Nanopartide-aptamer bioconjugates: A new approach for targeting prostate cancer cells
Nanopartide-aptamer bioconjugates: A new approach for targeting prostate cancer cells
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DOI：
10.1158/0008-5472.can-04-2550
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发表时间：
2004-11-01
期刊：
影响因子：
11.2
通讯作者：
Langer, R
中科院分区：
文献类型：
--
作者：
Farokhzad, OC;Jon, SY;Langer, R
核酸配体（适体）可能非常适合以细胞或组织特异性的方式对包封药物的控释聚合物颗粒进行治疗靶向。我们合成了一种由控释聚合物纳米颗粒和适体组成的生物共轭物，并检测了其对前列腺癌细胞靶向递送的功效。具体而言，我们合成了带有末端羧酸官能团的聚乳酸 - 嵌段 - 聚乙二醇（PEG）共聚物（PLA - PEG - COOH），并将罗丹明标记的葡聚糖（作为模型药物）包封在PLA - PEG - COOH纳米颗粒内。这些纳米颗粒具有以下理想特性：（a）负表面电荷（-50 ± 3 mV，平均值±标准差，n = 3），这可能会使与带负电荷的核酸适体的非特异性相互作用最小化；（b）颗粒表面的羧酸基团可用于潜在的修饰以及与胺修饰的适体共价结合；（c）颗粒表面存在PEG，这可提高循环半衰期，同时有助于减少非靶向细胞的摄取。接下来，我们利用与前列腺特异性膜抗原结合的RNA适体生成了纳米颗粒 - 适体生物共轭物，前列腺特异性膜抗原是一种众所周知的前列腺癌肿瘤标志物，在前列腺腺泡上皮细胞中过度表达。我们证明这些生物共轭物能够有效地靶向并被前列腺LNCaP上皮细胞摄取，这些细胞表达前列腺特异性膜抗原蛋白（与对照组相比，结合增加77倍，每组n = 150个细胞）。与LNCaP细胞相反，在不表达前列腺特异性膜抗原蛋白的细胞中，这些颗粒的摄取没有增强。据我们所知，这是关于纳米颗粒 - 适体生物共轭物靶向药物递送的首次报道。
Nucleic acid ligands (aptamers) are potentially well suited for the therapeutic targeting of drug encapsulated controlled release polymer particles in a cell- or tissue-specific manner. We synthesized a bioconjugate composed of controlled release polymer nanoparticles and aptamers and examined its efficacy for targeted delivery to prostate cancer cells. Specifically, we synthesized poly(lactic acid)-block-polyethylene glycol (PEG) copolymer with a terminal carboxylic acid functional group (PLA-PEG-COOH), and encapsulated rhodamine-labeled dextran (as a model drug) within PLA-PEG-COOH nanoparticles. These nanoparticles have the following desirable characteristics: (a) negative surface charge (-50 +/- 3 mV, mean +/- SD, n = 3), which may minimize nonspecific interaction with the negatively charged nucleic acid aptamers; (b) carboxylic acid groups on the particle surface for potential modification and covalent conjugation to amine-modified aptamers; and (c) presence of PEG on particle surface, which enhances circulating half-life while contributing to decreased uptake in nontargeted cells. Next, we generated nanoparticle-aptamer bioconjugates with RNA aptamers that bind to the prostate-specific membrane antigen, a well-known prostate cancer tumor marker that is overexpressed on prostate acinar epithelial cells. We demonstrated that these bioconjugates can efficiently target and get taken up by the prostate LNCaP epithelial cells, which express the prostate-specific membrane antigen protein (77-fold increase in binding versus control, n = 150 cells per group). In contrast to LNCaP cells, the uptake of these particles is not enhanced in cells that do not express the prostate-specific membrane antigen protein. To our knowledge, this represents the first report of targeted drug delivery with nanoparticle-aptamer bioconjugates.