Prostate-targeted biodegradable nanoparticles loaded with androgen receptor silencing constructs eradicate xenograft tumors in mice.
Prostate-targeted biodegradable nanoparticles loaded with androgen receptor silencing constructs eradicate xenograft tumors in mice.
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载有雄激素受体沉默结构的前列腺靶向可生物降解纳米颗粒可根除小鼠异种移植肿瘤。
DOI：
10.2217/nnm.12.14
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发表时间：
2012-09
期刊：
影响因子：
--
通讯作者：
Li B
中科院分区：
文献类型：
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作者：
Yang J;Xie SX;Huang Y;Ling M;Liu J;Ran Y;Wang Y;Thrasher JB;Berkland C;Li B
前列腺癌是男性癌症死亡的主要原因，雄激素受体（AR）已被证明在疾病的进展中起关键作用。我们以前的报告表明，在前列腺癌细胞中使用基于siRNA的方法敲低AR基因的表达导致凋亡性细胞死亡和异种移植肿瘤根除。在这项研究中，我们利用可生物降解的纳米颗粒将治疗性AR shRNA构建体特异性地递送到前列腺癌细胞。使用聚（dl-乳酸-共-乙醇酸）聚合物制造可生物降解的纳米颗粒，并将AR shRNA构建体装载在颗粒内部。然后将纳米颗粒的表面与前列腺特异性膜抗原适体A10缀合，用于前列腺癌细胞特异性靶向。在细胞培养和异种移植模型中，A10-缀合大大增强了纳米颗粒的细胞摄取。包封在纳米颗粒中的AR shRNA对AR基因沉默的功效在裸鼠中的PC-3/AR衍生的异种移植物中得到证实。在具有不同前列腺癌细胞系22 RV 1、LAPC-4和LNCaP的异种移植物模型中评价了负载A10缀合的AR shRNA的纳米颗粒的治疗性质。在两次注射载有AR shRNA的纳米颗粒后，在2周内观察到快速肿瘤消退。与先前的报道一致，与非缀合的纳米颗粒相比，A10适体缀合显著增强异种移植肿瘤消退。这些数据表明，使用可生物降解的纳米颗粒方法的AR shRNA的组织特异性递送代表了威胁生命的前列腺癌的新疗法。
Prostate cancer is the major cause of cancer death in men and the androgen receptor (AR) has been shown to play a critical role in the progression of the disease. Our previous reports showed that knocking down the expression of the AR gene using a siRNA-based approach in prostate cancer cells led to apoptotic cell death and xenograft tumor eradication. In this study, we utilized a biodegradable nanoparticle to deliver the therapeutic AR shRNA construct specifically to prostate cancer cells. The biodegradable nanoparticles were fabricated using a poly(dl-lactic-co-glycolic acid) polymer and the AR shRNA constructs were loaded inside the particles. The surface of the nanoparticles were then conjugated with prostate-specific membrane antigen aptamer A10 for prostate cancer cell-specific targeting. A10-conjugation largely enhanced cellular uptake of nanoparticles in both cell culture- and xenograft-based models. The efficacy of AR shRNA encapsulated in nanoparticles on AR gene silencing was confirmed in PC-3/AR-derived xenografts in nude mice. The therapeutic property of A10-conjugated AR shRNA-loaded nanoparticles was evaluated in xenograft models with different prostate cancer cell lines: 22RV1, LAPC-4 and LNCaP. Upon two injections of the AR shRNA-loaded nanoparticles, rapid tumor regression was observed over 2 weeks. Consistent with previous reports, A10 aptamer conjugation significantly enhanced xenograft tumor regression compared with nonconjugated nanoparticles. These data demonstrated that tissue-specific delivery of AR shRNA using a biodegradable nanoparticle approach represents a novel therapy for life-threatening prostate cancers.