Targetable Multi-Drug Nanoparticles for Treatment of Glioblastoma with Neuroimaging Assessment

Indiana University-Purdue University Indianapolis (IUPUI)Glioblastoma (GBM) is a deadly, malignant brain tumor with a poor long-term prognosis. The current median survival is approximately fifteen to seventeen months with the standard of care therapy which includes surgery, radiation, and chemotherapy. An important factor contributing to recurrence of GBM is high resistance of GBM cancer stem cells (CSCs), for which a systemically delivered single drug approach will be unlikely to produce a viable cure. Therefore, multi-drug therapies are needed. Currently, only temozolomide (TMZ), which is a DNA alkylator, affects overall survival in GBM patients. CSCs regenerate rapidly and over-express a methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to drug resistance. Idasanutlin (RG7388, R05503781) is a potent, selective MDM2 antagonist that additively kills GBM CSCs when combined with TMZ. By harnessing the strengths of nanotechnology, therapy can be combined with diagnostics in a truly theranostic manner for enhancing personalized medicine against GBM. The goal of this thesis was to develop a multi-drug therapy using multi-functional nanoparticles (NPs) that preferentially target the GBM CSC subpopulation and provide in vivo preclinical imaging capability. Polymer-micellar NPs composed of poly(styrene-b-ethylene oxide) (PS-b-PEO) and poly(lactic-co-glycolic) acid (PLGA) were developed investigating both single and double emulsion fabrication techniques as well as combinations of TMZ and RG7388. The NPs were covalently bound to a 15 base-pair CD133 aptamer in order to target a specific epitope on the CD133 antigen expressed on the surface of GBM CSC subpopulation. For theranostic functionality, the NPs were also labelled with a positron emission tomography (PET) radiotracer, zirconium-89 (89Zr). The NPs maintained a small size of less than 100 nm, a relatively neutral charge and exhibited the ability to produce a cytotoxic effect on CSCs. There was a slight increase in killing with the aptamer-bound NPs compared to those without a targeting agent. This work has provided a potentially therapeutic option for GBM specific for CSC targeting and future in vivo biodistribution studies

A Large-Diameter Hollow-Shaft Cryogenic Motor Based on a Superconducting Magnetic Bearing for Millimeter-Wave Polarimetry

In this paper we present the design and measured performance of a novel cryogenic motor based on a superconducting magnetic bearing (SMB). The motor is tailored for use in millimeter-wave half-wave plate (HWP) polarimeters, where a HWP is rapidly rotated in front of a polarization analyzer or polarization-sensitive detector. This polarimetry technique is commonly used in cosmic microwave background (CMB) polarization studies. The SMB we use is composed of fourteen yttrium barium copper oxide (YBCO) disks and a contiguous neodymium iron boron (NdFeB) ring magnet. The motor is a hollow-shaft motor because the HWP is ultimately installed in the rotor. The motor presented here has a 100 mm diameter rotor aperture. However, the design can be scaled up to rotor aperture diameters of approximately 500 mm. Our motor system is composed of four primary subsystems: (i) the rotor assembly, which includes the NdFeB ring magnet, (ii) the stator assembly, which includes the YBCO disks, (iii) an incremental encoder, and (iv) the drive electronics. While the YBCO is cooling through its superconducting transition, the rotor is held above the stator by a novel hold and release mechanism (HRM). The encoder subsystem consists of a custom-built encoder disk read out by two fiber optic readout sensors. For the demonstration described in this paper, we ran the motor at 50 K and tested rotation frequencies up to approximately 10 Hz. The feedback system was able to stabilize the the rotation speed to approximately 0.4%, and the measured rotor orientation angle uncertainty is less than 0.15 deg. Lower temperature operation will require additional development activities, which we will discuss

Vertical Force-deflection Characteristics of a Pair of 56-inch-diameter Aircraft Tires from Static and Drop Tests with and Without Prerotation

The vertical force-deflection characteristics were experimentally determined for a pair of 56-inch-diameter tires under static and drop-test conditions with and without prerotation. For increasing force, the tires were found to be least stiff for static tests, almost the same as for the static case for prerotation drop tests as long as the tires remain rotating, and appreciably stiffer for drop tests without prerotation