Enhanced in vivo antitumor efficacy of dual-functional peptide-modified docetaxel nanoparticles through tumor targeting and Hsp90 inhibition
Enhanced in vivo antitumor efficacy of dual-functional peptide-modified docetaxel nanoparticles through tumor targeting and Hsp90 inhibition
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DOI：
10.1016/j.jconrel.2015.11.029
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发表时间：
2016-01-10
影响因子：
10.8
通讯作者：
Zuo, Pingping
中科院分区：
文献类型：
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作者：
Jiang, Yao;Yang, Nan;Zuo, Pingping
虽然传统的抗癌药物表现出优异的疗效，但由于其非选择性，已经发生了严重的不良反应和/或甚至毒性。此外，主动选择目标的办法并不总是取得成功的结果。同时具有靶向能力并对细胞内信号传导级联产生强烈影响的配体可预期改善主动靶向纳米颗粒载体的治疗功效。在本研究中，我们筛选了一个靶向肽，LPLTPLP，其特异性结合非小细胞肺癌（NSCLC）标本在体外。令人惊讶的是，这种肽抑制Hsp 90的表达，并通过阻止多西他赛处理的A549细胞中的自噬诱导细胞凋亡。结果表明，该肽有可能作为一种具有双重功能的配体用于肿瘤治疗。基于这些发现，我们设计并开发了一种新型的主动靶向给药系统，通过修饰多西他赛纳米粒（DNP）与双功能配体LPLTPLP。我们一致地证明了纳米颗粒（NPs）的细胞摄取在体外显著增强。此外，与非靶向纳米药物和游离多西他赛相比，靶向纳米颗粒表现出显著改善的抗肿瘤疗效和生物分布。这些发现证明了双功能纳米颗粒用于有效抗癌治疗的可行性。(C)2015爱思唯尔B. V.保留所有权利。
Although conventional anticancer drugs exhibit excellent efficacy, serious adverse effects and/or even toxicity have occurred due to their nonselectivity. Moreover, active targeting approaches have not consistently led to successful outcomes. Ligands that simultaneously possess targeting capability and exert a strong influence on intracellular signaling cascades may be expected to improve the therapeutic efficacy of active targeting nanoparticulate carriers. In this study, we screened a targeting peptide, LPLTPLP, which specifically bound to non-small cell lung cancer (NSCLC) specimens in vitro. Surprisingly, this peptide inhibited the expression of Hsp90 and induced apoptosis by preventing autophagy in A549 cells treated with docetaxel. The results suggested that this peptide might be used as a promising dual-functional ligand for cancer treatment. Based on these findings, we designed and developed a novel active targeting delivery system by modifying docetaxel nanoparticles (DNP) with the dual-functional ligand LPLTPLP. We consistently demonstrated that the cellular uptake of nanoparticles (NPs) was significantly enhanced in vitro. Furthermore, the targeting NPs exhibited significantly improved antitumor efficacy and biodistribution compared with nontargeting nanodrug and free docetaxel. These findings demonstrate the feasibility of dual-functional NPs for efficient anticancer therapy. (C) 2015 Elsevier B.V. All rights reserved.