Department of Biology, Georgia State University, Atlanta, GA 30303, United States.
J Control Release. 2011 Feb 10;149(3):314-22. doi: 10.1016/j.jconrel.2010.10.030. Epub 2010 Nov 1.
The tubulin-binding anticancer activity of noscapine, an orally available plant-derived anti-tussive alkaloid, has been recently identified. Noscapine inhibits tumor growth in nude mice bearing human xenografts of hematopoietic, breast, lung, ovarian, brain and prostate origin. Despite its nontoxic attributes, significant elimination of the disease has not been achieved, perhaps since the bioavailability of noscapine to tumors saturates at an oral dose of 300 mg/kg body weight. To enable the selective and specific delivery of noscapine to prostate cancer cells, we have engineered a multifunctional nanoscale delivery vehicle that takes advantage of urokinase plasminogen activator receptor (uPAR) overexpression in prostate cancer compared to normal prostate epithelia and can be tracked by magnetic resonance imaging (MRI) and near-infrared (NIR) imaging. Specifically, we employed the human-type 135 amino-acid amino-terminal fragment (hATF) of urokinase plasminogen activator (uPA), a high-affinity natural ligand for uPAR. Noscapine (Nos) was efficiently adsorbed onto the amphiphilic polymer coating of uPAR-targeted nanoparticles (NPs). Nos-loaded NPs were uniformly compact-sized, stable at physiological pH and efficiently released the drug at pH 4 to 5 within a span of 4h. Our results demonstrate that these uPAR-targeted NPs were capable of binding to the receptor and were internalized by PC-3 cells. uPAR-targeted Nos-loaded NPs enhanced intracellular noscapine accumulation as evident by the ~6-fold stronger inhibitory effect on PC-3 growth compared to free noscapine. In addition, Nos-loaded iron oxide NPs maintained their T2 MRI contrast effect upon internalization into tumor cells owing to their significant susceptibility effect in cells. Thus, our data provide compelling evidence that these optically and magnetic resonance imaging (MRI)-trackable uPAR-targeted NPs may offer a great potential for image-directed targeted delivery of noscapine for the management of prostate cancer.
纳布啡是一种口服植物衍生镇咳药，最近被发现具有结合微管的抗癌活性。纳布啡能抑制荷人源异体肿瘤的裸鼠的肿瘤生长，这些异种移植瘤源自造血系统、乳腺、肺、卵巢、脑和前列腺。尽管其毒性低，但并未显著消除疾病，这也许是因为纳布啡在 300mg/kg 体重的口服剂量下对肿瘤的生物利用度达到饱和。为了使纳布啡能够选择性和特异性地递送至前列腺癌细胞，我们设计了一种多功能纳米递药载体，该载体利用了与正常前列腺上皮相比，前列腺癌中尿激酶型纤溶酶原激活物受体（uPAR）的过度表达，并且可以通过磁共振成像（MRI）和近红外（NIR）成像进行追踪。具体来说，我们使用了尿激酶纤溶酶原激活物（uPA）的人源 135 个氨基酸氨基末端片段（hATF），它是 uPAR 的高亲和力天然配体。纳布啡（Nos）能有效地被吸附到靶向 uPAR 的纳米颗粒（NPs）的两亲聚合物涂层上。载有 Nos 的 NPs 粒径均匀且紧凑，在生理 pH 下稳定，在 4 小时内可在 pH 4 到 5 的范围内有效地释放药物。我们的结果表明，这些靶向 uPAR 的 NPs 能够与受体结合，并被 PC-3 细胞内化。与游离纳布啡相比，靶向 uPAR 的载有 Nos 的 NPs 增强了细胞内纳布啡的积累，从而对 PC-3 细胞的生长表现出约 6 倍更强的抑制作用。此外，载有 Nos 的氧化铁 NPs 在被内化到肿瘤细胞后仍保持其 T2 MRI 对比效应，这归因于它们在细胞中的显著磁化率效应。因此，我们的数据提供了有力的证据，表明这些光学和磁共振成像（MRI）可追踪的靶向 uPAR 的 NPs 可能为基于图像的纳布啡靶向递药提供巨大潜力，用于治疗前列腺癌。
