Enhanced noscapine delivery using uPAR-targeted optical-MR imaging trackable nanoparticles for prostate cancer therapy

JOURNAL OF CONTROLLED RELEASE

卷:149

Article

Abdalla, Mohamed O.^1,2,3  Karna, Prasanthi¹  Sajja, Hari Krishna¹  Mao, Hui⁴  Yates, Clayton^2,3  Turner, Timothy^2,3  Aneja, Ritu¹ 

[1] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA

[2] Dept Biol, Tuskegee, AL 36088 USA

[3] Ctr Canc Res, Tuskegee, AL 36088 USA

[4] Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA

关键词: Prostate;    Noscapine;    Nanoparticles;    uPAR;    MRI;   

DOI  :  10.1016/j.jconrel.2010.10.030

来源: Elsevier

【 摘 要 】

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 4 h. 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 similar to 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. (C) 2010 Elsevier B.V. All rights reserved.

【 授权许可】

Free