This paper presents the computer simulation results on the delivery of Etanidazole (radiosensitiser) to the brain tumor and examines several factors affecting the delivery. The simulation consists of a 3D model of tumor with poly (lactide-co-glycolide) (PLGA) wafers of 1% Etanidzole loading implanted in the resected cavity. A zero-order release device will produce a concentration profile in the tumor which increases with time until the drug in the carrier is depleted. This causes toxicity complications during the later stages of drug treatment. However, for wafers of similar loading, such release results in a higher drug penetration depth and therapeutic index as compared to the double drug burst profile. The numerical accuracy of the model was verified by the similar results obtained in the two-dimensional and three-dimensional models. / Singapore-MIT Alliance (SMA)

Drug delivery methods for the treatment of brain tumor cells have been both inefficient and potentially dangerous for cancer patients. Drug delivery must be done in a controlled manner so that the effective amount of medication is delivered to the patient and ensure over-dosage does not cause adverse side reactions in the patient. The focus of this investigation is to design a drug delivery system that would allow for site-specific administration of the drug, protection of the drug from the surrounding environment, and controlled sustained release of the drug. We have proposed a model that incorporates a niosome, which is a non-ionic surfactant vesicle, within a biodegradable polymer hydrogel. The drug is encapsulated in the niosome, and the niosome is embedded within a three-dimensional hydrogel network. It is therefore critical that the release rate of the drug from the niosome be studied. This investigation provides information about the release rate and behavior of the drug within the niosome as it is placed in a semi-permeable membrane. The niosome and dye solution in the cellulose membrane are placed in contact with water or PBS. Intensity measurements are taken using fluorescence spectrometry, and the readings are converted to concentration and moles values. The release rates of the dye from of the niosome and across the membrane are studied as the concentration data is collected over time. The results indicate that most of the niosomes will release their dye within ten hours. The water will create instability in the niosomes, while the PBS solution will maintain the stability of the niosomes. The concentration that diffuses across the cellulose membrane will steadily increase and can be predicted well by a simple diffusion model. We hope to use the information provided in this study to continue to design a drug delivery method that will stabilize the niosomes and allow for the maximum control over the release rate of the drug.

Die Aufrechterhaltung der sogenannten failsafe Programme ist ein wichtiges Kennzeichen des zellulären Lebens, da das genaue Gleichgewicht zwischen Proliferation und Wachstumsarrest es sicherstellt, dass die Zelle sich selber vor potentiell gefährlichen Mutationen schützen kann. Apoptose und Seneszenz bewahren die Zellhomeostase und sind von aüsserster Bedeutung dafür, die Zelle vor maligner Transformation zu bewahren. Die Seneszens zeichnet sich dabei durch Veränderungen des Heterochromatins bei Genen aus, welche für den Eintritt in die DNA-Synthese-Phase des Zellzyklus verantwortlich sind. Insgesamt wurde die Bedeutung epigenetischer Modifikationen bei malignen Erkrankungen in den letzten Jahren immer deutlicher. So konnte gezeigt werden, dass die Rb-assoziierte Histon-Methyltransferase Suv39h1 ein entscheidender Vermittler der Seneszenz in Ras-induziertem Maus Lymphom-Modell ist. In dieser Arbeit wurde gezeigt, dass die transgenen Eµ-myc Maüse (ähnlich dem Burkitt''s Lymphom im Menschen), wenn sie mit Suv39h1-defizienten Maüsen gekreuzt werden. Die Überexpression von Myc, wie sie in humanen und murinen Tumoren zu beobachten ist, induziert primär ein apoptotische Antwort mit dem zentralen Vermittler p53. Allerdings bewirkte die Suv39h1 Defizienz, obwohl sie die Lebenserwartung signifikant verkürzte, keine Veränderung der Apoptose-Rate in diesem Modell. Dieses Ergebnis demonstriert die Tumor-suprimierende Wirkung des Suv39h1 in Myc-getriebener Lymphomagenese. Weiterhin wurde in dieser Arbeit ein zusätzlicher Mechanismus zur Vermittlung Myc-induzierter Seneszenz unter Einbeziehung des Zytokin-Signaling identifiziert. Im Falle der Expression von intaktem Suv39h1 in der Tumorzelle kann TGF-beta die Myc-induzierte Seneszenz in vivo beeinflussen. Schliesslich ergaben die Untersuchungen, dass die Suv39h1-defizienten Lymphome über eine beeinträchtigte Therapie-Anwort verfügen, da sie keine Therapeutika-induzierte Seneszenz ausführen können. / Maintenance of cellular failsafe pathways (apoptosis and senescence) is one of the hallmarks of life, as fine equilibrium between proliferation and growth arrest ensures that the cell can protect itself from the potentially dangerous mutations. Senescence is a mechanism distinguished by heterochromatin modifications leading to silencing of the genes responsible for the entry to the DNA synthesis [S] phase of the cell cycle. Involvement of epigenetic modifications in cancer development has been subject of a more intense research in the past few years. It was shown that the Rb-associated histone methyltransferase Suv39h1 is a critical mediator of senescence in a Ras-induced mouse lymphoma model. Additional mechanisms of the senescence regulation are currently being under investigation. In this thesis Eµ-myc transgenic mice, crossed to mice deficient for Suv39h1, were shown to succumb to the same type of B-cell lymphoma (similar to Burkitt''s lymphoma in humans). Overexpression of Myc, as seen in human and mouse tumors will primarily induce an apoptotic response using p53 as a mediator of this response. In Eµ-myc, Suv39h1-/- mouse model deficiency in Suv39h1 has significantly shortened life expectancy, but it did not affect spontaneous apoptosis rates. This finding established Suv39h1 as a tumor suppressor in Myc-lymphomagenesis. Further, an additional mechanism of mediating oncogene-induced senescence involving cytokine signaling was identified and reported here. When intact Suv39h1 is present in the tumor, TGF-beta is able to mediate oncogene-induced senescence in vivo. Finally, in the treatment studies it was shown that Suv39h1 deficient lymphomas have an impaired response to chemotherapy, caused by their inability to execute drug-induced senescence. This finding can be of use for the design of novel cancer therapies.