Magnetic nanoparticles for gene and drug delivery

Investigations of magnetic micro- and nanoparticles for targeted drug delivery began over 30 years ago. Since that time, major progress has been made in particle design and synthesis techniques, however, very few clinical trials have taken place. Here we review advances in magnetic nanoparticle design, in vitro and animal experiments with magnetic nanoparticle-based drug and gene delivery, and clinical trials of drug targeting

HGF-Induced PKCζ Activation Increases Functional CXCR4 Expression in Human Breast Cancer Cells

The chemokine receptor CXCR4 and its ligand CXCL12 have been shown to mediate the metastasis of many malignant tumors including breast carcinoma. Interaction between hepatocyte growth factor (HGF) and the Met receptor tyrosine kinase mediates development and progression of cancers. HGF is able to induce CXCR4 expression and contributes to tumor cell invasiveness in breast carcinoma. However, the mechanism of the CXCR4 expression modulated by c-Met-HGF axis to enhance the metastatic behavior of breast cancer cells is still unclear. In this study, we found that HGF induced functional CXCR4 receptor expression in breast cancer cells. The effect of HGF was specifically mediated by PKCζ activity. After transfection with PKCζ-siRNA, the phosphorylation of PKCζ and CXCR4 was abrogated in breast cancer cells. Interference with the activation of Rac1, a downstream target of HGF, prevented the HGF-induced increase in PKCζ activity and CXCR4 levels. The HGF-induced, LY294002-sensitive translocation of PKCζ from cytosol to plasma membrane indicated that HGF was capable of activating PKCζ, probably via phosphoinositide (PI) 3-kinases. HGF treatment also increased MT1-MMP secretion. Inhibition of PKCζ, Rac-1 and phosphatidylinositol 3-kinase may attenuate MT1-MMP expression in cells exposed to HGF. Functional manifestation of the effects of HGF revealed an increased ability for migration, chemotaxis and metastasis in MDA-MB-436 cells in vitro and in vivo. Our findings thus provided evidence that the process of HGF-induced functional CXCR4 expression may involve PI 3-kinase and atypical PKCζ. Moreover, HGF may promote the invasiveness and metastasis of breast tumor xenografts in BALB/c-nu mice via the PKCζ-mediated pathway, while suppression of PKCζ by RNA interference may abrogate cancer cell spreading

Illustration of the use of thiol linkers for binding biomolecules onto gold coated magnetic nanoparticles

<p><b>Copyright information:</b></p><p>Taken from "Magnetic nanoparticles for gene and drug delivery"</p><p></p><p>International Journal of Nanomedicine 2008;3(2):169-180.</p><p>Published online Jan 2008</p><p>PMCID:PMC2527670.</p><p>© 2008 Dove Medical Press Limited. All rights reserved</p

Novel magnetite-silica nanocomposite (Fe<SUB>3</SUB>O<SUB>4</SUB>-SBA-15) particles for DNA binding and gene delivery aided by a magnet array

Novel magnetite-silica nanocomposite particles were prepared using SBA-15 nanoporous silica as template. Magnetite nanoparticles were impregnated into the nanopore array of the silica template through thermal decomposition of iron(III) acetylacetonate, Fe(AcAc)(3) at 200 degrees C. These composite particles were characterized using TEM, XRD and SQUID magnetometry. The TEM images showed that the size of composite particles was around 500 nm and the particles retained the nanoporous array of SBA-15. The formation of magnetite nanoparticles was confirmed by the powder XRD study. These composite particles also exhibited ferrimagnetic properties. By coating with short chain polyethyleneimine (PEI), these particles are capable of binding DNA molecules for gene delivery and transfection. With an external magnetic field, the transfection efficiency was shown to have an increase of around 15%. The results indicated that these composite nanoparticles may be further developed as a new tool for nanomagnetic gene transfection

Factors determining the efficacy of distal excitatory synapses in rat hippocampal CA1 pyramidal neurones

A new preparation of the in vitro rat hippocampal slice has been developed in which the synaptic input to the distal apical dendrites of CA1 pyramidal neurones is isolated. This has been used to investigate the properties of distally evoked synaptic potentials.Distal paired-pulse stimulation (0.1 Hz) evoked a dendritic response consisting of a pair of EPSPs, which showed facilitation. The first EPSP had a rise time (10–90 %) of 2.2 ± 0.05 ms and a half-width of 9.1 ± 0.13 ms. The EPSPs were greatly reduced by CNQX (10 μm) and the remaining component could be enhanced in Mg2+-free Ringer solution and blocked by AP5 (50 μm). In 70 % of the dendrites, the EPSPs were followed by a prolonged after-hyperpolarizarion (AHP) which could be blocked by a selective and potent GABAB antagonist, CGP 55845A (2 μm). These results indicate that the EPSPs are primarily mediated by non-NMDA receptors with a small contribution from NMDA receptors, whereas the AHP is a GABAB receptor-mediated slow IPSP.With intrasomatic recordings, the rise time of proximally generated EPSPs (3.4 ± 0.1 ms) was half that of distally generated EPSPs (6.7 ± 0.5 ms), whereas the half-widths were similar (19.6 ± 0.8 ms and 23.8 ± 1 ms, respectively). These results indicate that propagation through the proximal apical dendrites slows the time-to-peak of distally generated EPSPs.Distal stimulation evoked spikes in 60 % of pyramidal neurones. At threshold, the distally evoked spike always appeared on the decaying phase of the dendritic EPSP, indicating that the spike is initiated at some distance proximal to the dendritic recording site. Furthermore, distally and proximally generated threshold spikes had a similar voltage dependency. These results therefore suggest that distally generated threshold spikes are primarily initiated at the initial segment.At threshold, spikes generated by stimulation of distal synapses arose from the decaying phase of the dendritic EPSPs with a latency determined by the time course of the EPSP at the spike initiation zone. With maximal stimulation, however, the spikes arose directly from the peak of the EPSPs with a time-to-spike similar to the time-to-peak of subthreshold dendritic EPSPs. Functionally, this means that the effect of dendritic propagation can be overcome by recruiting more synapses, thereby ensuring a faster response time to distal synaptic inputs.In 42 % of the neurones in which distal EPSPs evoked spikes, the relationship between EPSP amplitude and spike latency could be accounted for by a constant dendritic modulation of the EPSP. In the remaining 58 %, the change in latency was greater than can be accounted for by a constant dendritic influence. This additional change in latency is best explained by a sudden shift in the spike initiation zone to the proximal dendrites. This would explain the delay observed between the action of somatic application of TTX (10 μm) on antidromically evoked spikes and distally evoked suprathreshold spikes.The present results indicate that full compensation for the electrotonic properties of the main proximal dendrites is not achieved despite the presence of Na+ and Ca2+ currents. Nevertheless, distal excitatory synapses are capable of initiating spiking in most pyramidal neurones, and changes in EPSP amplitude can modulate the spike latency. Furthermore, even though the primary spike initiation zone is in the initial segment, the results suggest that it can move into the proximal apical dendrites under physiological conditions, which has the effect of further shortening the response time to distal excitatory synaptic inputs