Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo
Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo
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DOI：
10.1073/pnas.0601755103
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发表时间：
2006-04-18
影响因子：
11.1
通讯作者：
Langer, R
中科院分区：
文献类型：
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作者：
Farokhzad, OC;Cheng, JJ;Langer, R
以细胞、组织或疾病特异性方式靶向摄取治疗性纳米颗粒代表了一种潜在的强大技术。以前列腺癌为模型，我们报告了多西他赛（Dtxl）包裹纳米粒，（D，L-乳酸-羟基乙酸共聚物）-嵌段-聚（乙二醇）（PLGA-b-PEG）共聚物和用识别前列腺特异性膜抗原（PSMA）的细胞外结构域的A10 2 ′-氟嘧啶RNA适体官能化的表面，一种在前列腺癌细胞表面表达的充分表征的抗原。这些Dtxl包封的纳米颗粒-适体生物缀合物（Dtxl-NP-Apt）与LNCaP前列腺上皮细胞表面上表达的PSMA蛋白结合，并被这些细胞摄取，导致与缺乏PSMA适体的非靶向纳米颗粒（Dtxl-NP）相比，体外细胞毒性显著增强（P < 0.0004）。Dtxl-NP-Apt生物缀合物还表现出显著的功效和降低的毒性，如通过体内平均体重减轻（BWL）所测量的[Dtxl-NP-Apt相对于Dtxl-NP在最低点的体重减轻分别为7.7 +/-4%对18 +/-5%（平均值+/- SD）; n = 7]。在单次瘤内注射Dtxl-NP-Apt生物缀合物后，在七只LNCaP异种移植裸鼠中的五只中观察到完全肿瘤减小（初始肿瘤体积约为300 mm 3（3）），并且这些动物中的100%在我们的109天研究中存活。相比之下，Dtxl-NP组中七只小鼠中的两只具有完全的肿瘤减少，109天存活率仅为57%。单独使用Dtxl的存活率仅为14%。盐水和无药物的纳米颗粒同样无效。本报告证明了纳米粒子-适体生物缀合物用于治疗应用的潜在效用。
Targeted uptake of therapeutic nanoparticles in a cell-, tissue-, or disease-specific manner represents a potentially powerful technology. Using prostate cancer as a model, we report docetaxel (Dtxl)-encapsulated nanoparticles formulated with biocompatible and biodegradable poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2'-fluoropyrimidine RNA aptamers that recognize the extracellular domain of the prostate-specific membrane antigen (PSMA), a well characterized antigen expressed on the surface of prostate cancer cells. These Dtxl-encapsulated nanoparticle-aptamer bioconjugates (Dtxl-NP-Apt) bind to the PSMA protein expressed on the surface of LNCaP prostate epithelial cells and get taken up by these cells resulting in significantly enhanced in vitro cellular toxicity as compared with nontargeted nanoparticles that lack the PSMA aptamer (Dtxl-NP) (P < 0.0004). The Dtxl-NP-Apt bioconjugates also exhibit remarkable efficacy and reduced toxicity as measured by mean body weight loss (BWL) in vivo [body weight loss of 7.7 +/- 4% vs. 18 +/- 5% for Dtxl-NP-Apt vs. Dtxl-NP at nadir, respectively (mean +/- SD); n = 7]. After a single intratumoral injection of Dtxl-NP-Apt bioconjugates, complete tumor reduction was observed in five of seven LNCaP xenograft nude mice (initial tumor volume of approximate to 300 mm(3)), and 100% of these animals survived our 109-day study. In contrast, two of seven mice in the Dtxl-NP group had complete tumor reduction with 109-day survivability of only 57%. Dtxl alone had a survivability of only 14%. Saline and nanoparticles without drug were similarly nonefficacious. This report demonstrates the potential utility of nanoparticle-aptamer bioconjugates for a therapeutic application.