Dendrimer-Mediated Targeted Immunotherapies for the Treatment of Glioblastoma
LIAW-DISSERTATION-2020.pdf (9.081Mb) (embargoed until: 2024-05-01)
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Glioblastoma is among the most severe types of cancer, with poor patient prognoses due to barriers associated the brain and solid tumors. Advances in cancer treatments have failed to address glioblastoma because of their inabilities to achieve clinically relevant doses within tumors, thereby requiring high doses that lead to systemic toxicities. Dendrimer-based nanomedicines have shown promise for targeted delivery in neuroinflammation from systemic circulation. Here, we demonstrate that hydroxyl-terminated polyamidoamine dendrimers localize specifically to tumor-associated macrophages (TAMs) from systemic administration. This targeting can be leveraged or tailored for targeted delivery of immunotherapies for treating glioblastoma. We first explored how dendrimer physicochemical properties influence their biological interactions. We show that surface functionality has significant impacts on cellular internalization, with hydroxyl-terminated dendrimers conferring the greatest cellular uptake while amine-terminated dendrimers partition to the nucleus. We also demonstrate the dendrimer size-dependence of TAMs targeting in vivo due to constraints with tumor penetration and renal clearance. These results demonstrate that manipulating dendrimer physicochemical properties has implications for their clinical application. We then explored how TAMs targeting improves delivery of immunotherapies. Dendrimer delivery of BLZ945, an inhibitor of tumor TAMs recruitment, significantly improved reprogramming of TAMs and subsequent repolarization of the tumor immune profile from pro- towards anti-tumor. This reprogramming translated to improved survival by ~30% compared to BLZ945 with a single systemic dose, as well as significant improvements to behavioral markers of disease burden. We also show that by designing release mechanisms to enable triggered release of therapeutic payloads in intracellular and intratumor conditions, we can reduce treatment-induced systemic toxicities. These results indicate that dendrimer targeted delivery and triggered drug release can provide broad therapeutic windows to achieve significant improvements in cancer immunotherapy for glioblastoma treatment. Finally, we investigated how dendrimers can be tailored to specific intracellular or cellular targets. We show that through electrostatic- and receptor-mediated ligands, dendrimers can be modified to target mitochondria and promote anti-tumor immune activation. Surface decoration of dendrimers with sugar moieties can be designed to enhance or alter dendrimer targeting. Therefore, dendrimers are a versatile nanoparticle platform that can be modified to tailor intracellular and cellular specific targeting.