A cell delivery strategy was investigated that was hypothesized to enable magnetic targeting of endothelial cells to the steel surfaces of intraarterial stents because of the following mechanisms: (i) preloading cells with biodegradable polymeric superparamagnetic nanoparticles (MNPs), thereby rendering the cells magnetically responsive; and (ii) the induction of both magnetic field gradients around the wires of a steel stent and magnetic moments within MNPs because of a uniform external magnetic field, thereby targeting MNP-laden cells to the stent wires. In vitro studies demonstrated that MNP-loaded bovine aortic endothelial cells (BAECs) could be magnetically targeted to steel stent wires. In vivo MNP-loaded BAECs transduced with adenoviruses expressing luciferase (Luc) were targeted to stents deployed in rat carotid arteries in the presence of a uniform magnetic field with significantly greater Luc expression, detected by in vivo optical imaging, than nonmagnetic controls.cell therapy ͉ gene therapy ͉ local delivery ͉ nanotechnology C ell therapy represents a forefront approach with great promise. In particular, reendothelization of diseased or injured arteries is a goal of endothelial-related cell therapies (1, 2). However, there is a paucity of delivery strategies for localizing cell therapy to target sites (1, 2). The present studies report an approach for delivering endothelial cells to intravascular steel stents. Balloon-deployable stents are now the treatment of choice for vasoocclusive disease. Advanced stent designs with drug-eluting capabilities have resulted in a paradigm shift in the care of coronary disease (3-6). However, the lack of reendothelization (1, 2) after stent angioplasty remains an unsolved problem (3-6). Stents are commonly composed of steel alloys, such as the medical-grade stainless-steel 316L, which exhibits a minimal response to external magnetic fields. However, we hypothesized that by using a more magnetically responsive alloy, such as a 304-grade stainless steel, instead of 316L, it would be possible to locally deliver genetically modified endothelial cells to stent surfaces by using magnetic gradient-related mechanisms.Previous investigations of magnetically targeted cell-delivery systems, which have all exclusively used locally applied magnets, rather than uniform magnetic fields, have been hampered by a number of factors. These studies by others (7-9) have used nonbiodegradable magnetic nanoparticles that cannot be removed from the tissue after delivery. More fundamentally, these previous studies used magnetic field sources in a suboptimal manner. Thus, prior work has been limited to using a single source of magnetic field, in which either a locally applied permanent magnet (7,8) or a ferromagnetic medical implant (9) was used to implement the magnetic capture system. Such sources can be designed to increase the magnetizing field of cells loaded with magnetic nanoparticles or the field gradient, but not both, making it impossible to maximize the fraction of captured nanopar...

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The use of stents for vascular disease has resulted in a paradigm shift with significant improvement in therapeutic outcomes. Polymer-coated drug-eluting stents (DES) have also significantly reduced the incidence of reobstruction post stenting, a disorder termed in-stent restenosis. However, the current DESs lack the capacity for adjustment of the drug dose and release kinetics to the disease status of the treated vessel. We hypothesized that these limitations can be addressed by a strategy combining magnetic targeting via a uniform field-induced magnetization effect and a biocompatible magnetic nanoparticle (MNP) formulation designed for efficient entrapment and delivery of paclitaxel (PTX). Magnetic treatment of cultured arterial smooth muscle cells with PTX-loaded MNPs caused significant cell growth inhibition, which was not observed under nonmagnetic conditions. In agreement with the results of mathematical modeling, significantly higher localization rates of locally delivered MNPs to stented arteries were achieved with uniform-field-controlled targeting compared to nonmagnetic controls in the rat carotid stenting model. The arterial tissue levels of stent-targeted MNPs remained 4-to 10-fold higher in magnetically treated animals vs. control over 5 days post delivery. The enhanced retention of MNPs at target sites due to the uniform field-induced magnetization effect resulted in a significant inhibition of in-stent restenosis with a relatively low dose of MNP-encapsulated PTX (7.5 μg PTX/stent). Thus, this study demonstrates the feasibility of site-specific drug delivery to implanted magnetizable stents by uniform fieldcontrolled targeting of MNPs with efficacy for in-stent restenosis.angioplasty | biodegradable nanoparticles | magnetic targeting | restenosis | rat model

Remarkable progress has recently been made in the synthesis and characterization of engineered nanoparticles for imaging and treatment of cancers, resulting in several promising candidates in clinical trials. Despite these advances, clinical applications of nanoparticle-based therapeutic/imaging agents remain limited by biological, immunological, and translational barriers. In order to overcome the existing status quo in drug delivery, there is a need for open and frank discussion in the nanomedicine community on what is needed to make qualitative leaps toward translation. In this Nano Focus, we present the main discussion topics and conclusions from a recent workshop: “Mechanisms and Barriers in Nanomedicine”. The focus of this informal meeting was on biological, toxicological, immunological, and translational aspects of nanomedicine and approaches to move the field forward productively. We believe that these topics reflect the most important issues in cancer nanomedicine.