Targeting Mitochondria in Tumor-Associated Macrophages using a Dendrimer-Conjugated TSPO Ligand that Stimulates Antitumor Signaling in Glioblastoma
- 31 August 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Biomacromolecules
- Vol. 21 (9), 3909-3922
- https://doi.org/10.1021/acs.biomac.0c01033
Abstract
Mitochondria mediate critical cellular processes, including proliferation, apoptosis, and immune responses; as such, their dysfunction is pathogenic in many neurodegenerative disorders and cancers. In glioblastoma, targeted delivery of mitochondria-focused anti-cancer therapies have failed to translate into clinical successes due to their nonspecific cellular localization, heterogeneity of receptor expression across patients, poor transport across biological barriers to reach the brain, tumor, and mitochondria, as well as systemic side effects. Strategies that can overcome brain and solid tumor barriers and selectively target mitochondria within specific cell types may yield improvements to glioblastoma treatment. Developments in dendrimer-mediated nanomedicines have shown promise targeting tumor-associated macrophages (TAMs) in glioblastoma following systemic administration. Here, we present a novel dendrimer conjugated to the translocator protein 18KDa (TSPO) ligand 5,7-dimethylpyrazolo[1,5-α]pyrimidin-3-ylacetamide (DPA). We developed a clickable DPA for conjugation on dendrimer surface and demonstrate in vitro that the dendrimer-DPA conjugate (D-DPA) significantly increases dendrimer co-localization with mitochondria. Compared to free TSPO ligand PK11195, D-DPA stimulates greater anti-tumor immune signaling. In vivo, we show that D-DPA targets mitochondria specifically within TAMs following systemic administration. Our results demonstrate that dendrimers can achieve TAMs specific targeting in glioblastoma and can be further modified to target specific intracellular compartments for organelle-specific drug delivery.Keywords
Funding Information
- National Institute of Neurological Disorders and Stroke (5R01NS093416)
- National Institute of Biomedical Imaging and Bioengineering (R01EB01 8306)
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