Targeting Mitochondria in Tumor-Associated Macrophages using a Dendrimer-Conjugated TSPO Ligand that Stimulates Antitumor Signaling in Glioblastoma.
Targeting Mitochondria in Tumor-Associated Macrophages using a Dendrimer-Conjugated TSPO Ligand that Stimulates Antitumor Signaling in Glioblastoma.
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DOI：
10.1021/acs.biomac.0c01033
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发表时间：
2020-09-14
影响因子：
6.2
通讯作者：
Kannan RM
中科院分区：
文献类型：
--
作者：
Sharma A;Liaw K;Sharma R;Thomas AG;Slusher BS;Kannan S;Kannan RM
线粒体介导关键的细胞过程，包括增殖、凋亡和免疫反应;因此，它们的功能障碍在许多神经退行性疾病和癌症中是致病的。在胶质母细胞瘤中，由于非特异性细胞定位、患者间受体表达的异质性、穿过生物屏障到达脑、肿瘤和线粒体的不良转运以及全身性副作用，靶向递送以肿瘤为中心的抗癌疗法未能转化为临床成功。可以克服脑和实体瘤屏障并选择性靶向特定细胞类型内的线粒体的策略可能会导致胶质母细胞瘤治疗的改善。树状聚合物介导的纳米药物的发展已经显示出在全身给药后靶向胶质母细胞瘤中的肿瘤相关巨噬细胞（TAM）的前景。在这里，我们提出了一种新的树枝状聚合物结合到转运蛋白（18 kDa）（TSPO）配体5，7-二甲基吡唑并[1，5-α]嘧啶-3-基乙酰胺（DPA）。我们开发了一种可点击的DPA，用于在树枝状聚合物表面缀合，并在体外证明树枝状聚合物-DPA缀合物（D-DPA）显着增加了树枝状聚合物与线粒体的共定位。与游离TSPO配体PK 11195相比，D-DPA刺激更大的抗肿瘤免疫信号传导。在体内，我们表明，D-DPA的目标是线粒体内的TAM系统管理后。我们的研究结果表明，树枝状聚合物可以实现胶质母细胞瘤中的TAM特异性靶向，并可以进一步修饰以靶向特定的细胞内隔室，用于细胞器特异性药物递送。
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.
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影响因子：
4.1
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通讯作者：
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影响因子：
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影响因子：
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作者：
Kitov, PI;Bundle, DR
通讯作者：
Bundle, DR