Local Delivery of Therapeutic Nanoparticles for Treatment of Malignant Glioma
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The treatment regimen for patients that present with glioblastoma (GBM) has improved over the years with the advent of the chemotherapeutic Temodar® and the inclusion of concurrent radiotherapy. However, the 5 year survival rate remains below 10% . The current treatment regimen is unable to effectively eradicate all pathological tumor cells that can reside up to centimeters away from the tumor bulk. This leads to tumor recurrence, the main culprit behind the disease’s low survival rate. In addition, currently developed conventional therapies fail to address this need for improved therapeutic distribution in order to achieve therapeutic outcome. In this thesis, we develop 3 different nanotechnology platforms that are engineered to distribute throughout the brain and tumor microenvironment upon intracranial administration using an optimized form of convection enhanced delivery (CED). It is my belief that this technology represents a promising start towards addressing the poor survival rates and quality of life of those patients suffering from GBM. We began by tailoring the parameters that allow for effective administration of therapeutics using CED. Following the size and surface chemistry criteria established by our recent Science Translational Medicine publication (sub-100nm, near neutral surface charge) , we demonstrate that a probe, brain penetrating nanoparticle (NP) can achieve synergistically improved distribution in the brain of both mice and rats when delivered using CED. Furthermore, a mechanistic investigation of the parameters of CED reveals a combination strategy (i.e. hyperosmolar infusate solution + brain penetrating NP) that can enable more homogeneous therapeutic distribution in the brain, which is currently the main obstacle in successful translation of CED-based therapies to the clinic. With the understanding gained from these probe NPs, we developed three therapeutic brain penetrating NP formulations with dense surface coatings of polyethylene glycol (PEG) that are capable of delivering chemotherapeutics or therapeutic gene sequences. When administered using CED, these therapeutic NPs similarly achieve widespread distribution in the brain. The first platform is a biodegradable poly(lactic-co-glycolic acid)(PLGA) polymer and we demonstrate its ability to rapidly penetrate and distribute in the brain tissue as compared to gold standard NPs that have been engineered to pass through the blood brain barrier (BBB). Secondly, we developed a non-viral brain penetrating gene vector platform derived from a highly efficient polyethylenimine (PEI) polymer. When administered using CED, they successfully deliver higher overall levels of widespread reporter gene expression. These NPs can be rapidly adopted to deliver therapeutic plasmids that can encode for p53 for anti-tumoral efficacy or glial derived neurotrophic factor (GDNF) for treatment of Parkinson’s disease. Finally, we’ve engineered brain penetrating cisplatin NPs that, when administered using CED, leads to curative effects in a clinically relevant, orthotopic rodent model of human GBM. Together, these three brain penetrating NP formulations, in conjunction with optimized CED administration, represent promising adjuvant therapies to be tested for treatment of GBM.