Micellear Gold Nanoparticles as Delivery Vehicles for Dual Tyrosine Kinase Inhibitor ZD6474 for Metastatic Breast Cancer Treatment

The therapeutic index of poorly water-soluble drugs is often hampered due to poor pharmatokinetics,reduced blood retention, and lack of effective drug, concentrations in the tumor region. In order to overcome these issues, drugs are often delivered by use of delivery vehicles :to provide an enhanced therapeutic index. Gold nanoparticles synthesized in micellar networks of amphiphilic block: copolymer (AuNM) provide an efficient nanocarriet for tissue- and site-specific :drug delivery owing to their low cytotoxicity and immunogenicity. AuNM is formed by exploiting the properties of both inorganic Au material and an amphiphilic polymer Of poly(ethylene glycol)-block-poly(propylene glycol)-blotk-poly(ethylene glycol) :(PEG-PPG PEG). We further functionalized AuNM with the FDA-approved dual tyrosine kinase inhibitor ZD6474 and studied the physicochemical properties of the conjugate ZD6474 AuNM. Both AuNM and ZD6474 AuNM, with a diameter of,similar to 40 nm, were very stable at physiological pH. Conversely, at an acidic pH of 5.2, a slow sustained-release profile of ZD6474 was evident from AuNM, which could provide a method of facilitating release of the drug in an acidic tumor environment. In vitro, in triple-negative breast cancer cells, ZD6474 AuNM inhibited tumor cell proliferation, migration, and invasion and induced apoptosis. There was no detectable lysis of red blood cells observed when they were treated with AuNM and ZD6474 AuNM, confirming hemocompatibility. To reinforce the possibility of AuNM serving as a delivery vehicle, AuNM was conjugated with the IR680 dye for tracking, and this conjugate was systemically delivered in female nude mice bearing MDA-MB-231 human breast cancer xenografts. Fluorescence signal was retained in the tumor' region, in a temporal manner as compared to other organs, indicating passive retention of AuNM in the tumor locale. MOreover, delivery of ZD6474 AuNM in nude mite bearing MDA-MB-231 xenografts led to decreased tumor size as compared to the control group. The promising safety, targeting, and therapeutic results of systemic delivery of ZD6474 by AuNM provide an attractive alternative method for treating patients with metastatic breast cancer.