Targeting Mitochondria in Tumor-Associated Macrophages using a Dendrimer-Conjugated TSPO Ligand that Stimulates Antitumor Signaling in Glioblastoma

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 anticancer therapies has failed to translate into clinical success due to the nonspecific cellular localization, heterogeneity of receptor expression across patients, poor transport across biological barriers to reach the brain, tumor, and mitochondria, and systemic side effects. Strategies that can overcome brain and solid tumor barriers and selectively target mitochondria within specific cell types may lead to improvements in 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 (18 kDa) (TSPO) ligand 5,7-dimethylpyrazolo­[1,5-α]­pyrimidin-3-ylacetamide (DPA). We developed a clickable DPA for conjugation on the dendrimer surface and demonstrated in vitro that the dendrimer-DPA conjugate (D-DPA) significantly increases dendrimer colocalization with mitochondria. Compared to free TSPO ligand PK11195, D-DPA stimulates greater antitumor immune signaling. In vivo, we show that D-DPA targets mitochondria specifically within TAMs following systemic administration. Our results demonstrate that dendrimers can achieve TAM-specific targeting in glioblastoma and can be further modified to target specific intracellular compartments for organelle-specific drug delivery.

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

“…In another study, a novel dendrimer conjugated to the translocator protein (18 kDa) (TSPO) ligand 5,7-dimethylpyrazolo [1,5-α]pyrimidin-3-ylacetamide (DPA) is presented. These dendrimers can achieve GAMs-specific targeting in GBM and can be further modified to target specific intracellular compartments for organelle-specific drug delivery [ 96 ]. Targeted delivery with CHA-encapsulated mannosylated liposomes enhances the immunotherapeutic efficacy of CHA by inducing a shift from the pro-tumoral to the anti-tumoral macrophage phenotype effectively [ 97 ].…”

Synthesis and Characterization of a “Clickable” PBR28 TSPO-Selective Ligand Derivative Suitable for the Functionalization of Biodegradable Polymer Nanoparticles

“…A striking increase in TSPO expression was reported in several tumors, with a correlation with the level of malignancy, suggesting that TSPO ligands may be exploited also to identify cancerous cells and potentially target them with therapeutics. Accordingly, the development of bivalent compounds, derived from the conjugation of a TSPO ligand with a chemotherapic or a drug delivery system, is regarded as a promising strategy to achieve cell-selective targeting of therapeutics, testified by the increasing number of studies in the literature, reporting the exploitation of a diverse range of small molecule TSPO-ligands as a targeting moiety, ranging from TSPO-ligand chemotherapic (doxorubicin or cytarabine) [ 27 , 28 ] to TSPO-ligand dendrimers [ 9 , 29 ] or iron-oxide nanoparticle [ 7 , 30 ] conjugates. In line with these studies, in our work we demonstrated that the functionalization with a TSPO-targeted ligand enhances the internalization of polymer nanoparticles in TSPO-expressing cells; moreover, the internalized 6PBR30 NPs displayed a high degree of co-localization with the mitochondrial network.…”

Polymeric Nanoparticles for Mitochondria Targeting Mediated Robust Cancer Therapy

“…In particular, TSPO is significantly upregulated in anti-inflammatory macrophages, providing a new way to promote mitochondria-related immunotherapy (Mukherjee et al, 2019). Sharma et al adopted 5, pyrimidin-3-ylacetamide (DPA), a novel class of TSPO ligands, to endow (G (4)-PAMAM) nanoparticles with mitochondria specific affinity property (Sharma et al, 2020). The DPA moieties decorated dendrimer nanoparticles presented promising targeting to GBM-associated macrophages (TAMs) and the mitochondria in TAMs.…”