LIGHT ACTIVATABLE PURE PORPHYRIN NANOPARTICLES FOR THE PHOTODYNAMIC OPENING OF THE BLOOD-BRAIN BARRIER AND GLIOBLASTOMA TREATMENT

Abstract

Glioblastoma (GBM) consistently recurs due to infiltrating cancer cells that cannot be removed by surgery and chemotherapy. The diffusive nature of GBM makes complete surgical resection unsafe, and the intact blood-brain barrier (BBB) prevents the penetration and accumulation of nearly all chemotherapy in infiltrative GBM cells. Existing BBB opening strategies are often associated with increased risk of edema, hemorrhage, or neurotoxicity and thus have limited clinical success. Photodynamic therapy (PDT) is a photochemistry-based treatment modality that has shown promise in treating GBM and opening the BBB in the clinic. In fact, a single adjunctive dose of PDT has been shown to add as much as 18 months to patient survival. However, the full potential of PDT is limited by the light activation depth of the ‘gold standard’ pro-drug photosensitizer, 5-aminolevulinic acid (5-ALA). In addition, large doses of PDT can result in edema and neurotoxicity. To address these issues, our lab has developed a photodynamic priming (PDP) strategy using the verteporfin (VP) photosensitizer, which operates at low optical energy to enhance intratumoral drug accumulation without damaging the healthy brain tissues. Unfortunately, VP is hydrophobic and requires liposomal encapsulation for intravenous administration, which can alter the photosensitizers cellular pharmaceutics. Here, we develop and compare a novel carrier-free pure-photosensitizer nanoparticle to a clinically relevant liposomal formulation.This dissertation covers a complementary, four-pronged approach to enhance drug delivery to brain tumors and treat GBM: (1) Understand the photoactivation depth of clinically relevant photosensitizers in the rodent brain for the targeting of infiltrative GBM cells. (2) Explore the mechanisms of photochemistry-induced BBB opening. (3) Engineer light-activable nanotechnology that can open the BBB, improve drug delivery, and eradicate GBM cells. And (4) develop a high-throughput model to examine the BBB integrity and efflux transporter function. The central hypothesis of this dissertation is the delivery of photoactivatable pure-photosensitizer nanoparticles can eradicate GBM cells and enhance drug delivery to microscopic GBM tumors.