Charles E. Seeney

Magnetic nanovectors for drug delivery.

Nanotechnology holds the promise of novel and more effective treatments for vexing human health issues. Among these are the use of nanoparticle platforms for site-specific delivery of therapeutics to tumors, both by passive and active mechanisms; the latter includes magnetic vectoring of magnetically responsive nanoparticles (MNP) that are functionalized to carry a drug payload that is released at the tumor. The conceptual basis, which actually dates back a number of decades, resides in physical (magnetic) enhancement, with magnetic field gradients aligned non-parallel to the direction of flow in the tumor vasculature, of existing passive mechanisms for extravasation and accumulation of MNP in the tumor interstitial fluid, followed by MNP internalization. In this review, we will assess the most recent developments and current status of this approach, considering MNP that are composed of one or more of the three elements that are ferromagnetic at physiological temperature: nickel, cobalt and iron. The effects on cellular functions in vitro, the ability to successfully vector the platform in vivo, the anti-tumor effects of such localized nano-vectors, and any associated toxicities for these MNP will be presented. The merits and shortcomings of nanomaterials made of each of the three elements will be highlighted, and a roadmap for moving this long-established approach forward to clinical evaluation will be put forth.

Magnetic nanovectors for drug delivery

Nanotechnology holds the promise of novel and more effective treatments for vexing human health issues. Among these are the use of nanoparticle platforms for site-specific delivery of therapeutics to tumors, both by passive and active mechanisms; the latter includes magnetic vectoring of magnetically responsive nanoparticles (MNP) that are functionalized to carry a drug payload that is released at the tumor. The conceptual basis, which actually dates back a number of decades, resides in physical (magnetic) enhancement, with magnetic field gradients aligned non-parallel to the direction of flow in the tumor vasculature, of existing passive mechanisms for extravasation and accumulation of MNP in the tumor interstitial fluid, followed by MNP internalization. In this review, we will assess the most recent developments and current status of this approach, considering MNP that are composed of one or more of the three elements that are ferromagnetic at physiological temperature: nickel, cobalt and iron. The effects on cellular functions in vitro, the ability to successfully vector the platform in vivo, the anti-tumor effects of such localized nano-vectors, and any associated toxicities for these MNP will be presented. The merits and shortcomings of nanomaterials made of each of the three elements will be highlighted, and a roadmap for moving this long-established approach forward to clinical evaluation will be put forth.

Magnetically-responsive nanoparticles for vectored delivery of cancer therapeutics

We propose that physical targeting of therapeutics to tumors using magnetically‐responsive nanoparticles (MNPs) will enhance intratumoral drug levels compared to free drugs in an effort to overcome tumor resistance. We evaluated the feasibility of magnetic enhancement of tumor extravasation of systemically‐administered MNPs in human xenografts implanted in the mammary fatpads of nude mice. Mice with orthotopic tumors were injected systemically with MNPs, with a focused magnetic field juxtaposed over the tumor. Magnetic resonance imaging and scanning electron microscopy both indicated successful tumor localization of MNPs. Next, MNPs were modified with poly‐ethylene‐glycol (PEG) and their clearance compared by estimating signal attenuation in liver due to iron accumulation. The results suggested that PEG substitution could retard the rate of MNP plasma clearance, which may allow greater magnetically‐enhanced tumor localization. We propose that this technology is clinically scalable to many types of both superficial as well as some viscerable tumors with existing magnetic technology.

Method and apparatus for improving hearing

A system and method for affecting the function of a mammalian ear. The system and method uses an oscillating magnetic field to move nanospheres comprised of single-domain nanoparticles. In a preferred embodiment a receiving assembly detects sound waves and transmits the sound waves to a processor. The processor drives an electromagnetic coil in response to the detected sound waves. The electromagnetic coil transmits a signal that causes vibration of the nanoparticles and the tissues within which the nanoparticles are implanted.

Anti-Tumor Activity of Drug-Loaded Magnetic Nanoparticles

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.