Novel DZ-SIM Conjugate Targets Cancer Mitochondria and Prolongs Survival in Pancreatic Ductal Adenocarcinoma,Advanced Therapeutics

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Novel DZ-SIM Conjugate Targets Cancer Mitochondria and Prolongs Survival in Pancreatic Ductal Adenocarcinoma
Advanced Therapeutics ( IF 3.7 ) Pub Date : 2022-07-19 , DOI: 10.1002/adtp.202200021
Yan Ou _{1,

2} , Ruoxiang Wang ₁ , Gina Chia-Yi Chu ₁ , Omer Hany Miligy Elmadbouh ₁ , Adrian Lim ₁ , Leland Wei-Kuo Chung ₁ , Mouad Edderkaoui _{1,

3,

4} , Yi Zhang ₃ , Stephen Jacob Pandol _{1,

3,

4}

Affiliation

Pancreatic ductal adenocarcinoma (PDAC) is a disease with no effective therapeutics. A novel targeted therapy drug consisting of a tumor-targeting ligand, near-infrared (NIR) organic heptamethine carbocyanine dye (DZ), and HMG-CoA inhibitor simvastatin (SIM), is developed and its efficacy in PDAC is assessed. PDAC cell specific targeting of DZ-SIM is measured by determining the fluorescence in cells and animals. Mitochondrial bioenergetics and functions are measured by Seahorse and flow cytometry, respectively. Apoptosis is assessed by DNA fragmentation, annexin V/propidium iodide staining, and TUNEL. Markers of cell invasion, epithelial-to-mesenchymal transition, and cancer stemness are measured. The effect of DZ-SIM on survival, tumor growth, and metastasis is measured in the Kras^þ/LSLG12D;Trp53^þ/LSLR172H;Pdx-1^−Cre transgenic mice and in syngeneic and subcutaneous PDAC models. NIR fluorescence imaging shows specific localization of DZ-SIM to cancer, but not to normal cells and tissues. DZ-SIM significantly inhibits tumor growth and re-sensitizes therapeutically resistant PDAC cells to conventional therapies. DZ-SIM kills cancer cells through unique pathways involving decreasing mitochondrial bioenergetics, including oxygen consumption and ATP production, and increasing ROS production. Mitochondrial depletion prevents the effect of DZ-SIM. Administration of DZ-SIM in three PDAC animal models results in a marked increase in survival and a decrease in tumor growth and metastasis.

中文翻译：

新型 DZ-SIM 缀合物靶向癌症线粒体并延长胰腺导管腺癌的生存期

胰腺导管腺癌（PDAC）是一种尚无有效治疗方法的疾病。开发了一种由肿瘤靶向配体、近红外 (NIR) 有机七次甲基碳花青染料 (DZ) 和 HMG-CoA 抑制剂辛伐他汀 (SIM) 组成的新型靶向治疗药物，并评估了其在 PDAC 中的疗效。 DZ-SIM 的 PDAC 细胞特异性靶向通过测定细胞和动物中的荧光来测量。线粒体生物能学和功能分别通过海马和流式细胞术测量。通过 DNA 片段化、膜联蛋白 V/碘化丙啶染色和 TUNEL 评估细胞凋亡。测量细胞侵袭、上皮间质转化和癌症干性的标志物。在 Kras ^+/LSLG12D ；Trp53 ^+/LSLR172H ；Pdx-1 ^−Cre转基因小鼠以及同基因和皮下 PDAC 模型中测量 DZ-SIM 对生存、肿瘤生长和转移的影响。 NIR 荧光成像显示 DZ-SIM 对癌症的特异性定位，但对正常细胞和组织没有特异性定位。 DZ-SIM 显着抑制肿瘤生长，并使治疗耐药的 PDAC 细胞对传统疗法重新敏感。 DZ-SIM 通过减少线粒体生物能量（包括耗氧量和 ATP 产生）以及增加 ROS 产生的独特途径杀死癌细胞。线粒体耗竭会阻止 DZ-SIM 的作用。在三种 PDAC 动物模型中使用 DZ-SIM 可显着提高存活率并减少肿瘤生长和转移。

更新日期：2022-07-19

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