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Nanocarrier Composed of Magnetite Core Coated with Three Polymeric Shells Mediates LCS-1 Delivery for Synthetic Lethal Therapy of BLM-Defective Colorectal Cancer Cells
Biomacromolecules ( IF 6.2 ) Pub Date : 2018-02-16 00:00:00 , DOI: 10.1021/acs.biomac.7b01607
Anuradha Gupta 1 , Anas Ahmad 1 , Hardeep Singh 1 , Sharanjeet Kaur 1 , Neethu K M 1 , Md. Meraj Ansari 1 , Govindasamy Jayamurugan 1 , Rehan Khan 1
Affiliation  

Synthetic lethality is a molecular-targeted therapy for selective killing of cancer cells. We exploited a lethal interaction between superoxide dismutase 1 inhibition and Bloom syndrome gene product (BLM) defect for the treatment of colorectal cancer (CRC) cells (HCT 116) with a customized lung cancer screen-1-loaded nanocarrier (LCS-1-NC). The drug LCS-1 has poor aqueous solubility. To overcome its limitations, a customized NC, composed of a magnetite core coated with three polymeric shells, namely, aminocellulose (AC), branched poly(amidoamine), and paraben-PEG, was developed for encapsulating LCS-1. Encapsulation efficiency and drug loading were found to be 74% and 8.2%, respectively. LCS-1-NC exhibited sustained release, with ∼85% of drug release in 24 h. Blank NC (0.5 mg/mL) exhibited cytocompatibility toward normal cells, mainly due to the AC layer. LCS-1-NC demonstrated high killing selectivity (104 times) toward BLM-deficient HCT 116 cells over BLM-proficient HCT 116 cells. Due to enhanced efficacy of the drug using NC, the sensitivity difference for BLM-deficient cells increased to 1.7 times in comparison to that with free LCS-1. LCS-1-NC induced persistent DNA damage and apoptosis, which demonstrates that LCS-1-NC effectively and preferentially killed BLM-deficient CRC cells. This is the first report on the development of a potential drug carrier to improve the therapeutic efficacy of LCS-1 for specific killing of CRC cells having BLM defects.

中文翻译:

纳米载体由包裹三个聚合物壳的磁铁矿芯组成,介导LCS-1传递,用于合成致死性治疗BLM缺陷性结直肠癌细胞。

合成杀伤力是一种分子靶向疗法,可选择性杀死癌细胞。我们利用超氧化物歧化酶1抑制和布鲁姆综合征基因产物(BLM)缺陷之间的致死性相互作用,用定制的载有肺癌筛查1的纳米载体(LCS-1-NC)来治疗结直肠癌(CRC)细胞(HCT 116)。 )。药物LCS-1的水溶性差。为了克服其局限性,开发了一种定制的NC,该磁体由包裹有三个聚合物壳(即氨基纤维素(AC),支化聚(酰胺基胺)和对羟基苯甲酸酯-PEG)的磁铁矿芯组成,用于封装LCS-1。封装效率和载药量分别为74%和8.2%。LCS-1-NC表现出持续释放,在24小时内约有85%的药物释放。空白NC(0.5 mg / mL)对正常细胞表现出细胞相容性,主要是由于交流电层。LCS-1-NC对BLM缺乏的HCT 116细胞表现出对BLM缺乏的HCT 116细胞高的杀伤选择性(104倍)。由于使用NC增强了药物的疗效,与不含LCS-1的细胞相比,缺乏BLM的细胞的灵敏度差异增加了1.7倍。LCS-1-NC引起持续的DNA损伤和凋亡,这表明LCS-1-NC有效并优先杀死了BLM缺陷的CRC细胞。这是关于开发潜在的药物载体以改善LCS-1特异性杀伤具有BLM缺陷的CRC细胞的疗效的第一份报告。与缺乏LCS-1的细胞相比,缺乏BLM的细胞的敏感性差异增加了1.7倍。LCS-1-NC引起持续的DNA损伤和凋亡,这表明LCS-1-NC有效并优先杀死了BLM缺陷的CRC细胞。这是关于开发潜在药物载体以改善LCS-1对具有BLM缺陷的CRC细胞的特异性杀伤的治疗功效的第一份报告。与缺乏LCS-1的细胞相比,缺乏BLM的细胞的敏感性差异增加了1.7倍。LCS-1-NC引起持续的DNA损伤和凋亡,这表明LCS-1-NC有效并优先杀死了BLM缺陷的CRC细胞。这是关于开发潜在的药物载体以改善LCS-1特异性杀伤具有BLM缺陷的CRC细胞的疗效的第一份报告。
更新日期:2018-02-16
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