Implant-based direction of magnetic nanoporous silica nanoparticles - influence of macrophage depletion and infection.

Implant associated infections are still key problem in surgery. In the present study, the combination of a magnetic implant with administered magnetic nanoporous silica nanoparticles as potential drug carriers was examined in mice in dependence of local infection and macrophages as influencing factors. Four groups of mice (with and without implant infection and with and without macrophage depletion) received a magnet on the left and a titanium control on the right hind leg. Then, fluorescent nanoparticles were administered and particle accumulations at implant surfaces and in inner organs as well as local tissue reactions were analyzed. Magnetic nanoparticles could be found at the surfaces of magnetic implants in different amounts depending on the treatment groups and only rarely at titanium surfaces. Different interactions of magnetic implants, particles, infection and surrounding tissues occurred. The general principle of targeted accumulation of magnetic nanoparticles could be proven.

Biodistribution, biocompatibility and targeted accumulation of magnetic nanoporous silica nanoparticles as drug carrier in orthopedics.

BACKGROUND: In orthopedics, the treatment of implant-associated infections represents a high challenge. Especially, potent antibacterial effects at implant surfaces can only be achieved by the use of high doses of antibiotics, and still often fail. Drug-loaded magnetic nanoparticles are very promising for local selective therapy, enabling lower systemic antibiotic doses and reducing adverse side effects. The idea of the following study was the local accumulation of such nanoparticles by an externally applied magnetic field combined with a magnetizable implant. The examination of the biodistribution of the nanoparticles, their effective accumulation at the implant and possible adverse side effects were the focus. In a BALB/c mouse model (n = 50) ferritic steel 1.4521 and Ti90Al6V4 (control) implants were inserted subcutaneously at the hindlimbs. Afterwards, magnetic nanoporous silica nanoparticles (MNPSNPs), modified with rhodamine B isothiocyanate and polyethylene glycol-silane (PEG), were administered intravenously. Directly/1/7/21/42 day(s) after subsequent application of a magnetic field gradient produced by an electromagnet, the nanoparticle biodistribution was evaluated by smear samples, histology and multiphoton microscopy of organs. Additionally, a pathohistological examination was performed. Accumulation on and around implants was evaluated by droplet samples and histology. RESULTS: Clinical and histological examinations showed no MNPSNP-associated changes in mice at all investigated time points. Although PEGylated, MNPSNPs were mainly trapped in lung, liver, and spleen. Over time, they showed two distributional patterns: early significant drops in blood, lung, and kidney and slow decreases in liver and spleen. The accumulation of MNPSNPs on the magnetizable implant and in its area was very low with no significant differences towards the control. CONCLUSION: Despite massive nanoparticle capture by the mononuclear phagocyte system, no significant pathomorphological alterations were found in affected organs. This shows good biocompatibility of MNPSNPs after intravenous administration. The organ uptake led to insufficient availability of MNPSNPs in the implant region. For that reason, among others, the nanoparticles did not achieve targeted accumulation in the desired way, manifesting future research need. However, with different conditions and dimensions in humans and further modifications of the nanoparticles, this principle should enable reaching magnetizable implant surfaces at any time in any body region for a therapeutic reason.

Nanoporous hybrid core-shell nanoparticles for sequential release.

In this article, a new type of core-shell nanoparticle is introduced. In contrast to most reported core-shell systems, the particles presented here consist of a porous core as well as a porous shell using only non-metal materials. The core-shell nanoparticles were successfully synthesized using nanoporous silica nanoparticles (NPSNPs) as the starting material, which were coated with nanoporous phenylene-bridged organosilica, resulting in a total particle diameter of about 80 nm. The combination of a hydrophilic nanoporous silica core and a more hydrophobic nanoporous organosilica shell provides regions of different chemical character and slightly different pore sizes within one particle. These different properties combined in one particle enable the selective adsorption of guest molecules at different parts of the particle depending on the molecular charge and polarity. On the other hand, the core-shell make-up of the particles provides a sequential release of guest molecules adsorbed at different parts of the nanoparticles. As a proof of concept, loading and release experiments with dyes were performed using non polar fluorescein and polar and charged methylene blue as model guest molecules. Non polar fluorescein is mostly adsorbed on the hydrophobic organosilica shell and therefore quickly released whereas the polar methylene blue, accumulated in the hydrophilic silica core, is only released subsequently. This occurs in small doses for an extended time corresponding to a sustained release over at least one year, controlled by the organosilica shell which acts as a diffusion barrier. An initial experiment with two drugs - non polar ibuprofen and polar and charged procaine hydrochloride - has been carried out as well and shows that the core-shell nanoparticles presented here can also be used for the sequential release of more relevant combinations of molecules.

A Low-Temperature Approach for the Phase-Pure Synthesis of MIL-140 Structured Metal-Organic Frameworks.

In a systematic investigation, the synthesis of metal-organic frameworks (MOFs) with MIL-140 structure was studied. The precursors of this family of MOFs are the same as for the formation of the well-known UiO-type MOFs although the synthesis temperature for MIL-140 is significantly higher. This study is focused on the formation of Zr-based MIL-140 MOFs with terephthalic acid (H2 bdc), biphenyl-4,4'-dicarboxylic acid (H2 bpdc), and 4,4'-stilbenedicarboxylic acid (H2 sdc) and the introduction of synthesis field diagrams to discover parameters for phase-pure products. In this context, a MIL-140 network with H2 sdc as linker molecule is first reported. Additionally, an important aspect is the reduction of the synthesis temperature to make MIL-140 MOFs more accessible even though linkers with a more delicate nature are used. The solvothermal syntheses were conducted in highly concentrated reaction mixtures whereby a targeted synthesis to yield the MIL-140 phase is possible. Furthermore, the effect of the often-used modulator approach is examined for these systems. Finally, the characteristics of the synthesized MOFs are compared with physisorption measurements, thermogravimetric analyses, and scanning electron microscopy.

Macrophage entrapped silica coated superparamagnetic iron oxide particles for controlled drug release in a 3D cancer model.

Targeted delivery of drugs is a major challenge in treatment of diverse diseases. Systemically administered drugs demand high doses and are accompanied by poor selectivity and side effects on non-target cells. Here, we introduce a new principle for targeted drug delivery. It is based on macrophages as transporters for nanoparticle-coupled drugs as well as controlled release of drugs by hyperthermia mediated disruption of the cargo cells and simultaneous deliberation of nanoparticle-linked drugs. Hyperthermia is induced by an alternating electromagnetic field (AMF) that induces heat from silica-coated superparamagnetic iron oxide nanoparticles (SPIONs). We show proof-of-principle of controlled release by the simultaneous disruption of the cargo cells and the controlled, AMF induced release of a toxin, which was covalently linked to silica-coated SPIONs via a thermo-sensitive linker. Cells that had not been loaded with SPIONs remain unaffected. Moreover, in a 3D co-culture model we demonstrate specific killing of associated tumour cells when employing a ratio as low as 1:40 (SPION-loaded macrophage: tumour cells). Overall, our results demonstrate that AMF induced drug release from macrophage-entrapped nanoparticles is tightly controlled and may be an attractive novel strategy for targeted drug release.

In vitro and in vivo accumulation of magnetic nanoporous silica nanoparticles on implant materials with different magnetic properties.

BACKGROUND: In orthopedic surgery, implant-associated infections are still a major problem. For the improvement of the selective therapy in the infection area, magnetic nanoparticles as drug carriers are promising when used in combination with magnetizable implants and an externally applied magnetic field. These implants principally increase the strength of the magnetic field resulting in an enhanced accumulation of the drug loaded particles in the target area and therewith a reduction of the needed amount and the risk of undesirable side effects. In the present study magnetic nanoporous silica core-shell nanoparticles, modified with fluorophores (fluorescein isothiocyanate/FITC or rhodamine B isothiocyanate/RITC) and poly(ethylene glycol) (PEG), were used in combination with metallic plates of different magnetic properties and with a magnetic field. In vitro and in vivo experiments were performed to investigate particle accumulation and retention and their biocompatibility. RESULTS: Spherical magnetic silica core-shell nanoparticles with reproducible superparamagnetic behavior and high porosity were synthesized. Based on in vitro proliferation and viability tests the modification with organic fluorophores and PEG led to highly biocompatible fluorescent particles, and good dispersibility. In a circular tube system martensitic steel 1.4112 showed superior accumulation and retention of the magnetic particles in comparison to ferritic steel 1.4521 and a Ti90Al6V4 control. In vivo tests in a mouse model where the nanoparticles were injected subcutaneously showed the good biocompatibility of the magnetic silica nanoparticles and their accumulation on the surface of a metallic plate, which had been implanted before, and in the surrounding tissue. CONCLUSION: With their superparamagnetic properties and their high porosity, multifunctional magnetic nanoporous silica nanoparticles are ideal candidates as drug carriers. In combination with their good biocompatibility in vitro, they have ideal properties for an implant directed magnetic drug targeting. Missing adverse clinical and histological effects proved the good biocompatibility in vivo. Accumulation and retention of the nanoparticles could be influenced by the magnetic properties of the implanted plates; a remanent martensitic steel plate significantly improved both values in vitro. Therefore, the use of magnetizable implant materials in combination with the magnetic nanoparticles has promising potential for the selective treatment of implant-associated infections.