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Enhanced noscapine delivery using uPAR-targeted optical-MR imaging trackable nanoparticles for prostate cancer
Mohamed O Abdalla1, Prasanthi Karna, Hari Krishna Sajja
1Department of Biology, Georgia State University, Atlanta, GA 30303, United States.
Abstract:
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.
Insights
Engineered nanoparticles deliver the anticancer drug noscapine specifically to prostate cancer cells, enhancing its tumor-inhibiting effects and enabling tracking via MRI and near-infrared imaging.
Area of Science:
- Nanotechnology
- Oncology
- Pharmacology
Background:
- Noscapine, a plant-derived alkaloid, exhibits tubulin-binding anticancer activity but faces bioavailability limitations.
- Prostate cancer overexpresses the urokinase plasminogen activator receptor (uPAR), presenting a target for drug delivery.
Purpose of the Study:
- To develop a targeted nanoparticle system for selective noscapine delivery to prostate cancer cells.
- To enable image-guided tracking of noscapine delivery using MRI and NIR imaging.
Main Methods:
- Engineered nanoparticles coated with a uPAR-targeting ligand (hATF of uPA) were loaded with noscapine.
- Nanoparticle characterization included size, stability, and drug release profiles at different pH.
- In vitro studies assessed nanoparticle binding, internalization by PC-3 prostate cancer cells, and anti-proliferative effects.
Main Results:
- Noscapine-loaded nanoparticles demonstrated efficient uPAR targeting and internalization by PC-3 cells.
- Targeted nanoparticles significantly enhanced intracellular noscapine accumulation, resulting in a ~6-fold greater inhibition of PC-3 cell growth compared to free noscapine.
- Iron oxide-containing nanoparticles retained MRI contrast properties after cellular uptake.
Conclusions:
- uPAR-targeted nanoparticles offer a promising platform for image-directed, enhanced delivery of noscapine in prostate cancer treatment.
- The developed system allows for simultaneous therapeutic delivery and real-time monitoring of drug distribution.
