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ROS-Responsive Polymeric Micelles for Triggered Simultaneous Delivery of PLK1 Inhibitor/miR-34a and Effective Synergistic Therapy in Pancreatic Cancer
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2019-04-01 00:00:00 , DOI: 10.1021/acsami.9b02756 Xiaofei Xin 1, 2 , Feng Lin 1 , Qiyue Wang 1 , Lifang Yin 2 , Ram I Mahato 1
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2019-04-01 00:00:00 , DOI: 10.1021/acsami.9b02756 Xiaofei Xin 1, 2 , Feng Lin 1 , Qiyue Wang 1 , Lifang Yin 2 , Ram I Mahato 1
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Ineffective drug delivery and poor prognosis are two major challenges in the treatment of pancreatic ductal adenocarcinoma (PDAC). While there is significant downregulation of tumor suppressor microRNA-34a (miR-34a), which targets many oncogenes related to proliferation, apoptosis, and invasion, high expression level of Polo-like kinase 1 (PLK1) is closely associated with short survival rates of pancreatic cancer patients. Therefore, the objective is to codeliver miR-34a mimic and small molecule PLK1 inhibitor volasertib (BI6727) using poly(ethylene glycol)–poly[aspartamidoethyl(p-boronobenzyl)diethylammonium bromide] (PEG-B-PAEBEA). This polymer could self-assemble into micelles of ∼100 nm with 10% drug loading of volasertib and form a complex with miR-34a at the N/P ratio of 18 and higher. Combination treatment of volasertib and miR-34a displayed the synergistic effect and superior antiproliferative activity along with an enhanced G2/M phase arrest and suppression of colony formation, leading to cell death due to potential c-myc targeting therapeutics. Orthotopic pancreatic tumor bearing NSG mice were scanned for fluorescence by IVIS after systemic administration of micelles encapsulating volasertib and miR-34a at doses of 5 and 1 mg/kg, respectively. Cy5.5 concentration in plasma and major organs was determined by measuring fluorescence intensity. There was significant reduction in tumor volume, and histological examination of major organs suggested negligible systemic toxicity. In conclusion, PEG-B-PAEBEA micelles carrying volasertib and miR-34a mimic have the potential to treat pancreatic cancer.
中文翻译：
ROS 响应性聚合物胶束触发同时递送 PLK1 抑制剂/miR-34a 并有效协同治疗胰腺癌
药物递送无效和预后不良是胰腺导管腺癌（PDAC）治疗的两大挑战。虽然肿瘤抑制因子 microRNA-34a (miR-34a) 显着下调，该基因针对许多与增殖、凋亡和侵袭相关的癌基因，但 Polo 样激酶 1 (PLK1) 的高表达水平与肿瘤的短生存率密切相关。胰腺癌患者。因此，我们的目标是使用聚乙二醇-聚[天冬酰胺乙基（对硼苄基）二乙基溴化铵]（PEG-B-PAEBEA）共同递送miR-34a模拟物和小分子PLK1抑制剂volasertib（BI6727）。这种聚合物可以自组装成~100 nm的胶束，其中volasertib载药量为10%，并与miR-34a以18或更高的N/P比形成复合物。 volasertib 和 miR-34a 的联合治疗显示出协同效应和卓越的抗增殖活性，同时增强 G 2 /M 期阻滞和抑制集落形成，从而因潜在的 c-myc 靶向治疗而导致细胞死亡。分别以 5 mg/kg 和 1 mg/kg 的剂量全身施用封装 volasertib 和 miR-34a 的胶束后，通过 IVIS 扫描原位胰腺肿瘤 NSG 小鼠的荧光。通过测量荧光强度来确定血浆和主要器官中的Cy5.5浓度。肿瘤体积显着减小，主要器官的组织学检查表明全身毒性可以忽略不计。总之，携带volasertib和miR-34a模拟物的PEG-B-PAEBEA胶束具有治疗胰腺癌的潜力。
更新日期：2019-04-01
中文翻译：
ROS 响应性聚合物胶束触发同时递送 PLK1 抑制剂/miR-34a 并有效协同治疗胰腺癌
药物递送无效和预后不良是胰腺导管腺癌（PDAC）治疗的两大挑战。虽然肿瘤抑制因子 microRNA-34a (miR-34a) 显着下调，该基因针对许多与增殖、凋亡和侵袭相关的癌基因，但 Polo 样激酶 1 (PLK1) 的高表达水平与肿瘤的短生存率密切相关。胰腺癌患者。因此，我们的目标是使用聚乙二醇-聚[天冬酰胺乙基（对硼苄基）二乙基溴化铵]（PEG-B-PAEBEA）共同递送miR-34a模拟物和小分子PLK1抑制剂volasertib（BI6727）。这种聚合物可以自组装成~100 nm的胶束，其中volasertib载药量为10%，并与miR-34a以18或更高的N/P比形成复合物。 volasertib 和 miR-34a 的联合治疗显示出协同效应和卓越的抗增殖活性，同时增强 G 2 /M 期阻滞和抑制集落形成，从而因潜在的 c-myc 靶向治疗而导致细胞死亡。分别以 5 mg/kg 和 1 mg/kg 的剂量全身施用封装 volasertib 和 miR-34a 的胶束后，通过 IVIS 扫描原位胰腺肿瘤 NSG 小鼠的荧光。通过测量荧光强度来确定血浆和主要器官中的Cy5.5浓度。肿瘤体积显着减小，主要器官的组织学检查表明全身毒性可以忽略不计。总之，携带volasertib和miR-34a模拟物的PEG-B-PAEBEA胶束具有治疗胰腺癌的潜力。
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