Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Particulate matter
Reexamination Certificate
2002-05-24
2004-07-27
Kiliman, Leszek (Department: 1773)
Stock material or miscellaneous articles
Coated or structually defined flake, particle, cell, strand,...
Particulate matter
C428S403000, C428S402240, C428S407000, C428S690000, C436S524000, C436S525000, C436S526000, C436S527000, C435S006120, C435S007500, C435S007210
Reexamination Certificate
active
06767635
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to magnetic nanoparticles, their production, and their use.
The most frequent causes of death include cancers. In particular, more and more people die from lung, breast and prostate cancers. Presently, the primary objectives of medicine therefore include the control of cancers.
In addition to operative removal of affected organs, conventional methods of treatment for controlling metastasizing tumors include chemotherapy with its well-known pattern of side effects, because these medications also do damage to healthy cells as a result of their non-specific effects, namely, in susceptible regions throughout the body.
Inter alia, new approaches of therapy utilize immune reactions in such a way that, on the one hand, endogenous resistance is activated by messenger substances or cytokines and, on the other hand, protein molecules and/or monoclonal antibodies destroy the tumor cells.
New developments in the field of tumor cell separation already use particles including a magnetic core, which particles are modified with biologically active envelope substances. So-called “drug targeting” using substances such as doxorubicin or other cytostatic agents coupled to magnetic microspheres is in development. “Microbeads” and “dynabeads”, also well-known, are already being used in diagnostic methods wherein magnetic micro-spheres are adsorbed on the cell membrane of malignant cells by biological interaction and subsequently subjected to magnetic separation. In general, the surface structure of cell membranes is non-specific and therefore, however, the separation rates are less than 80%. As a consequence, there is a risk in that many cancer cells will not undergo separation, maintaining their ability of forming metastases.
Separation for diagnostic purposes is invariably performed on the extracorporeal route, i.e., the fluid including the cells to be separated is treated in a suitable vessel outside the human body. Following separation, the purified liquid can be re-supplied into the human body.
Due to incomplete separation of malignant cells, it must be expected that this procedure has to be repeated after some time. This procedure does severe stress to persons who are sick anyway, so that repeated treatment is possible to only a limited extent.
DE 41 16 093 A1 describes a method of obtaining magnetic carriers by controlled modification of the surface of magnetic particles. According to this method, magnetic particles are described which can also form magnetic fluids, and which are characterized in that they carry heteropolyanions and saturated or unsaturated surface-active agents. Such surface modification is intended to permit binding of biologically active molecules such as antibodies, among others, to the surface of the particles. The biologically active molecules are bound to polythiols via thio bridges. Inter alia, dicar-boxylic acids and hydroxycarboxylic acids, as well as dimer-captosuccinic acid are used as linker substances. Owing to an iron-chelating group, these compounds are capable of binding to the magnetic particle.
Having insufficient biocompatibility, these magnetic particles including biologically active molecules on their surface were found unsuitable for the purpose of permeating into intracellular compartments to couple with biomacromolecules therein.
DE 196 24 426 A1 describes magnetic fluids used to transport diagnostically or therapeutically active substances. The magnetic core particles are enveloped with polymers having reactive groups capable of covalent binding or ion exchange. On this envelope, which indeed is biocompatible and may consist of dextran, among other things, new or additional functional groups can be attached or activated, e.g. succinic anhydride or chloroacetic acid, to which diagnostically or therapeutically active substances then can be fixed either via a heteropolar or a covalent bond. The pharmaceutical agent bound to the magnet particle in the way as described should be administrable on the intravenous route and is to be fixed by means of a high-gradient magnetic field within the region of a target area such as a tumor or an inflammatory tissue region to develop its diagnostic and therapeutic effects therein. To enable such transport in a magnetic field, high intravascular availability of the magnet particles is required, the particle size of which being specified as 200-500 nm. In this case as well, the particles are incapable of permeating into intracellular compartments due to the mere size of the particles. Moreover, specific binding to intracellular biomacromolecules is not feasible with these particles.
SUMMARY OF THE INVENTION
The object of the invention is to provide nanoparticles capable of specifically forming bonds to intracellular biomacromolecules even in the intracellular region of cells, so that separation is possible by exposure to an exterior magnetic field.
According to the invention, said object is accomplished with the characterizing sections of claims 1, 9, 13, 17, 18, 19, 21, and 23 to 25.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Advantageously, the magnetic nanoparticles of the invention are capable of permeating through cell membranes and into intracellular compartments to interact with intracellular biomacromolecules therein.
The magnetic nanoparticles consist of a ferri- or ferromagnetic material and have biologically active and/or therapeutically effective envelope layers. On the one hand, they are able to permeate the cell membrane of cells and, on the other hand, to attach with high specificity to targets present in the intracellular region of malignant cells.
As a rule, the size of the nanoparticles according to the invention is from 2 to 100 nm. The nanoparticles have out-standing properties with respect to their capability of permeating cell membranes and their improved physical compatibility. Although having a relatively low magnetic moment as a result of their small volume, intracellular particle agglomeration caused by binding to intracellular target biomacromolecules results in an augmented concentration with increased magnetic moment of the malignant cells to be removed, thereby promoting magnetic separation.
Typical core materials of the nanoparticles according to the invention are ferrites of general composition MeO
x
Fe
2
O
3
wherein Me is a bivalent metal such as Co, Mn or Fe. Other suitable materials are &ggr;-Fe
2
O
3
, the pure metals Co, Fe, Ni, and metal compounds such as carbides and nitrides.
The magnetic moment of cobalt and iron is up to four times higher than that of ferrites and therefore, given same particle size and same magnet field, these materials are removed more effectively. However, it must be considered that the biological compatibility of these materials is lower. This could be an advantage if additional damage is done to e.g. malignant cells in this way. On the other hand, the time of exposure to and concentration of these substances in healthy cells must be limited.
The interplay of biochemical, medical and physical properties requires producing tailored magnetic core materials and envelope layers.
According to the invention, the magnetic nanoparticles according to claim 1 enable permeation of the cell membranes and interaction of the magnetic nanoparticles with intracellular target biomacromolecules. To this end, homogeneous dispersion of the magnetic nanoparticles in body fluids is necessary, because aggregated nanoparticles are incapable of permeating the cell membrane. Inter alia, this requires an envelope layer of sufficient thickness which must be at least in the range of the core radius, and good biocompatibility of the envelope layer components. Charge carriers in the envelope material, i.e., an increased zeta potential, may have an additional beneficial effect on the dispersibility in a body fluid.
A particularly beneficial administration form of the magnetic nanoparticles is a dispersion in accordance with claim 9.
Homogeneous distribution of the magnetic nanoparticles according to the invention can be promoted b
Bahr Michael
Berkov Dimitri
Buske Norbert
Clement Joachim
Gansau Christian
Biomedical Apherese Systeme GmbH
Kiliman Leszek
Norris & McLaughlin & Marcus
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