Anti-Tumor Activity of Drug-Loaded Magnetic Nanoparticles

Abstract

Superparamagnetic iron oxide nanoparticles (SPION), carrying a covalently linked chemotherapeutic agent, can be magnetically directed to concentrate at a tumor under the influence of external shaped/focused magnetic field gradients. Following extravasation, the pro-drug will be activated after cleavage of the bioreversible linker within the tumor microenvironment, thus both selectively enhancing drug delivery to tumor tissue and minimizing harm to normal tissue, thereby raising the therapeutic index compared with that of free drugs. Paclitaxel (TXL) was covalently linked to silica-coated MNPs (SiMNP) using bioreversible bonds and the activity of each conjugate was evaluated in orthotopic human breast adenocarcinoma xenograft nude mouse models. In initial in vitro evaluations, MDA-MB-468 triple-negative human breast adenocarcinoma cells were treated with SiMNP-TXL pro-drug and SiMNP control (silane linker only) formulations over a range of concentrations for up to five days before staining with MTT to determine tumor cell survival. The TXL-loaded SiMNP formulations demonstrated concentration-dependent cytotoxicity against these tumor cells. In vivo, xenografted breast tumors of mice given either of the control SiMNP-linker preparations grew steadily; however, the pro-drugs demonstrated the ability to delay or reverse tumor growth following a multiple-dosing regimen. A pilot toxicology study revealed transient hepatocellular necrosis following i.v. administration of the parental, SiMNP; however, no lesions were observed in mice given the PEG-SiMNPs loaded with TXL. We propose to further develop the lead MNP-TXL constructs for systemic administration followed by magnetic vectoring to tumors in preparation for planned clinical trials.