Development of EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine delivery to treat multi-drug resistance in human breast and ovarian tumor cells.
Development of EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine delivery to treat multi-drug resistance in human breast and ovarian tumor cells.
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DOI：
10.1021/mp1002653
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发表时间：
2011-02-07
影响因子：
4.9
通讯作者：
Amiji M
中科院分区：
文献类型：
--
作者：
Milane L;Duan Z;Amiji M
多重耐药（MDR）癌症是一个重大的临床障碍，通常与复发性、无反应性疾病病例有关。通过合成聚（D,L-丙交酯-乙交酯）/聚（乙二醇）/表皮生长因子受体靶向肽（PLGA/PEG/EGFR-肽）构建体并掺入聚（ε-己内酯）（PCL）纳米颗粒中，制成靶向纳米颗粒。使用缺氧在一组九种人类乳腺癌和卵巢癌细胞系中诱导多药耐药。研究表明，靶向 EGFR 的聚合物共混纳米颗粒可主动靶向 EGFR 过度表达的细胞系，尤其是在诱导缺氧时。纳米颗粒能够持续释放药物。氯尼达明和紫杉醇联合治疗显着提高了两种药物的治疗指数。用纳米粒子剂量的 1 μM 紫杉醇/10 μM 氯尼达明处理导致所有缺氧/MDR 细胞系的细胞活力低于 10%，所有常氧细胞系的细胞活力低于 5%。相比之下，单独用1μM紫杉醇处理是MDR细胞的近似IC50值，而单独用氯尼达明处理几乎没有效果。 PLGA/PEG/EGFR 肽递送系统通过利用 EGFR 的表达主动靶向 MDR 细胞。该系统通过抑制 Warburg 效应并促进促凋亡 Bcl-2 蛋白（氯尼达明）的线粒体结合，同时使微管超稳定（紫杉醇）来治疗 MDR。该纳米载体系统主动针对MDR相关表型（EGFR受体过度表达），进一步增强两种药物的治疗指数，并加强氯尼达明/紫杉醇联合疗法在MDR癌症治疗中的应用。
Multi-drug resistant (MDR) cancer is a significant clinical obstacle and is often implicated in cases of recurrent, non-responsive disease. Targeted nanoparticles were made by synthesizing a poly(D,L-lactide-co-glycolide)/poly(ethylene glycol)/epidermal growth factor receptor targeting peptide (PLGA/PEG/EGFR-peptide) construct for incorporation in poly(epsilon-caprolactone) (PCL) nanoparticles. MDR was induced in a panel of nine human breast and ovarian cancer cell lines using hypoxia. EGFR-targeted polymer blend nanoparticles were shown to actively target EGFR over-expressing cell lines, especially upon induction of hypoxia. The nanoparticles were capable of sustained drug release. Combination therapy with lonidamine and paclitaxel significantly improved the therapeutic index of both drugs. Treatment with a nanoparticle dose of 1 μM paclitaxel/10 μM lonidamine resulted in less than 10% cell viability for all hypoxic/MDR cell lines and less than 5% cell viability for all normoxic cell lines. Comparatively, treatment with 1 μM paclitaxel alone was the approximate IC50 value of the MDR cells while treatment with lonidamine alone had very little effect. PLGA/PEG/EGFR-peptide delivery system actively targets a MDR cell by exploiting the expression of EGFR. This system treats MDR by inhibiting the Warburg effect and promoting mitochondrial binding of pro-apoptotic Bcl-2 proteins (lonidamine), while hyperstabilizing microtubules (paclitaxel). This nanocarrier system actively targets a MDR associated phenotype (EGFR receptor over-expression), further enhancing the therapeutic index of both drugs and potentiating the use of lonidamine/paclitaxel combination therapy in the treatment of MDR cancer.
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DOI：
10.1126/science.1168750
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Aller SG;Yu J;Ward A;Weng Y;Chittaboina S;Zhuo R;Harrell PM;Trinh YT;Zhang Q;Urbatsch IL;Chang G
通讯作者：
Chang G
影响因子：
14
作者：
Cheng, Jianjun;Teply, Benjamin A.;Farokhzad, Omid C.
通讯作者：
Farokhzad, Omid C.
影响因子：
5.8
作者：
Chawla, JS;Amiji, MM
通讯作者：
Amiji, MM
影响因子：
3.7
作者：
Buys, Timon P. H.;Chari, Raj;Ling, Victor
通讯作者：
Ling, Victor
影响因子：
3.1
作者：
HARRIS, AL;HOCHHAUSER, D
通讯作者：
HOCHHAUSER, D