DE102007005191A1 - Molecular drug transport system for producing medicine for specific transmission of incorporated active substance molecules into living cells in vitro and in vivo, has additional binding forces - Google Patents

Abstract

The molecular drug transport system based on a ktenate matrix, has an additional binding forces between the incorporated active substance molecules and the matrix. The additional binding force is non-covalent, electrostatic or is stack force. The side chains comprise the ktenate aromatic electron system and 10% of an aromatic group containing monomers. The monomers are selected from phenylalanine, tyrosine, p-aminobenzoic acid or p- hydroxybenzoic acid. An independent claim is also included for a method for producing a molecular drug transport system, which involves utilizing a synthesis of the matrix by condensation basically in a non-aromatic medium.

Description

The The invention relates to solid particles for the transport of pharmaceutical Active substances, process for their preparation, medicaments containing these particles as well as the use of these particles in different selected indications.

One The main objective of pharmaceutical research is currently to enhance the desired effects of known drugs and to minimize the systemic side effects, in particular for substances with high intrinsic and therefore inevitable Toxicity (eg cytostatics) of great importance is. This can be both about reducing the for the therapeutic effect needed total dose as well the accumulation of the active ingredients at the desired site of action can be achieved both through the controlled, spatially specific Release of drug molecules in the broadest sense (proteins, Peptides, nucleic acids or low-molecular substances) at the desired destination - d. H. in a target tissue or in individual target cells - can be accomplished. Among them is in particular the specific transfer of therapeutic or diagnostically usable substances in defined, in particular structurally defined biological targets ("drug delivery" or "drug targeting »), which is an important goal of the present day Pharmaceutical research is.

The Antibody technology available today the generation of high-affinity binding partners for nearly any biological structure; moreover, there are many natural ligands for cellular receptors characterized and cloned, so that it no longer a problem represents molecules with high and specific affinity to generate the desired goals. In many cases are also low molecular weight ligands such. B. Glycosides known, which mimics chemically and thus used for target control can be. The person skilled in the art is therefore familiar with various relevant ones Methods available, a binding partner with high and selective affinity for a defined biological To create a goal. Such a molecule is below referred to as the "Seeker molecule".

However, practice these Seeker molecules, whether micro- or macromolecular, themselves generally no pharmaceutically useful function while the Drug molecules themselves are not target specific. One The main focus must therefore be on bridging this separation and the therapeutic potential of the available drug molecules to connect with the target specificity of the searcher molecules.

Of the most efficient hitherto known and most versatile Approach to achieving this goal is the use of Support structures in the colloidal (i.e., sub-μm) Size range, corresponding to the surfaces Targeting molecules can be bound. Suitable support structures are colloidal particles containing antibodies against or with natural ligands for characteristic Molecular structures of the goal linked and at the same time inert coating of their surface against the detection and elimination by the immune system.

• – Die Stabilität der Partikel ist zeitlich begrenzt.
• – Die Liposomenmembran ist selbst innerhalb der Stabilitätszeit nicht voll ständig dicht, so dass mit Substanzverlust gerechnet werden muss.
• – Die Möglichkeiten der Oberflächengestaltung sind eingeschränkt.
• – Die wässrige Innenphase ist auf hydrophile Substanzen limitiert.
• – Die Beladungseffizienz ist gering: typischerweise < 0,5%.
• – Ungefähr 50% der zur Verknüpfung mit den Zielsuchermolekülen erforderlichen reaktiven Gruppen sind auf der Innenseite der Vesikelmembran gelegen (nicht mehr praktisch verfügbar, kann jedoch unvorhersehbare Reaktionen bewirken).
• – Die Kopplung von Proteinen an Membranen kann zur Bildung von hochimmunogenen Strukturen führen und damit eine Immunreaktion gegen die Liposomen auslösen, die jede weitere Anwendung von Liposomen verhindert.

Numerous liposome-based approaches are known in the prior art, but they are characterized by the following disadvantages:

• - The stability of the particles is limited in time.
• - The liposome membrane is not fully constantly tight even within the stability time, so that must be expected with loss of substance.
• - The possibilities of surface design are limited.
• - The aqueous inner phase is limited to hydrophilic substances.
• - The loading efficiency is low: typically <0.5%.
• Approximately 50% of the reactive groups needed to link to the targeting molecules are located on the inside of the vesicle membrane (no longer practically available, but can cause unpredictable reactions).
• - The coupling of proteins to membranes can lead to the formation of highly immunogenic structures and thus trigger an immune reaction against the liposomes, which prevents any further use of liposomes.

WO96 / 20698 describes as an alternative to liposomes polymolecular solid nanoparticles of natural or synthetic polycondensates having a predominantly generally described property-modifying surface coating of natural or synthetic macromolecules. However, stability and applicability of these particles are very limited.

More solid nanoparticles are in WO02 / 00162 and WO02 / 00191 discloses what is fully incorporated herein by reference.

The solid nanoparticles known from the prior art often have problems in stability and manufacturability as well as in the degree and extent of the loading and have so far been used only to a very limited extent. In particular, the problem of targeted application of the drug at the desired site of action and the stability of the nanoparticles after administration until reaching the site of action, the "drug targeting", only inadequately solved. A key problem here is the surface modification of nanoparticles. Conventional solid-nanoparticular systems (in Unlike liposomes) due to their extremely high specific interphase between the hydrophobic particle matrix and hydrophilic medium is an energetically unfavorable system that is unstable in the absence of stabilizers: By aggregation of particles, the energetically unfavorable contact surface is minimized; a precipitation of the hydrophobic particulate material is the result. Therefore, solid nanoparticles require a coating, eg. B. from amphiphilic molecules that reduce the interfacial energy and thus stabilize the particles. This coating completely covers the particle matrix, removing it from the access of modifying agents; However, a modification of the coating itself on the other hand leads to a drastic change of the physical properties and thus to a destabilization of the coating, which is why it is not possible to modify conventional nanoparticles for ligand binding and thus for "drug targeting".

B

für ein Polymer aus Y Untereinheiten steht, z. B. Polyvinylalkohol,

G und G'

unabhängig voneinander jeweils für -O-, -C(O)O-, -OC(O)-, C(O)N(H)- oder -N(H)C(O)- stehen,

M und N

unabhängig voneinander für aliphatisches Alkyl stehen,

E

für -COOH, -NH₂ oder -SH steht, und

X und Y

unabhängig voneinander jeweils für eine ganze Zahl von 1 bis 10000 stehen.

DE 100 30 786.8 . DE 100 3 811.8 . DE 101 18 312.7 . DE 101 18 852.8 . WO 02/00162 . WO 02/00191 and Flaig et al. 2005 ( J Drug Del. Sci. Tech. 15 (1): 59-63 ), to which reference is made in its entirety, describe a system of surface-modifiable solid particles based on monomolecular particles called "Bdellosomes". In summary, this system is based on a comb-shaped poly-polymer known as "Ktenat" with a continuous central backbone and hydrophobic side chains with reactive, hydrophilic end groups, which adopt a bottle brush shape in an aqueous environment, so that the drug molecules are transformed into hydrophobic by the described loading process Inside the Ktenat molecule can be packaged, while the hydrophilic ends form a layer surrounding this zone, which prevents the Abdiffusion of drug molecules, the so loaded Ktenatmoleküle holds in solution and at the same time attaching homing molecules, either directly or via wildcards such. B. polyethylene glycol allowed. The basic formula of in WO 02/00162 Ktenat is disclosed B - ([GM] _X -G'-NE) _Y (I) in which

B

represents a polymer of Y subunits, e.g. For example, polyvinyl alcohol,

G and G '

each independently of one another are -O-, -C (O) O-, -OC (O) -, C (O) N (H) - or -N (H) C (O) -,

M and N

independently of one another represent aliphatic alkyl,

e

is -COOH, -NH ₂ or -SH, and

X and Y

each independently represent an integer from 1 to 10,000.

It can z. B. by polycondensation of a molecule B with X.Y of the M-based side chain monomers and Y the N-E based side chain tails. In a typical embodiment, a molecule becomes Polyvinyl alcohol from 4000 vinyl units with 400000 molecules Lactic acid and 4000 molecules of FMOC-protected Alanine by reaction with thionyl chloride in pyridine in a molecule Ktenat, which thus 4000 alanine-terminated polylactide side chains with an average length of 100 units. It is typically with drug dissolved in benzyl alcohol mixed and the benzyl alcohol then by mixing with water and deprived of dialysis so that the drug-loaded ketenate molecules remain behind, with the hydrophilic end groups around put the molecule around as described above. This loaded Molecule can z. B. over polyethylene glycol with Antibodies are linked, and then shows good Homing activity.

Conveniently, a terminal bifunctionalized polyethylene glycol can be used as an intermediate piece, preferably a polyethylene glycol, which at one end with an amino-reactive group such as. B. NHS ester and at the other end with a thiol-reactive group such. B. vinyl sulfone is provided. Such groups, polyethyleneglycols derivatized therewith and their use are familiar to the person skilled in the art; see, for. B. WO 02/00162 and Flaig et al. 2005 ( J Drug Del. Sci. Tech. 15 (1): 59-63 ).

In a particular embodiment is a part of the polyethylene glycol monofunctional, especially with only one terminal amino-reactive group provided so that only part of the attached to a Ktenatmolekül bonded polyethylene glycol chains as an intermediate between Matrix and pointfinder can serve while the rest act as an inert coating that contains the Ktenatmolekül deprives the immune system of access.

A disadvantage of this system is the restriction to hydrophobic or (for example by esterification with fatty acids) hydrophobized active ingredients, as more hydrophilic drugs in general only embedded in the hydrophobic inner zone of the Ktenatmoleküls and so laden Ktenatpartikel in aqueous medium tend to lose their active ingredient content rapidly.

task The present invention was therefore an opposite to provide the improved Ktenat known from the prior art, the also store more hydrophilic substances and in aqueous Environment over times suitable for practical use can hold stable bound.

Surprisingly has now been found that such reinforcement and stabilization the interaction between the drug molecules and the Ktenat matrix without affecting the other advantageous properties of the Ktenat taking advantage of the stacking forces between aromatic ring systems is possible.

object Thus, the present invention is based on a molecular drug delivery system on a Ktenat matrix, characterized in that between a embedded drug molecule and the covalent with at least additional matrix associated with a searcher molecule Binding forces exist.

As the "drug molecule" is In this case, each substance denotes a detectable in an organism biological or chemical, preferably biological and especially prefers a potentially therapeutically or diagnostically useful Effect causes.

As the «Seeker molecule» becomes Hereby denotes a molecule, which leads to a strong and selective interaction with a biological molecular structure, preferred a structurally defined molecular structure (target structure), z. A cell surface protein or glycoprotein.

In a preferred embodiment, the searcher molecule is a natural interaction partner or ligand of the target structure or a derivative or mutant thereof, as long as it is still capable of binding to the target structure. In this embodiment, it is preferred that the searcher molecule is originally from the same species to which the target structure belongs. Appropriate methods for the identification of ligands and their derivatization are familiar to the skilled worker and z. As described in relevant known textbooks and manuals such "Molecular Cloning - A Laboratory Manual" by Sambrook, Fritsch & Maniatis ; Current Protocols in Molecular Biology by Ausubel et al. ; "Proteins and Proteomics: A Laboratory Manual" by Richard J. Simpson ; "Techniques in Protein Modification" by Roger L. Lundblad ; "Antibodies: A Laboratory Manual" by Harlow & Lane ; "Antibody Engineering" by Kontermann & Dübel ; and many others.

In In another preferred embodiment, the searcher molecule is an antibody or a derivative of an antibody, in particular a polyclonal antibody, a monoclonal antibody Antibodies, e.g. B. one after the standard technique of Köhler and Milstein available monoclonal antibody, or a recombinant antibody, in particular a humanized antibody, a chimeric antibody, a CDR graft antibody or a diabody, or a derivative of one of said molecules, as long as it is still able to bind to the target structure. Appropriate Process for the preparation of antibodies and antibody derivatives are familiar to the skilled person (a.O.).

As "matrix" becomes in this case denotes the polymeric matrix, which as such neither significant biological effects still triggers a significant has specific affinity to any target structures. In a particularly preferred embodiment of the invention the matrix consists of Ktenat.

As "Ktenat" here is a comb-shaped branched poly-polymer, as in DE 100 30 786.8 . DE 100 3 811.8 . DE 101 18 312.7 . DE 101 18 852.8 . WO 02/00162 and Flaig et al. 2005 ( J Drug Del. Sci. Tech. 15 (1): 59-63 ) basically described.

In In a preferred embodiment, the binding forces noncovalent between the drug molecule and the matrix, especially electrostatic. It is particularly preferred if these Binding forces the stacking forces between aromatic ring systems are.

As «stack forces» (π - π forces) Here are the non-covalent interactions between aromatic Electron systems of spatially adjacent molecules or parts of the molecule, which by the inter- or intramolecular overlaps of the p orbitals of the conjugated π-electron systems come about.

In a preferred embodiment, the side chains of the ketenate molecule contain aromatic electron systems. Basically, as the side group monomer comprising an aromatic group, any molecule comprising at least one aromatic group is suitable. Herein, a set chain may include one or more types of side chain monomers, the proportions of which may be the same or different. It is particularly preferred if each ketenate side chain comprises at least one aromatic electron system, and especially if at least 10%, e.g. B. 25%, the monomers at least one aromatic Electron system include.

Gund G'

wie oben definiert sind,

Ak und Ak'

für eine kovalente Bindung oder für einen linearen oder verzweigten, optional substituierten Kohlenwasserstoffrest stehen und

Ao

für ein aromatisches, optional substituiertes und/oder heterocyclisches Ringsystem steht, vorzugsweise ein aromatisches Ringsystem ausgewählt unter Phenyl, Naphthyl, Anthracyl, Tetracenyl, Pentacenyl, Benzopyrenyl, Chrysenyl, Coronenyl, Ovalenyl, Fluoranthrenyl, Phenanthrenyl, Pyrenyl, Triphenyl, Pyridinyl, Imidazolyl, Pyrazolyl, Oxazolyl, Thiophenyl und ihren benzannelierten Derivaten, besonders bevorzugt Phenyl.

In a particularly preferred embodiment, a monomer comprising an aromatic group has the formula HG-Ak-Ao-Ak'-G'-H (II), in which

Gund G '

as defined above,

Ak and Ak '

are a covalent bond or a linear or branched, optionally substituted hydrocarbon radical and

Ao

is an aromatic, optionally substituted and / or heterocyclic ring system, preferably an aromatic ring system selected from phenyl, naphthyl, anthracyl, tetracenyl, pentacenyl, benzopyrenyl, chrysenyl, coronenyl, ovalenyl, fluoranthrenyl, phenanthrenyl, pyrenyl, triphenyl, pyridinyl, imidazolyl, pyrazolyl , Oxazolyl, thiophenyl and their benzannelated derivatives, more preferably phenyl.

D. h., the aromatic system is in this embodiment linearly integrated into the Ktenat side chain.

Especially it is preferred if Ak and Ak 'are not adjacent to C atoms the ring system are, for. B. in para position. In a most preferred Embodiment, the side chain monomer is selected under para-amino-benzoic acid and para-hydroxy-benzoic acid. A "substituted ring system" is hereby with 1 to Q - 2 linear or branched, optionally independent substituted from each other substituted hydrocarbon radicals Ring system, where Q is the number of carbon atoms in the ring system is.

A "hydrocarbon radical" here is an aliphatic, linear or branched, C ₁ -C ₁₀ alkyl; aliphatic C ₃ -C ₈ cycloalkyl; aliphatic, linear or branched, C ₁ -C ₁₀ alkenyl; or aliphatic, linear or branched, C ₁ -C ₁₀ -alkynyl radical.

A "substituted hydrocarbon radical" here is an aliphatic, linear or branched, C ₁ -C ₁₀ alkyl; aliphatic C ₃ -C ₈ cycloalkyl; aliphatic, linear or branched, C ₁ -C ₁₀ alkenyl; or aliphatic, linear or branched, C ₁ -C ₁₀ -alkynyl radical which is mono- to trisubstituted independently of one another by hydroxy, halogen, carbonyl, carboxyl, amine or imine.

G, G' und Ao

wie oben definiert sind und

Aq

für einen optional substituierten Kohlenwasserstoffrest steht; d. h., das aromatische System stellt in dieser besonderen Ausführungsform einen Nebenzweig der Ktenatseitenkette dar.

In another particularly preferred embodiment, a monomer comprising an aromatic group has the formula HG-Aq (Ao) -G'-H (III), in which

G, G 'and Ao

as defined above and

Aq

is an optionally substituted hydrocarbon radical; ie, the aromatic system in this particular embodiment is a minor branch of the ketenate side chain.

In an extremely preferred embodiment the side chain monomer is selected from phenylalanine and tyrosine.

In a preferred embodiment, at least 10%, z. B. 25%, preferably at least 40%, z. At least 60%, especially preferably at least 80%, z. B. at least 90%, in particular at least 95%, z. At least 99%, of all side chain monomers in the whole Molecule containing an aromatic group monomers.

G''

für -O-, -OC(O)- oder -N(H)C(O)- steht,

An

für einen optional substituierten Kohlenwasserstoffrest oder ein aromatisches, optional substituiertes und/oder heterocyclisches Ringsystem steht und

E

wie oben definiert ist und optional durch eine leicht abspaltbare Schutzgruppe wie z. B. BOC oder FMOC geschützt ist.

In a preferred embodiment, the end group monomer has the formula H-G "- An-E (IV), in which

G''

is -O-, -OC (O) - or -N (H) C (O) -,

At

represents an optionally substituted hydrocarbon radical or an aromatic, optionally substituted and / or heterocyclic ring system and

e

as defined above and optionally by an easily cleavable protecting group such. B. BOC or FMOC is protected.

In a preferred embodiment of the invention the embedded molecules are aromatic electron systems. In principle, every molecule that is at least an aromatic system is used. Preferably the molecule comprises a mono- or polycyclic aromatic Heterocycle. In an exemplary embodiment the embedded molecule daunomycin.

In Another particular embodiment is the drug molecule derivatized by conjugation with an aromatic ring system; In this case, it is particularly preferred if the drug molecule with the aromatic ring system via an easily cleavable Ether or ester bond is linked. Corresponding derivatization procedures are familiar to the skilled person.

The invention further relates to a process for the preparation of a molecular drug delivery system as described above, characterized in that it comprises the synthesis of the kettenate matrix by condensation in a substantially aromatic-free medium. In a preferred embodiment, the method comprises reacting a mixture of Z molecules of polyvinyl alcohol having a number average length of Y vinyl units, X · Y · Z molecules of side chain monomers, e.g. A mixture of (X.Y.Z) / 2 molecules of lactic acid and para-hydroxybenzoic acid, Y.Z end group monomers, e.g. N-FMOC-β-alanine, and at least X · Y · Z molecules of thionyl chloride in an apolar, non-aromatic solvent, preferably an apolar, non-aromatic, low boiling-temperature solvent, e.g. For example, CH ₂ Cl ₂ .

Prefers After the reaction, the solvent is removed, for. B. by evaporation.

In a preferred embodiment, the kettenate for loading with the active ingredient with this together in a solvent, for. Example, a slightly polar or non-polar solvent, preferably a slightly polar or apolar, non-aromatic solvent and more preferably a low-polar or non-polar, non-aromatic solvent with low boiling point, z. As an aliphatic alcohol. The second solvent may be the same as or different from the first. Preferably, the method comprises gradually diluting the thus obtained solution of Ktenate and the active ingredient with a more polar solvent, e.g. Water or a saline solution, optionally followed by dialysis and / or conjugation of the ketene with targeting molecules, as generally described in Flaig et al. 2005 ( J Drug Del. Sci. Tech. 15 (1): 59-63 ).

The The invention further relates to the use of an inventive Molecular drug delivery system for the specific transmission of embedded drug molecules in living cells in vitro and for the manufacture of a medicament for specific delivery of stored drug molecules in living cells in vivo. Preferably, the living cells are tumor cells or cells eukaryotic parasites, especially eukaryotic parasites of the genus Trypanosoma.

The Invention will now be apparent from the following, not exhaustive or limiting to examples to understand explained. The skilled artisan recognizes that in the context of the present Invention numerous modifications and variations of the described Procedure are possible. They are all considered to be the invention proper to look at.

Examples

Example 1: Preparation of aromatic Ktenat

For the preparation of aromatic ketenate with X; Y ≈ 50; 20000, 27 mg of polyvinyl alcohol ("Mowiol") having an average molecular weight of 100 kDa, 311 mg of N-FMOC-β-alanine and 6.91 g of para-hydroxybenzoic acid are thoroughly mixed in the dry state and dissolved at room temperature in about 1 liter of anhydrous, suspended with molecular sieve CH ₂ Cl ₂ by vigorous stirring. With continued stirring, 5.9 g of SOCl _{2 are} added dropwise. The condensation reaction can be recognized by the release of SO ₂ as well as by the increase in viscosity and yellowish discoloration of the reaction mixture. The resulting Ktenat goes into solution; during the reaction, the volume is increased continuously to a total of 3 liters by adding anhydrous CH ₂ Cl ₂ .

After completion of the condensation reaction, any unreacted SOCl ₂ is inactivated with continued stirring by addition of 10 ml of water, then the reaction mixture is concentrated to dryness in a rotary evaporator, again taken up in 3 l CH ₂ Cl ₂ for washing and evaporated again.

For cleavage of the FMOC protective group, the product is taken up in 500 ml of water, added with stirring at room temperature with 5 ml of piperidine and incubated for 1-2 hours with continued stirring, then again in a rotary evaporator to dryness, for washing again in 2 l CH ₂ Cl _{2 was} taken and re-evaporated. The Ktenat arises here as a yellowish, waxy mass.

Example 2: Loading of aromatic Ktenate with daunomycin

100 mg of the aromatic kettenate from Example 1 and 1 mg of daunomycin are dissolved in 3.5 ml of CH ₂ Cl ₂ and incubated with gentle stirring for 1 h at room temperature; then 6.5 ml of 1 mM Tris-HCl pH 6.5 are added dropwise with vigorous stirring. The crude suspension thus obtained is taken up in 190 ml of 1 mM Tris-HCl pH 6.5 and incubated overnight at room temperature with gentle stirring.

It In this way, an optically clear solution of daunomycin-laden Ktenat received.

The radioactive determination of the loading efficiency is carried out as indicated, with an additional 1 μCi of [ ³ H (G) -] daunomycin being added to the loading batch.

Example 3: Conjugation of aromatic Ktenate with antibody fragments

to Adjust the pH to that for the conjugation of the Ktenat's ideal value is 90 ml of the solution of daunomycin-loaded Ktenat from Example 3 mixed with 10 ml of 25 mM Tris-HCl pH 6.0 and thoroughly stirred, then with 3 mol% (based on the ketenate) of NHS ester / vinyl sulfone polyethylene glycol with an average molecular weight of 3400 Da and over Incubated at room temperature overnight.

Subsequently is the reaction mixture to remove unreacted polyethylene glycol and to set the conjugate of the pointfinder ideal value through a membrane with an exclusion size of about 13 kDa dialysed against 10 mM Tris-HCl pH 8.0. In connection the targeting molecules (antibody Fab fragments) become in at least 20-fold molar excess, based on the Ktenatmoleküle, added and again over Incubated at room temperature overnight.

to Inactivation of the last unreacted groups Finally, it adds 100 mg of cysteine to the batch Incubated for 1 h with gentle stirring and then through for purifying the finished conjugates through a membrane with an exclusion size of about 100 kDa dialysed against 10 mM Tris-HCl pH 7.0.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• WO 96/20698 [0007]
• - WO 02/00162 [0008, 0010, 0010, 0012, 0023]
• WO 02/00191 [0008, 0010]
• - DE 10030786 [0010, 0023]
• - DE 1003811 [0010, 0023]
• - DE 10118312 [0010, 0023]
• - DE 10118852 [0010, 0023]

Cited non-patent literature

• - J Drug Del. Sci. Tech. 15 (1): 59-63 [0010]
• - J Drug Del. Sci. Tech. 15 (1): 59-63 [0012]
• - "Molecular Cloning - A Laboratory Manual" by Sambrook, Fritsch & Maniatis [0020]
• - "Current Protocols in Molecular Biology" by Ausubel et al. [0020]
• - "Proteins and Proteomics: A Laboratory Manual" by Richard J. Simpson [0020]
• - "Techniques in Protein Modification" by Roger L. Lundblad [0020]
• - "Antibodies: A Laboratory Manual" by Harlow & Lane [0020]
• - "Antibody Engineering" by Kontermann & Dübel [0020]
• - J Drug Del. Sci. Tech. 15 (1): 59-63 [0023]
• - J Drug Del. Sci. Tech. 15 (1): 59-63 [0040]

Claims (15)

Molecular drug delivery system based on a Ktenat matrix, characterized in that between the stored drug molecules and the matrix additional binding forces exist. The molecular drug delivery system of claim 1, wherein the additional binding forces noncovalent are. The molecular drug delivery system of claim 2, wherein the additional binding forces electrostatically are. A molecular drug delivery system according to claim 2 or 3, wherein the additional binding forces stacking forces are. Molecular drug delivery system according to one of the previous Claims, characterized in that the side chains of Ktenate aromatic electron systems include. The molecular drug delivery system of claim 5, wherein the side chains comprise at least 10% of an aromatic group Monomers. The molecular drug delivery system of claim 6, wherein in the side chains of the ketten a total of at least 50% of the monomers are selected from phenylalanine, tyrosine, para-amino-benzoic acid and para-hydroxybenzoic acid. Molecular drug delivery system according to one of the previous Claims, characterized in that the stored Molecules include aromatic electron systems. Molecular drug delivery system according to one of the previous Claims, wherein the incorporated molecule daunomycin is. Process for the preparation of a molecular drug delivery system according to one of the preceding claims, characterized that it is the synthesis of the matrix by condensation in a substantially comprising aromatics-free medium. Process for the preparation of a molecular drug delivery system according to one of the preceding claims, characterized that it is the incorporation of drug molecules in one comprises substantially aromatics-free medium. Use of a molecular drug delivery system according to any one of claims 1 to 9 for specific transmission of stored drug molecules in living cells in vitro. Use of a molecular drug delivery system according to any one of claims 1 to 9 for the manufacture of a medicament for the specific transfer of the stored drug molecules into living cells in vivo. Use according to claim 12 or 13, wherein the living cells Tumor cells or cells of eukaryotic parasites. Use according to claim 14, wherein the eukaryotic parasites belong to the genus Trypanosoma.