This master thesis deals with the preparation of the cyclodextrin (CD) derivatives that are suitable for complexation of the electron-rich aromatic compounds such as helicenes. The basic skeleton of native CD was perbenzoylated in all positions 2, 3 and 6 in the first place. Then the nucleophilic attack of carboxylates of benzoic acids with electron- withdrawing groups (NO2) or electron-donating group (NH2) to per(6-deoxy-6-iodo)-CD derivatives were used to prepare the perbenzoylated CD derivatives in the postition 6. Binding constant was determined for the prepared benzoylated derivatives of CD and the racemate of the hexahelicene using the NMR titration. Perbenzoylated derivatives of β-CD in all position 2,3 and 6 with one azido group in position 6 were prepared as well. These derivatives could be covalently bonded as chiral selectors in the stationary phase for the HPLC separation of aromatic enantiomers. Keywords: cylodextrins, persubstitution, benzoyl, 4-nitrobenzoyl, 3,5-dinitrobenzoyl, helicenes, NMR titration, binding constants

Master of Science (Nanoscience) / Neuroblastomas (NBs) are the most common solid extra-cranial tumours diagnosed in childhood and characterized by a high risk of tumour relapse. Like in other tumour types, there are major concerns about the specificity and safety of available drugs used for the treatment of NBs, especially because of potential damage to the developing brain. Many plant-derived bioactive compounds have proved effective for cancer treatment but are not delivered to tumour sites in sufficient amounts due to compromised tumour vasculature characterized by leaky capillary walls. Betulinic acid (BetA) is one such naturally-occurring anti-tumour compound with minimum to no cytotoxic effects in healthy cells and rodents. BetA is however insoluble in water and most aqueous solutions, thereby limiting its therapeutic potential as a pharmaceutical product. Liposomes are self-assembling closed colloidal structures composed of one or more concentric lipid bilayers surrounding a central aqueous core. The unique ability of liposomes to entrap hydrophilic molecules into the core and hydrophobic molecules into the bilayers renders them attractive for drug delivery systems. Cyclodextrins (CDs) are non-reducing cyclic oligosaccharides which proximate a truncated core, with features of a hydrophophilic outer surface and hydrophobic inner cavity for forming host-guest inclusion complexes with poorly water soluble molecules. CDs and liposomes have recently gained interest as novel drug delivery vehicles by allowing lipophilic/non-polar molecules into the aqueous core of liposomes, hence improving the therapeutic load, bioavailability and efficacy of many poorly water-soluble drugs. The aim of the study was to develop nano-drug delivery systems for BetA in order to treat human neuroblastoma (NB) cancer cell lines. This was achieved through the preparation of BetA liposomes (BetAL) and improving the percent entrapment efficiency (% EE) of BetA in liposomes through double entrapment of BetA and gamma cyclodextrin BetA inclusion complex (γ-CD-BetA) into liposomes (γ-CD-BetAL). We hypothesized that the γ-CD-BetAL would produce an increased % EE compared to BetAL, hence higher cytotoxic effects. Empty liposomes (EL), BetAL and γ-CD-BetAL were synthesized using the thin film hydration method followed by manual extrusion. Spectroscopic and electron microscopic characterization of these liposome formulations showed size distributions of 1-4 μm (before extrusion) and less than 200 nm (after extrusion). As the liposome size decreased, the zeta-potential (measurement of liposome stability) decreased contributing to a less stable liposomal formulation. Low starting BetA concentrations were found to be more effective in entrapping higher amounts of BetA in liposomes while the incorporation of γ-CD-BetA into liposomes enhanced the % EE when compared to BetAL, although this was not statistically significant. Cell viability studies using the WST-1 assay showed a time-and concentration-dependent decrease in SK-N-BE(2) and Kelly NB cell lines exposed to free BetA, BetAL and γ-CD-BetAL at concentrations of 5-20 ug/ml for 24, 48 and 72 hours treatment durations. The observed cytotoxicity of liposomes was dependant on the % EE of BetA. The γ-CD-BetAL was more effective in reducing cell viability in SK-N-BE(2) cells than BetAL whereas BetAL was more effective in KELLY cells at 48-72 hours. Exposure of all cells to EL showed no toxicity while free BetA was more effective overall than the respective liposomal formulations. The estimated IC₅₀ values following exposure to free BetA and BetAL were similar and both showed remarkable statistically significant decrease in NB cell viability, thus providing a basis for new hope in the effective treatment of NBs.

Magister Pharmaceuticae - MPharm / Background: Zidovudine (AZT) is a very useful drug for the management of Human Immunodeficiency Virus (HIV) infection. Its optimal use is limited by its bitter taste, sparing solubility (20.1 mg/ml) and acid lability. Cyclodextrins (CD) are a class of compounds which can be used to form inclusion complexes with drugs such as AZT to improve it is taste, solubility and palatability. Purpose: This study complexed hydroxypropyl-beta-cyclodextrin (HPβCD) with AZT. The formulated inclusion complex was evaluated for suitability as a dosage form and as a tool for improving AZT’s palatability, solubility and acid liability. Method: AZT was complexed with HPβCD using the lyophilisation method. The binding constant for the formulation was determined by the phase solubility method, and complex formation between AZT and HPβCD evaluated using proton nuclear magnetic resonance (1H NMR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and hot stage microscopy (HSM). Tablets of the inclusion complex were formulated by direct compression, using the least possible amount of excipients, and the dosage form evaluated for hardness, friability, durability, disintegration time and dissolution. Results: The binding constant of the formulation was 3.919, and the degree of incorporation was 4.0 mg AZT/g of CD per complex. 1H NMR showed significant chemical shifts between the inclusion complex and AZT. DSC and TGA analyses showed significant differences in the curves for the pure AZT and HPβCD. Values for tablet hardness, friability, durability and disintegration time were 236 ± 20 N, 0.7 %, 1.02 % and 10.25 minutes, respectively. The solubility of the formulation was 148.08 mg/ml, and its dissolution profile was different from that of the branded formulation. Conclusions: AZT-HPβCD inclusion complex, with a 7.4-fold increase in AZT solubility, was successfully prepared using the lyophilisation method. The binding constant and friability of the formulation were within acceptable limits. Although the hardness value is high, the tablet still disintegrated within acceptable specified times. This study has significant implications for anti-retroviral complex formulations.

Orientador: Inez Valeria Pagotto Yoshida / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-14T14:08:08Z (GMT). No. of bitstreams: 1 Abbehausen_Camilla_M.pdf: 940208 bytes, checksum: 2b2315fde8a813d9a3f372ac94b57962 (MD5) Previous issue date: 2009 / Resumo: No presente trabalho obteve-se híbridos de siloxano e b-ciclodextrina (b-CD). Baseando-se na comprovada reatividade das ciclodextrinas frente a grupos isocianatos, sintetizou-se um híbrido de b-ciclodextrina e siloxano, pela reação da b-ciclodextrina com g-isocianatopropiltrietoxissilano (IPTS), formando uma ligação uretana entre o silano e a b-ciclodextrina. O alcoxissilano, posteriormente hidrolisado, deu origem a um material resinoso do tipo polissilsesquioxano (PSS) modificado por b-ciclodextrina. O mesmo alcoxissilano foi também submetido à condensação com poli(dimetilsiloxano) contendo ¿Si(CH3)2-OH em finais de cadeia, dando origem a uma rede polimérica, também de aspecto resinoso, contendo nos nós de reticulação a b-cyclodextrin. Os materiais obtidos foram caracterizados estruturalmente por espectro infravermelho (IV), ressonância magnética nuclear de C (RMN C) e de Si (RMN Si) e análise por difração de raios X (DRX). O comportamento térmico dos materiais foi analisado por termogravimetria (TGA). A capacidade formadora de complexos de inclusão das ciclodextrinas inseridas no polímero PSS-b-CD foi avaliada pela inclusão de fenolftaleína, monitorada por espectrofotometria na região UV-vis e a difusão de água pelo material foi avaliada por ensaios de intumescimento. A morfologia dos filmes dos materiais preparados foi analisada por microscopia eletrônica de varredura (SEM). / Abstract: In this study, hybrid polymers derived from siloxane and b-cyclodextrin (b-CD) were obtained, by reaction of b-CD with g-isocianatepropyltriethoxysilane (IPTS), forming a urethane bond between these components. The resulting alkoxysilane was hydrolyzed generating b-CD-modified polysilsesquioxane resin (b-CD-PSS). The alkoxysilane was also submitted to condensation with poly(dimethylsiloxane) with ¿ Si(CH3)2-OH end groups, giving rise to a resinous polymeric network. These materials were characterized by infrared spectrum, C and Si nuclear magnetic resonance and X ray diffraction. The thermal behavior was analyzed by thermogravimetry. The capability of b-CD grafted in the siloxane polymers to form inclusion complexes was evaluated by the formation of b-CD-phenolphthalein, by UV-vis sectra. The ability of water diffusion into b-CD-PSS film was evaluated by swelling measurement. b-CD modified siloxanes were able to form films and their morphologies were evaluated by scanning electron microscopy. / Mestrado / Quimica Inorganica / Mestre em Química

[EN] Cryopreserved boar sperm is not used extensively for artificial insemination due to poor fertility rates of the sperm after freezing and thawing. The sperm membrane is damaged when cooled from body temperature to 5 ºC (cold shock), as well as during the freeze-thaw process. Increasing the cholesterol content of boar sperm membranes could increase their post-thaw survival, similarly to other species that are cold shock sensitive. Cholesterol can be easily added to sperm membranes using cholesterol-loaded cyclodextrins (CLC). Treating sperm from different species susceptible to cold-shock with CLC before cryopreservation improves sperm cryosurvival. Egg yolk and glycerol are common constituents of extenders used for boar sperm cryopreservation. However, conventional freezing extenders could not be the appropriate for CLC-treated sperm. The aim of this Thesis is to evaluate cryosurvival of CLC or cyclodextrin-treated boar sperm in three different conditions: using conventional freezing extenders, using extenders with alternative concentrations of glycerol and egg yolk and using amides as cryoprotectants. CLC or methyl- ß-cyclodextrin treatment (1 mg/120 x 106 sperm) prior to cryopreservation using a conventional freezing extenders provided either slight or no benefit, respectively, to post-thaw sperm plasma membrane integrity (+ 8%; P < 0.05) and motility (P > 0.05). In addition, sperm from both, good and poor freezers, responded similarly to CLC treatment (P > 0.05). Reduction in egg yolk concentration from 20 to 10% was detrimental for post-thaw sperm viability, even in semen treated with CLC (- 12%; P < 0.05). On the other hand, it was observed that traditional concentration of glycerol (3%) was not the appropriate to freeze CLC-treated sperm (- 13% viable sperm compared to control; P < 0.05). Thus, CLC-treated sperm showed a higher tolerance (+ 13 % sperm viability; P < 0.05) to high glycerol concentrations (5%) than non-treated sperm. Regarding the efficacy of amides as cryoprotectants, three of the amides (lactamide, acetamide and formamide) produced deleterious effects in fresh boar sperm (P < 0.05). The other amides (methylformamide, dimethylacetamide and dimethylformamide) efficiently improved post-thaw sperm viability (+ 5 to 15 %; P < 0.05) but negatively affected the sperm motility (- 11 to 16% total motile sperm; P < 0.05) and the sperm fertilizing ability in vitro (dimethylformamide: - 64 % penetration rate; P < 0.05), irrespective of the sperm treatment. On the other hand, CLC-treated samples showed better in vitro fertilizing ability than control samples when glycerol was used as cryoprotectant (+ 2 penetrated spermatozoa/oocyte; P < 0.05). The results obtained in this Thesis suggest that conventional freezing protocols should be optimized for CLC-treated boar sperm in order to obtain the benefit of CLC treatment observed in other species sensitive to cold shock. / [ES] Las inseminaciones artificiales en la especie porcina se realizan habitualmente con semen refrigerado, debido a las bajas tasas de fertilidad obtenidas con el semen congelado-descongelado. La membrana del espermatozoide sufre importantes daños cuando es sometida a la fase de enfriamiento desde la temperatura corporal hasta alcanzar los 5 ºC (choque térmico), así como durante el proceso de congelación y descongelación. El aumento del contenido de colesterol en las membranas de los espermatozoides de cerdo podría mejorar su supervivencia tras la descongelación, como sucede en otras especies sensibles al choque térmico. Este incremento en la cantidad de colesterol se puede realizar fácilmente utilizando ciclodextrinas saturadas de colesterol (CLC). El tratamiento con CLC de espermatozoides de varias especies susceptibles al choque térmico antes de la congelación ha conseguido mejorar su supervivencia tras la descongelación. En los protocolos convencionales de congelación de semen porcino se utilizan habitualmente diluyentes de congelación compuestos por yema de huevo y glicerol, sin embargo, puede que estos diluyentes de congelación convencionales no sean los más apropiados para congelar espermatozoides tratados con CLC. El objetivo de esta Tesis es evaluar la supervivencia a la congelación de los espermatozoides porcinos tratados con CLC o ciclodextrinas utilizando diluyentes de congelación convencionales, utilizando concentraciones alternativas tanto de yema de huevo como de glicerol o utilizando amidas en lugar de glicerol como crioprotectores Utilizando diluyentes convencionales, el tratamiento con 1mg de CLC o de metil-ß-ciclodextrina/120 millones de espermatozoides previamente a la congelación proporcionó una leve mejora de la integridad de la membrana plasmática espermática (+ 8%; P < 0,05) y ningún beneficio sobre la movilidad espermática (P > 0,05). Además, la respuesta al tratamiento con CLC fue similar independientemente de si los espermatozoides procedían de verracos buenos o malos congeladores (P > 0,05). Una reducción de la concentración de yema de huevo de un 20 a un 10% fue perjudicial para la supervivencia de los espermatozoides tras la descongelación, incluidos aquellos que habían sido tratados previamente con CLC (- 12% espermatozoides vivos; P < 0,05). Por otro lado, observamos que las concentraciones de glicerol utilizadas habitualmente (3%) no son las más apropiadas para congelar espermatozoides tratados con CLC (- 13 % viabilidad espermática comparando con las muestras control; P < 0,05), ya que éstos mostraron una mayor tolerancia (+ 13 % espermatozoides vivos; P < 0,05) que las muestras control a las concentraciones de glicerol más altas (5%). Con respecto a la eficacia de las amidas como crioprotectores para semen porcino, tres de las amidas (lactamida, acetamida y formamida) produjeron efectos perjudiciales durante su incubación con semen fresco (P < 0,05). El resto de amidas evaluadas (metilformamida, dimetilacetamida y dimetilformamida) mejoraron eficientemente la viabilidad espermática tras la congelación (+ 5 a 15 %; P < 0,05), sin embargo, afectaron negativamente tanto la movilidad espermática (- 11 a 16% móviles totales; P < 0,05) como la capacidad de fecundación in vitro (dimetilformamida: - 64 % en la tasa de penetración; P < 0,05), independientemente de si el semen fue tratado con CLC o no. Por otro lado, las muestras tratadas con CLC mostraron mejor capacidad de fecundación in vitro que las muestras control cuando se utilizó el glicerol como crioprotector (+ 2 espermatozoides penetrados/ovocito; P < 0,05). Los resultados obtenidos en esta Tesis sugieren que sería necesaria la adecuación de los protocolos de congelación convencionales para congelar semen porcino tratado con CLC con el propósito de alcanzar los claros beneficios obtenidos con dicho tratamiento cuando ha sido evaluado en otras especies sensibles al choque térmico. / [CAT] Les inseminacions artificials en l'espècie porcina es realitzen habitualment amb semen refrigerat, a causa de les baixes taxes de fertilitat obtingudes amb el semen congelat-descongelat. La membrana de l'espermatozoide pateix importants danys quan és sotmesa a la fase de refredament des de la temperatura corporal fins a arribar als 5 ºC (xoc tèrmic), així com durant el procés de congelació i descongelació. L'augment del contingut de colesterol a les membranes dels espermatozoides de porc podria millorar la seva supervivència després de la descongelació, com succeeix en altres espècies sensibles al xoc tèrmic. Aquest increment en la quantitat de colesterol es pot realitzar fàcilment utilitzant ciclodextrines saturades de colesterol (CLC). El tractament amb CLC d'espermatozoides de diverses espècies susceptibles al xoc tèrmic abans de la congelació ha aconseguit millorar la seva supervivència després de la descongelació. En els protocols convencionals de congelació de semen porcí s'utilitzen habitualment diluents de congelació compostos per rovell d'ou i glicerol, però, pot ser que aquests diluents de congelació convencionals no siguin els més apropiats per congelar espermatozoides tractats amb CLC. L'objectiu d'aquesta Tesi és avaluar la supervivència a la congelació dels espermatozoides porcins tractats amb CLC o ciclodextrines utilitzant diluents de congelació convencionals, utilitzant concentracions alternatives tant de rovell d'ou com de glicerol o utilitzant amides en lloc de glicerol com crioprotectors Utilitzant diluents convencionals, el tractament amb 1 mg de CLC o de metil-ß-ciclodextrina / 120 milions d'espermatozoides prèviament a la congelació va proporcionar una lleu millora de la integritat de la membrana plasmàtica espermàtica (+ 8%; P <0,05) i cap benefici sobre la mobilitat espermàtica (P> 0,05). A més, la resposta al tractament amb CLC va ser similar independentment de si els espermatozoides procedien de verros bons o dolents congeladors (P> 0,05). Una reducció de la concentració de rovell d'ou d'un 20 a un 10% va ser perjudicial per a la supervivència dels espermatozoides després de la descongelació, inclosos aquells que havien estat tractats prèviament amb CLC (- el 12% espermatozoides vius; P <0,05) . D'altra banda, observem que les concentracions de glicerol utilitzades habitualment (3%) no són les més apropiades per congelar espermatozoides tractats amb CLC (- 13% viabilitat espermàtica comparant amb les mostres control; P <0,05), ja que aquests van mostrar una major tolerància (+ 13% espermatozoides vius; P <0,05) que les mostres control a les concentracions de glicerol més altes (5%). Pel que fa a l'eficàcia de les amides com crioprotectors per semen porcí, tres de les amides (lactamida, acetamida i formamida) van produir efectes perjudicials durant la seva incubació amb semen fresc (P <0,05). La resta de amides avaluades (metilformamida, dimetilacetamida i dimetilformamida) van millorar eficientment la viabilitat espermàtica després de la congelació (+ 5 a 15%, P <0,05), però, van afectar negativament tant la mobilitat espermàtica (- 11 a 16% mòbils totals; P <0,05) com la capacitat de fecundació in vitro (dimetilformamida: - el 64% en la taxa de penetració; P <0,05), independentment de si el semen va ser tractat amb CLC o no. D'altra banda, les mostres tractades amb CLC van mostrar millor capacitat de fecundació in vitro que les mostres control quan es va utilitzar el glicerol com crioprotector (+ 2 espermatozous penetrats / oòcit; P <0,05). Els resultats obtinguts en aquesta Tesi suggereixen que seria necessària l'adequació dels protocols de congelació convencionals per congelar semen porcí tractat amb CLC amb el propòsit d'assolir els clars beneficis obtinguts amb el tractament quan ha estat avaluat en altres espècies sensibles al xoc tèrmic. / Blanch Torres, E. (2015). Treating boar sperm with cholesterol-loaded cyclodextrins or cyclodextrins prior to cryopreservation: effects on post-thaw in vitro sperm quality of sperm cryopreserved in different freezing extenders [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/58773 / TESIS

Objectives Glyburide, an important drug for type 2 diabetes, has extremely poor aqueous solubility and resulting low bioavailability. This study describes the ability of hydroxybutenyl-β-cyclodextrin (HBenBCD) to form complexes with glyburide, with enhanced solubility and dissolution rate in vitro. Method Glyburide and glyburide-HBenBCD were evaluated in various test media known to simulate human gastrointestinal conditions in the fasted and fed states, respectively. Key findings At ~14 wt% drug load, in the presence of HBenBCD, an almost 400-fold increase in glyburide aqueous solubility was observed. In the presence of HBenBCD, glyburide solubility was also significantly improved in all physiologically relevant test media. Subsequent dissolution experiments confirmed the solubility study results; the dissolution rate and total amount of drug released were significantly increased. Conclusions Complexation with HBenBCD may be an effective way to increase the bioavailability of glyburide.

This diploma thesis deals with the synthesis of conjugates of cyclodextrin with the anticancer drug 5-fluorouracil and folic acid, which works as a targeting group. 5-Fluorouracil is connected to cyclodextrin via an acid-labile linker, which is expected to be cleaved in decreased pH in the proximity of malignant tissue or in the endosome. Malignant tissue also overexpresses receptor for folic acid, and this phenomenon is used for targeted delivery of therapeutic agents. Cyclodextrins are cyclic oligosaccharides, which are known for their ability to complex various compounds into their hydrophobic cavity and increase solubility, stability and bioavailability of these compounds. A synthetic approach for the preparation of conjugate of cyclodextrin with 5-fluorouracil and folic acid was designed and the conjugate was subsequently synthesized. Key words: cyclodextrin, fluorouracil, targeting group, folic acid, drug delivery

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19734号 / 工博第4189号 / 新制||工||1646(附属図書館) / 32770 / 京都大学大学院工学研究科物質エネルギー化学専攻 / (主査)教授 辻 康之, 教授 村田 靖次郎, 教授 杉野目 道紀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

No description available.