High field gradient targeting of magnetic nanoparticle-loaded endothelial cells to the surfaces of steel stents

Abstract

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...

Real-time analysis of composite magnetic nanoparticle disassembly in vascular cells and biomimetic media

“…At the same time, it may be predicted that local delivery of antirestenotic drugs inhibiting the proliferation of the neointimal cells can reverse the accelerated MNP processing and slow the degradation of the cell-associated MNP fraction. Similar predictions may be made regarding the fate of MNPs used to generate magnetically responsive endothelial cells for targeted delivery and enhanced reendothelialization of injured arteries (15,17). MNPs loaded into magnetically guided cells may exhibit faster disassembly at earlier time points, but their processing likely will occur at a slower rate when the cells reach the contact-inhibited state.…”

“…Thus, although our experiments did not reveal a significant delay in the onset of MNP disintegration, a detectable lag may be anticipated for NPs formed from a polymer with a larger initial molecular weight or a higher degree of crystallinity (6,8). Composite PLA-based magnetic particles were chosen as a model biodegradable NP formulation for evaluation in the present studies because of their rapid and quantitative, magnetically controlled cell uptake (17), facilitating and synchronizing measurements of the internalized MNP disassembly in cultured cells, and also because of their direct relevance to magnetically targeted cell and drug delivery to sites of arterial injury, which is the therapeutic focus of our recent research (14,15,17). Particle-forming polymer was monitored in our experiments as the primary component determining structural integrity of the particles.…”

“…Biodegradable composite MNPs applied in combination with a recently reported two-source magnetic guidance strategy have shown promise as carriers for targeting cells, genes, and small molecule therapeutics to sites of vascular injury (13)(14)(15). Although the properties of MNPs optimized for sitespecific delivery of these different classes of therapeutics vary significantly, the capacity for disintegration into bioeliminable products when the task of guiding the cargo to its site of action is completed is a common prerequisite in the design of these Significance Disassembly rates and patterns of nanoparticles used as drug carriers or diagnostic tools are important determinants of their performance and biocompatibility.…”

Cell Labeling and Targeting with Superparamagnetic Iron Oxide Nanoparticles

“…In both cases, magnetic fields are used to capture cells to the surface of the device and retain the cells when subjected to the shear stress generated by circulating blood. Magnetic vascular stents [24][25][26][27] and vascular grafts 28 have both been fabricated and tested for this purpose.…”

Nanomedicine’s promising therapy: magnetic drug targeting

“…• Re-endothelization of the artery wall by targeting endothelial cells loaded with magnetic nanoparticles to stented rat carotid arteries [22];…”