Resumo:
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.
