Nucleus-Targeted, Echogenic Polymersomes for Delivering a Cancer Sternness Inhibitor to Pancreatic Cancer Cells
Nucleus-Targeted, Echogenic Polymersomes for Delivering a Cancer Sternness Inhibitor to Pancreatic Cancer Cells
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DOI：
10.1021/acs.biomac.8b01133
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发表时间：
2018-10-01
影响因子：
6.2
通讯作者：
Mallik, Sanku
中科院分区：
文献类型：
--
作者：
Karandish, Fataneh;Mamnoon, Babak;Mallik, Sanku
用于治疗癌症的化疗药物表现出相当大的副作用、毒性和耐药性。为了缓解这些问题，我们设计了针对细胞核的、回声的、刺激响应的聚合物囊泡（聚合物囊泡），以在胰腺癌细胞的细胞核内运输并随后释放封装的抗癌药物。我们合成了炔烃-地塞米松衍生物，并利用 Cu2+ 催化的“点击”反应将其与 N-3-聚乙二醇 (PEG)-聚乳酸 (PLA) 共聚物缀合。我们从地塞米松-PEG-PLA 缀合物以及合成的刺激响应聚合物 PEG-S-S-PLA 制备了聚合物囊泡。地塞米松组扩张核孔复合物并将囊泡转运至细胞核。我们设计了聚合物囊泡，以便在胰腺癌细胞核中存在高浓度还原剂的情况下释放封装的药物。我们观察到，针对细胞核的刺激响应聚合物囊泡在模拟细胞核的环境中在 80 分钟内释放了 70% 的封装内容物。我们将癌症干细胞抑制剂 BBI608 封装在囊泡中，并观察到 BBI608 封装的聚合物囊泡在三维球状培养物中将 BxPC3 细胞的活力降低至 43%。聚合物囊泡是按照特殊方案制备的，因此它们可以散射超声波，从而可以通过医用超声波扫描仪进行成像。因此，这些回声、靶向、刺激响应和药物封装的聚合物囊泡具有作为化疗药物靶向癌细胞核的可追踪、靶向载体的潜力。
Chemotherapeutic agents for treating cancers show considerable side effects, toxicity, and drug resistance. To mitigate the problems, we designed nucleus-targeted, echogenic, stimuli-responsive polymeric vesicles (polymersomes) to transport and subsequently release the encapsulated anticancer drugs within the nuclei of pancreatic cancer cells. We synthesized an alkyne-dexamethasone derivative and conjugated it to N-3-polyethylene glycol (PEG)-polylactic acid (PLA) copolymer employing the Cu2+ catalyzed "Click" reaction. We prepared polymersomes from the dexamethasone-PEG- PLA conjugate along with a synthesized stimuli-responsive polymer PEG-S-S-PLA. The dexamethasone group dilates the nuclear pore complexes and transports the vesicles to the nuclei. We designed the polymersomes to release the encapsulated drugs in the presence of a high concentration of reducing agents in the nuclei of pancreatic cancer cells. We observed that the nucleus-targeted, stimuli-responsive polymersomes released 70% of encapsulated contents in the nucleus-mimicking environment in 80 min. We encapsulated the cancer stemness inhibitor BBI608 in the vesicles and observed that the BBI608 encapsulated polymersomes reduced the viability of the BxPC3 cells to 43% in three-dimensional spheroid cultures. The polymersomes were prepared following a special protocol so that they scatter ultrasound, allowing imaging by a medical ultrasound scanner. Therefore, these echogenic, targeted, stimuli-responsive, and drug-encapsulated polymersomes have the potential for trackable, targeted carrier of chemotherapeutic drugs to cancer cell nuclei.