Supramolecular Structure-Enabled Delivery of Porphyrin to Glioblastomas Beyond the Blood-Brain Barrier
Despite the use of aggressive surgical, radiation and chemo-therapies, glioblastomas remain incurable with a mere 6.8% five-year survival rate. This poor prognosis is rooted in treatment resistance and diffuse infiltration of cancer cells beyond surgical margins, leading to incomplete tumour resection, inevitable tumour regrowth and patient death. Porphyrin-mediated photodynamic therapy (PDT) and fluorescence-guided surgery (FGS) are two promising modalities for targeting glioblastoma infiltrates and overcoming therapy resistance. However, the presence of an intact blood-brain barrier (BBB) within infiltrative tumor tissue restricts porphyrin delivery and, thereby, therapeutic efficacy. This thesis leverages the drug delivery advantages of porphyrin supramolecular chemistry to address this limitation through the conception of two new platforms: porphyrin apolipoprotein E3 (apoE3) lipid nanoparticles (pyE-LNs) and 2) porphyrin microbubbles (pMBs). PyE-LNs were designed to exploit apoE3’s abilities to 1) chaperone nanoparticle transcytosis across the BBB, and 2) bind with high avidity to overexpressed low density lipoprotein receptor (LDLR) in glioblastoma cells for healthy tissue-sparing, biologically targeted porphyrin delivery. Systematic particle optimization was conducted, yielding 30 nm pyE-LNs that facilitated cell-specific, apoE3 and LDLR-mediated glioblastoma cell uptake, in vivo 4:1 tumour:healthy brain targeting specificity and potent in vitro PDT. The pMBs were alternatively designed to mediate mechanical porphyrin targeting by 1) enabling focused ultrasound (FUS) BBB opening, and 2) undergoing an in situ localized acoustic conversion into porphyrin nanoparticles for localized tissue delivery across permeabilized vasculature. Pharmacokinetic optimization of pMB composition was conducted by developing and applying a new microbubble radiolabeling strategy. Multimodal (ultrasound, PET, γ-counting and fluorescence) microbubble dissolution, shell blood clearance and biodistribution profiles were obtained ± FUS, yielding structure-activity relationships between pMB lipid composition and tissue uptake. The optimized pyE-LNs and pMBs were comparatively applied to healthy and 9L infiltrative tumor-bearing rats ± microbubble/FUS BBB opening. PyE-LNs, particularly in combination with microbubble/FUS, yielded potent brain drug delivery (4% ID·g-1), preferential (4:1) tumor:healthy tissue uptake and effective peritumoral porphyrin fluorescence (at least 1 mm depth from visible tumor boundaries). The effective trans-BBB, targeted glioblastoma and peritumoral porphyrin delivery achieved by pyE-LN ± microbubble/FUS opens new avenues for more effective glioblastoma therapies, the outlook for which is discussed.
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