora que sea capaz de unirse a la especie que queremos detectar y que a su vez, esta unión produzca un cambio en las propiedades físico-químicas de la entidad para producir una señal. Pero además, si aprovechamos el hecho de que los materiales silíceos nanoestructurados presentan una alta estabilidad física y química y que proporcionan cavidades donde alojar al sistema sensor, tenemos la combinación híbrida orgánico-inorgánico sintética similar a la natural. Con el objetivo de desarrollar esta idea, hemos utilizado sistemas sensores ampliamente estudiados en procedimientos de reconocimiento molecular en disolución acuosa y los hemos aplicado a los materiales híbridos orgánico-inorgànicos. De esta manera, el trabajo de tesis se ha estructurado en dos partes: por una parte, la síntesis y caracterización de materiales sólidos inorgánicos porosos funcionalizados para el estudio y detección de aminas utilizando el procedimiento de "dosímetro químico", y en una segunda parte, se ha llevado a cabo la síntesis y caracterización de sólidos inorgánicos porosos funcionalizados para el estudio y detección de especies aniónicas mediante el procedimiento de "ensayos por desplazamiento". / [CA] La tesis doctoral que es presenta sota el títol "Hybrid inorganic-organic materials for the optical recognition of neutral and anionic species" ha tingut com objectiu principal la síntesi i caracterització de materials híbrids orgànic-inorgànics basats en la combinació dels principis de la Química Supramolecular i la Ciència dels Materials. Estudis recents corroboren que la cooperació entre aquestes dues àrees de la Química permet simular el que ja fa milions d'anys realitzen de forma natural els organismes vius. A nivell cel·lular, moltes de les funcions vitals estan relacionades amb l'habilitat d'un receptor concret per a reconèixer una espècie determinada, donant una resposta específica. Però el que és més interessant, és que als organismes vius, la majoria d'aquests sistemes no existeixen en forma de molècules dissoltes, sinó que estan units amb major o menor flexibilitat a un esquelet bio(in)orgànic. Quan imitem aquests sistemes tenint en compte la química supramolecular i analítica, ens trobem que necessitem d'una molècula indicadora que sigui capaç d'unir-se a l'espècie que volem detectar i que alhora, aquesta unió produeixi un canvi en les propietats fisico-químiques de l'entitat per produir una senyal. Però a més, si aprofitem el fet que els materials silícics nanoestructurats presenten una alta estabilitat física i química i que proporcionen cavitats on es pot allotjar el sistema sensor, tenim la combinació híbrida orgànica-inorgànica sintètica semblant a la natural. Per tal de desenvolupar aquesta idea, hem utilitzat sistemes sensors ampliament estudiats en procediments de reconeixement molecular en dissolució aquosa i els hem aplicat als materials híbrids orgànic-inorgànics. Així el present treball de Tesis s'ha estructurat en dues parts: per una banda, la síntesis i caracterització de materials sòlids inorgànics porosos funcionalitzats per l'estudi i detecció d'amines utilitzant el procediment de "dosímetre químic", i en una segona part, s'ha realitzat la síntesis i caracterització de sòlids inorgànics porosos funcionalitzats per a l'estudi i detecció d'espècies aniòniques mitjançant el procediment "d'assajos per desplaçament". / Comes Navarro, M. (2016). Hybrid inorganic-organic materials for the optical recognition of neutral and anionic species [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/62153 / TESIS

Tesis por compendio / El presente proyecto de investigación está enfocado al desarrollo de sensores químicos fluoro-cromogénicos, para la detección y determinación de especies químicas de interés biológico, industrial y medioambiental de forma selectiva y con alta sensibilidad. En forma general, se busca el diseñar nuevos sistemas sensores basados en compuestos (receptores) formados por dos unidades: una unidad coordinante que interacciona con el anión a determinar y una unidad generadora de señal que alerta del reconocimiento molecular efectuado. Durante este estudio se están preparando diversas moléculas receptoras funcionalizandas con grupos modificadores de estructura para evaluar su influencia sobre las capacidades de detección y selectividad como receptores de especies específicas en diferentes condiciones y medios. Las diferentes aproximaciones en prueba implican a su vez el diseño y síntesis molecular, así como el análisis de las diferentes señales ópticas producidas en el reconocimiento, con el fin de diseñar sistemas de alta eficacia y eficiencia, y con posibilidades reales de aplicación. / Santos Figueroa, LE. (2014). New approaches for the development of chromo-fluorogenic sensors for chemical species of biological, industrial and environmental interest [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/43216 / TESIS / Premios Extraordinarios de tesis doctorales / Compendio