455 research outputs found
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Nanosized drug delivery systems are developed to improve the therapeutic efficacy and to reduce unwanted side effects of existing drugs as well as drug candidates. Liposomes are the most intensively studied drug delivery systems and a number of studies showed that encapsulation of doxorubicin (DOX) in liposomes resulted in an increased therapeutic index particularly due to a significant reduction in unwanted side effects. Nevertheless, the concentration of free drug in the tumor is relatively low due to the slow and uncontrolled release of the drug from the liposomes and as a consequence, cytotoxic free drug concentrations are not always obtained in the tumor. In order to optimize the free drug concentration in the tumor, liposomes should be capable of releasing drugs at the target site in response to a specific stimulus. Therefore, in this thesis temperature sensitive drug delivery systems were explored that release their content in a fast manner at mild hyperthermia while remaining stable at body temperature. Temperature sensitive liposomes with tunable release characteristics were developed that release their content at elevated temperatures. Temperature-sensitive N-(2-hydroxypropyl)methacrylamide mono/dilactate polymers were incorporated into liposomes via a cholesterol anchor (chol-pHPMAlac). The onset-temperature of the DOX release was dependent on the characteristics (copolymer composition and molecular weight) of the chol-pHPMAlac used. It was also shown that these liposomes released their DOX content quantitatively upon exposure to High Intensity Focused Ultrasound. The results of different in vitro assays suggested that chol-pHPMAlac liposomes are not cleared rapidly from the blood circulation after i.v. administration and these liposomes do most likely not generate serious complications e.g. the formation of thrombi after injection. Besides nanoparticles, also micro-sized drug delivery systems are often used for local drug delivery in tumors. This thesis describes the development and characterization of alginate microspheres that combine embolization with on-demand triggered drug release. For that purpose, alginate microspheres loaded with temperature sensitive liposomes (TSL-Ba-ms) were developed, which release their payload after mild hyperthermia. These liposomes contained DOX and [Gd(HPDO3A)(H2O)], a T1 MRI contrast agent, for real time monitoring of the release by MRI. Empty alginate microspheres were crosslinked with holmium ions (T2* MRI contrast agent) to allow microsphere visualization (Ho-ms). TSL-Ba-ms had a mean diameter of 76 µm and released DOX quantitatively within 3 minutes at 42 °C in 50% serum. The deposition of the microspheres and [Gd(HPDO3A)(H2O)] release after i.a. co-administration of TSL-Ba-ms and Ho-ms was monitored in the VX2 tumor model in the auricle of a New Zealand White rabbit. Microsphere clusters appeared on the T2*-wt image after the co-administration of TSL-Ba-ms and Ho-ms and these clusters remained visible after applying mild hyperthermia. The release of [Gd(HPDO3A)(H2O)] from the TSL-Ba-ms was visualized on the T1-wt image. The location of Ho-ms overlapped with the location of [Gd(HPDO3A)(H2O)] released from TSL-Ba-ms making Ho-ms a suitable marker for TSL-Ba-ms
The relationship between individual differences in gray matter volume and religiosity and mystical experiences: A preregistered voxel‐based morphometry study
Predictive processing and situation models: constructing and reconstructing religious experience
The relationship between individual differences in gray matter volume and religiosity and mystical experiences: A preregistered voxel‐based morphometry study
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