Mixture, aqueous solution containing the mixture, and uses of the aqueous solution

Abstract

The invention relates to a mixture containing a first polymer and a second polymer. The first polymer and the second polymer each comprise at least six nucleobases, wherein each nucleobase is covalently bonded to one monomer of the relevant polymer. The at least six nucleobases of the second polymer are complementary to the at least six nucleobases of the first polymer. Because of their mutually complementary nucleobases, the two polymers are suitable for forming micelles or vesicles (preferably vesicles) at temperatures of ≤ 37°C and are not suitable for forming micelles or vesicles at temperatures of > 37°C. According to the invention, an aqueous solution containing the mixture according to the invention is also provided and uses of the aqueous solution are proposed.

Description

[0001] Mixture, aqueous solution containing the mixture and uses of the aqueous solution

[0002] A mixture is provided which contains a first polymer and a second polymer. The first polymer and second polymer each have at least six nucleobases, wherein one nucleobase is covalently bonded to a monomer of the respective polymer. The at least six nucleobases of the second polymer are complementary to the at least six nucleobases of the first polymer. The two polymers, via their mutually complementary nucleobases, are suitable for use at a temperature of <

[0003] 37°C to assemble into micelles or vesicles (preferably vesicles) and not to assemble into micelles or vesicles at a temperature of > 37°C. The invention further provides an aqueous solution containing the mixture according to the invention and proposes uses of the aqueous solution. Temperature-controlled release of substances can play an important role in many fields of application. These range from medical applications (e.g., tumor treatment) and cosmetic applications to technical processes for the release of coolants or lubricants.

[0004] Stimuli-responsive drug delivery systems are designed to help release their active ingredient in a spatially, temporally, and dose-controlled manner. Control of release can be endogenous, i.e., triggered by conditions at the target site (e.g., pH, enzyme concentrations, redox gradients), or exogenous, i.e., triggered by an external stimulus (e.g., temperature change, magnetic field, ultrasound, light treatment).

[0005] Thermoresponsive systems are generally based on a temperature-dependent, preferably sharp, non-linear change in the physicochemical properties of at least one component of the carrier material, which leads to the release of the encapsulated active ingredient.

[0006] Polymer-based, thermoresponsive drug transporters based on so-called UCST polymers (upper critical solution temperature polymers) are known in the state of the art. The UCST polymer poly-2-oxazoline is, in principle, suitable for drug delivery, but is not suitable for targeted drug release in organisms with a body temperature of 37°C, as its switching temperature (release temperature) is already 30°C (Hoogenboom, R. et al., Soft Matter, 2009, Vol. 5, pp. 3590-3592). The UCST polymer poly(AAm-co-AN)-g-PEG is known to form vesicles in aqueous solution that can be loaded with the drug doxorubicin. However, the vesicles exhibit a temperature-dependent release of doxorubicin in a very broad temperature range between 4°C and 43°C, which also makes them unsuitable for targeted drug release in organisms that have a body temperature of 37°C (Li, WS et al., Angew. Chem.Int. Ed., 2015, Vol. 54, pp. 3126-3131).

[0007] With the known UCST polymer systems, it is not yet possible to precisely adjust a sharp switching threshold to achieve safe and sensitive release behavior under in vivo conditions. Ideally, for thermoresponsive systems as drug carriers, the switching temperature should be very close to the physiological body temperature of 37°C, so that no non-specific release occurs in healthy tissue, i.e., already at 37°C. On the other hand, however, ideally even a small local temperature increase of a few Kelvin (e.g., to approximately 40-42°C) should be sufficient to induce drug release, since excessively high switching temperatures require very high heating of body tissue, which can also damage certain healthy tissue in the body (e.g., neighboring tissue of a tumor).

[0008] A DNA-based drug delivery system is already known in the prior art, in which mesoporous silica particles are covalently bound to single-stranded DNA, and this single-stranded DNA hybridizes to a complementary single-stranded DNA covalently bound to iron oxide nanoparticles, thereby closing the pores of the mesoporous silica particles (Ruiz-Hernandez, E. et al., ACS Nano, 2011, Vol. 5, pp. 1259-1266). Melting the hybridization of the DNA by raising the temperature then allows the pores of the mesoporous silica particles to open and release an encapsulated drug. However, this DNA-based drug delivery system is complex to manufacture, allows only a relatively low drug loading relative to the total weight of the system, and has a relatively wide temperature range for drug release.

[0009] Based on this, the object of the present invention was to provide a drug release system (or a mixture) that does not have the disadvantages of the prior art. In particular, the drug system should be simple and economical to produce on an industrial scale, allow a high drug loading relative to the total weight of the system, and enable the release of active ingredients in the narrowest possible temperature range at a temperature of > 37°C. This object is achieved by the mixture having the features of claim 1, the aqueous solution having the features of claim 12, and the use having the features of claim 15. The dependent claims disclose advantageous developments.

[0010] According to the invention, a mixture is provided comprising a) a first polymer which has at least six nucleobases, each nucleobase being covalently bonded to a monomer of the polymer; and b) a second polymer which has at least six nucleobases, each nucleobase being covalently bonded to a monomer of the polymer, the at least six nucleobases of the second polymer being complementary to the at least six nucleobases of the first polymer; characterized in that the first polymer and the second polymer, via their mutually complementary nucleobases, are suitable for assembling into micelles or vesicles in an aqueous solution at a temperature of < 37°C by forming hydrogen bonds between their complementary nucleobases (i.e. forming micelles or vesicles).to exist as micelles or vesicles), and at a temperature of > 37°C, due to the absence of hydrogen bonds between their complementary nucleobases, not to assemble into micelles or vesicles (i.e. not to form micelles or vesicles or not to exist as micelles or vesicles).

[0011] The self-assembly of the polymer components of the mixture at a temperature of < 37°C is based on the formation of hydrogen bonds between the individual complementary nucleobases of the two polymers, which causes micelle or vesicle formation of the two polymers. If the melting temperature of the bond between the complementary nucleobases is exceeded at a temperature of > 37°C, the bond between the two polymers is lost, i.e., the two polymers dissociate and transition into a non-micellar or non-vesicular state. The micelles or vesicles dissolve in the process. If an active ingredient was enclosed in the micelles or vesicles, this is released. If the temperature range of the melting of the hydrogen bonds is narrow, i.e., only a few Kelvin wide, a temperature difference of just a few Kelvin above 37°C (e.g.,a temperature jump from 37 °C to 40 °C) can cause the release of active ingredient.

[0012] The mixture according to the invention has the advantage that a release of active ingredients is possible in a temperature range of > 37°C, in particular in a narrow temperature range above 37°C (e.g. 1 K to 5 K, preferably 1 K to 3 K, above 37°C). Furthermore, the mixture can be produced easily and economically on an industrial scale. In addition, the mixture allows a relatively high active ingredient loading if the first and second polymers form vesicles as active ingredient carriers. Vesicles provide a large interior space for loading with active ingredient, and the polymers that form the vesicles take up only a small volume and thus only a small weight relative to this large interior space. Consequently, it is preferred that the first and second polymers form vesicles. If the first and second polymers form micelles, a certain, albeit smaller, active ingredient loading is also possible (especially with more hydrophobic active ingredients).

[0013] This property makes the mixture according to the invention particularly useful for thermally induced switching in the body of a living being with a body temperature of 37°C, since it is particularly advantageous if the temperature required for the switching is not too high above 37°C (reason: less undesirable thermally induced tissue damage occurs). For example, it is also known that a cancerous tumor in the body can have a temperature 1 K to 2 K higher than the surrounding body tissue (which is at 37°C), whereby the mixture according to the invention can be used to release active ingredients in the body specifically at the site of the tumor.

[0014] The formation of vesicles is preferred because vesicles provide a larger internal space for loading with an active ingredient and thus allow loading with larger active ingredient molecules or a larger amount of smaller active ingredient molecules. It is thus preferred that the first polymer and the second polymer, via their mutually complementary nucleobases, are suitable for assembling into vesicles (i.e., forming vesicles or existing as vesicles) in an aqueous solution at a temperature of <37°C through the formation of hydrogen bonds between their complementary nucleobases, and for not assembling into vesicles (i.e., not forming vesicles or existing as vesicles) at a temperature of >37°C due to the absence of hydrogen bonds between their complementary nucleobases.

[0015] In a preferred embodiment, the mixture contains a magnesium salt (e.g., MgCl) and / or a magnesium complex, particularly preferably in a concentration of 10 to 30 mM. The presence of magnesium can be advantageous for the formation of vesicles or micelles if the first polymer and / or second polymer comprise at least one monomer containing a phosphate residue (e.g., a ribose-5-phosphate residue).

[0016] In a preferred embodiment, the mixture contains an active ingredient, wherein the active ingredient is preferably selected from the group consisting of medically active substances, cosmetic substances, sensor substances, lubricants, coolants, adhesives, and combinations thereof. The active ingredient is particularly preferably selected from the group consisting of medically active substances, fragrances, antiperspirants, UV protectants, coolants, lubricants, adhesives, and combinations thereof. The advantage here is that the active ingredient can be enclosed in an interior of the micelles or vesicles that are formed from the two polymers of the mixture according to the invention at a temperature of <37°C in aqueous solution.

[0017] In a further optional embodiment, the first polymer and / or the second polymer is a linear (i.e. unbranched) polymer. Alternatively, the first polymer and / or the second polymer is a non-linear (i.e. branched) polymer. In this case, the first polymer and / or the second polymer can have at least one branch, optionally two branches. If the first polymer and / or second polymer has one or two branches, it can be a modified 3-arm PEG or modified 4-arm PEG (e.g. with an average molar mass of 1000 to 6000 g / mol, preferably 2000 g / mol to 5000 g / mol) which has monomers on at least two arms of the PEG, preferably on at least three arms of the PEG (optionally on four arms of the PEG in the case of 4-arm PEG), each of which is covalently bonded to a nucleobase (preferably at one end of each arm).It is crucial that the 3-arm PEG or 4-arm PEG has at least six nucleobases, with each nucleobase covalently bonded to a monomer of the polymer. For example, one arm of the 3-arm PEG or 4-arm PEG can contain at least four or six such monomers, and a second arm of this PEG can contain four or six such monomers. It is possible for the other arms of the 3-arm PEG or 4-arm PEG to contain no such monomers, i.e., no monomers bonded to a nucleobase (nucleobase-free monomers).

[0018] The first polymer can contain or consist of at least 20, preferably at least 50, more preferably at least 100, most preferably at least 200, in particular at least 500, monomers. Furthermore, the second polymer can contain or consist of at least 20, preferably at least 50, more preferably at least 100, most preferably at least 200, in particular at least 500, monomers. The first and / or second polymer can have a maximum of 600 monomers, optionally a maximum of 500 monomers.

[0019] The first polymer can have at least ten, preferably at least twelve, more preferably at least 14, in particular at least 16, optionally a maximum of 18, nucleobases, each nucleobase being covalently bonded to a monomer of the first polymer. The second polymer can have at least ten, preferably at least twelve, more preferably at least 14, in particular at least 16, optionally a maximum of 18, nucleobases, each nucleobase being covalently bonded to a monomer of the second polymer, the nucleobases of the second polymer being complementary to the nucleobases of the first polymer. The more nucleobases that are complementary to one another the first and second polymers have, the higher the melting point of the hybridized nucleobases, i.e. the higher above >37°C is the temperature at which the micelles and / or vesicles disassemble.

[0020] It is possible for the first polymer to have a maximum of 16, preferably a maximum of 14, particularly preferably a maximum of 12, optionally a maximum of 10, nucleobases. Furthermore, it is possible for the second polymer to have a maximum of 16, preferably a maximum of 14, particularly preferably a maximum of 12, optionally a maximum of 10, nucleobases. The fewer complementary nucleobases the first and second polymers have, the lower the melting point of the hybridized nucleobases, i.e., the closer to >37°C the temperature at which the micelles and / or vesicles disassemble.

[0021] In the first polymer, a maximum of three monomers, preferably a maximum of two monomers, particularly preferably a maximum of one monomer, in particular no monomer, can be arranged between two consecutive monomers, each bonded to a nucleobase, that is, that is, that is, not bonded to a nucleobase-free monomer. The term "nucleobase-free monomer" refers to a monomer that itself (i.e., considered as an isolated building block in the polymer) has no bond to a nucleobase. In other words, the nucleobase-free monomers only have an (indirect) bond to a nucleobase via neighboring monomers of the polymer (which can then be considered "spacers").Furthermore, in the second polymer, a maximum of three monomers, preferably a maximum of two monomers, particularly preferably a maximum of one monomer, in particular no monomer, can be arranged between two consecutive monomers, each linked to a nucleobase, which is not each covalently linked to a nucleobase, i.e. which is not each linked to a nucleobase-free monomer. If no nucleobase-free monomer is arranged between two consecutive monomers linked to nucleobases, the nucleobases are bound to sequentially successive monomers of the polymer. Such an arrangement of the nucleobases along the polymer chain has the advantage that a reversible bonding mechanism is created over the shortest possible length, which can bind the first polymer and the second polymer to one another (T < 37 °C) or detach them from one another (T > 37 °C) reversibly and depending on the ambient temperature.

[0022] The first polymer and / or second polymer can comprise at least one monomer or oligomer (preferably at least one monomer, particularly preferably exactly one monomer) that is not covalently bonded to a nucleobase (i.e., that is a nucleobase-free monomer) and that is covalently bonded to at least one further polymer (optionally two further polymers, such as in 3-arm PEG or 4-arm PEG). The further polymer is preferably suitable for effecting phase separation after assembly of the first and second polymers in an aqueous medium. The further polymer can contain or consist of polyethylene glycol.

[0023] The nucleobases of the first polymer can be nucleobases that contain or consist of cytosine, isocytosine, and / or adenine, preferably cytosine. Furthermore, the nucleobases of the second polymer can be nucleobases that contain or consist of guanine, isoguanine, and / or thymine, preferably guanine. The combination of cytosine or isocytosine (first polymer) and guanine or isoguanine (second polymer) is preferred because the cytosine-guanine bond (or isocytosine-isoguanine bond), which is established by three hydrogen bonds, is stronger than the adenine-thymine bond, which is established by only two hydrogen bonds. The use of cytosine, guanine, isocytosine and isoguanine has the advantage that a smaller number of nucleobases is needed to set a specific (dis)assembly temperature than when using adenine and thymine.Consequently, the reversible binding mechanism can be established over a shorter length along the first and second polymers.

[0024] The nucleobases of the first polymer can be linked to the monomer of the first polymer via a ribose residue, with the nucleobase preferably being linked to the Cl atom of the ribose residue and the monomer being linked to the C5 atom of the ribose residue. Furthermore, the nucleobases of the second polymer can be linked to each monomer of the first polymer via a ribose residue, with the nucleobase preferably being linked to the Cl atom of the ribose residue and the monomer being linked to the C5 atom of the ribose residue. The advantage of the linkage via a ribose residue is that the ribose residue is relatively hydrophilic and can thus improve the water solubility of the first and / or second polymer.

[0025] The monomers of the first polymer and / or second polymer, each linked to a nucleobase, can each contain or consist of a residue selected from the group consisting of amino acid residues, sugar residues, ribose phosphate residues, methacrylamide residues, and combinations thereof. The residue is preferably selected from the group consisting of ribose phosphate residues, methacrylamide residues, and combinations thereof, particularly preferably selected from the group consisting of ribose 5-phosphate residues, / V-(3-aminopropyl)-methacrylamide residues, and combinations thereof. The advantage of the ribose 5-phosphate residue and the / V-(3-aminopropyl)-methacrylamide residue is that they are relatively hydrophilic and can thus improve the water solubility of the first and / or second polymer.

[0026] Furthermore, the monomers of the first polymer and / or second polymer, each linked to a nucleobase, can form a homopolymer. The homopolymer is preferably selected from the group consisting of polypeptide, polysaccharide, polyribose phosphate, polymethacrylamide, and combinations thereof. Particularly preferably, the homopolymer is selected from the group consisting of polyribose phosphate, polymethacrylamide, and combinations thereof. In particular, the homopolymer is selected from the group consisting of polyribose-5-phosphate, poly-(V-(3-aminopropyl)-methacrylamide), and combinations thereof. The advantage is that these homopolymers are relatively hydrophilic and can thus improve the water solubility of the first and / or second polymer.

[0027] Furthermore, the monomers of the first polymer and / or second polymer, each of which is linked to a nucleobase, can be covalently linked to the nucleobase via a bond (optionally via a ribose residue) selected from the group consisting of ester bonds, thioester bonds, ether bonds, and amide bonds. Preferably, the bond is an amide bond, particularly preferably an amide bond to a ribose residue covalently linked to the nucleobase. In particular, the bond is an amide bond to a C5 atom of a ribose residue covalently linked to the nucleobase at the Cl atom of the ribose residue. The amide bond is advantageous because it is a relatively stable bond in an aqueous environment.

[0028] It is further preferred that the first polymer and second polymer have the nucleobases, each covalently bonded to a respective monomer of the polymer, at a first end of the polymer, at a first end of the polymer and at a second end of the polymer, or in the middle of the polymer. In other words, the nucleobases along the polymer chain occur only in this respective section (or region or block) of the polymer and do not occur in a section (or region or block) of the polymer that differs from this section (or region or block) of the polymer.

[0029] If, for example, the nucleobases are arranged at a first end of the polymer, each monomer at a second end of the polymer would have no attached nucleobase, i.e., only nucleobase-free monomers would be present at the second end. If, for example, the nucleobases are arranged at a first end of the polymer and at a second end of the polymer, each monomer in the middle of the polymer would have no attached nucleobase, i.e., only nucleobase-free monomers would be present in the middle. If, for example, the nucleobases are arranged in the middle of the polymer, each monomer at the beginning and at the end of the polymer (i.e., in both directions away from the center of the polymer) would have no attached nucleobase, i.e., only nucleobase-free monomers would be present in these sections. The different sections (regions or blocks) of the polymer can therefore have different physical and / or chemical properties.For example, the sections of the first and / or second polymer whose monomers are not each linked to a nucleobase (sections with nucleobase-free monomers) exhibit a higher degree of freedom at a temperature of < 37 °C, since these regions are not involved in the hybridization of the two polymers, i.e., these sections do not experience any "immobilization" through hybridization. The longer this section with nucleobase-free monomers of the first and / or second polymer is, the more it determines the chemical and physical properties of the micelles or vesicles assembled from the two polymers.

[0030] Monomers of the first polymer and / or second polymer, each of which is not linked to a nucleobase (nucleobase-free monomers), can each contain or consist of a residue selected from the group consisting of (V-(2-hydroxypropyl)methacrylamide residue, vinylamine residue, butadiene residue, ethylene oxide residue, acrylic acid residue, amino acid residue (e.g. glutamic acid residue and / or lysine residue), sugar residue and combinations thereof. These monomers preferably contain or consist of a (V-(2-hydroxypropyl)methacrylamide residue and / or an ethylene oxide residue, since these monomers have good water solubility and can thus provide good water solubility of the first and / or second polymer.

[0031] Monomers of the first polymer and / or second polymer, each of which is not linked to a nucleobase (nucleobase-free monomers), can form a homopolymer, preferably a homopolymer selected from the group consisting of poly-(V-(2-hydroxypropyl)methacrylamide, polyvinylamine, polyethylene oxide, polypeptide (e.g. polyglutamic acid and / or polylysine), polysaccharide, and combinations thereof, particularly preferably poly-(V-(2-hydroxypropyl)methacrylamide). The formation of poly-(V-(2-hydroxypropyl)methacrylamide (pHPMA) and / or polyethylene oxide is advantageous because it has good water solubility and can thus provide good water solubility of the first and / or second polymer.Furthermore, monomers of the first polymer and / or second polymer that are not bonded to a nucleobase (nucleobase-free monomers) can form a block copolymer, preferably a block copolymer selected from the group consisting of polybutadiene-polyethylene oxide, polyvinylamine-polyethylene oxide, polyglutamic acid-polyethylene oxide, polyacrylic acid, and combinations thereof. Furthermore, monomers of the first polymer and / or second polymer that are not bonded to a nucleobase (nucleobase-free monomers) can form a heteropolymer, preferably a heteropolymer selected from the group consisting of polypeptide, polysaccharide, and combinations thereof.

[0032] In a preferred embodiment, the mixture contains no organic solvent. Consequently, the mixture can be provided with a lower safety risk, at lower cost, and in a more environmentally friendly manner than known prior art mixtures that employ an organic solvent. Furthermore, it enables the encapsulation of active ingredients that are damaged or even destroyed by organic solvents (e.g., certain macromolecular biotherapeutics such as certain proteins). The mixture according to the invention is further provided for use in medicine, preferably for the thermal release of an active ingredient, particularly preferably for the thermal release of an active ingredient for the treatment of cancer.

[0033] According to the invention, an aqueous solution is also provided which contains a mixture according to the invention, wherein the first polymer and the second polymer are at least partially (preferably completely) assembled into micelles or vesicles. The term "solution" is also understood to mean an emulsion and suspension, since the micelles and / or vesicles can also be emulsified and / or suspended in the water of the solution.

[0034] The aqueous solution can be provided, for example, by adding water at room temperature (25°C) to a mixture according to the invention, incubating the resulting mixture at a temperature above 37°C (e.g., 40 to 100°C) for a certain period of time (e.g., 10 to 100 minutes), and then cooling it to a temperature of <37°C. Alternatively, water at a temperature above 37°C (e.g., 40 to 100°C) can be added to the mixture according to the invention, incubated for a certain period of time (e.g., 10 to 100 minutes), and then cooling it to a temperature of <37°C.

[0035] In a preferred embodiment, the aqueous solution contains no organic solvent. The advantage is that the aqueous solution is more physiologically compatible and no harm is caused by organic solvents when the aqueous solution is administered to a living being.

[0036] The micelles and / or vesicles of the aqueous solution can have an average hydrodynamic radius, determined via dynamic light scattering, in the range of 30 nm to 300 nm, preferably in the range of 50 nm to 200 nm, optionally in the range of 100 nm to 150 nm. A hydrodynamic radius in this range has proven advantageous for the encapsulation and transport of active ingredients. The micelles and / or vesicles of the aqueous solution can contain an active ingredient in an interior space (of the micelles and / or vesicles), wherein the active ingredient is preferably selected from the group consisting of medicinally active substances, cosmetic substances, sensor substances, lubricants, coolants, and combinations thereof, wherein the active ingredient is particularly preferably selected from the group consisting of medicinally active substances, fragrances, antiperspirants, UV protectants, coolants, lubricants, and combinations thereof.

[0037] According to the invention, the use of the aqueous solution according to the invention for the thermal release of an active ingredient is further proposed, preferably for the release of an active ingredient selected from the group consisting of medically active substances, cosmetic substances, sensor substances, lubricants, coolants and combinations thereof, wherein the active ingredient is particularly preferably selected from the group consisting of medically active substances, fragrances, antiperspirants, UV protection substances, coolants, lubricants, adhesives and combinations thereof.

[0038] The subject matter of the invention will be explained in more detail with reference to the following figures and examples, without wishing to restrict it to the specific embodiments shown here.

[0039] Figure 1 schematically shows a polymerization and self-assembly (self-organization) of linear first polymers and second polymers formed from complementary nucleoside block copolymers (C and G) which the mixture according to the invention may contain.

[0040] Figure 2A shows a reaction scheme for the synthesis of nucleobase (NB) monomer derivatives: (i) TEMPO, BAIB, CH3CN / H2O, rt, overnight (3: 44%, 4: 98%); (ii) APMA*HCl, CDMT, NMM, MeOH, rt, overnight (1: 44%, 2: 52%).

[0041] Figure 2B shows the chemical structures of ribonucleoside methacrylamides, specifically a cytidine methacrylamide derivative (1) and a guanosine methacrylamine derivative (2), which can be polymerized to produce one end of the first polymer (e.g., polymerization of the cytidine methacrylamide derivative) and one end of the second polymer (e.g., polymerization of the guanosine methacrylamine derivative), wherein the first end comprises monomers each covalently linked to a nucleobase (= nucleobase-containing region of the first and / or second polymer).

[0042] Figure 2C shows a reaction scheme for the synthesis of pHPMA 9 and nucleoside-based block copolymers pHPMA-b-piCPMA 11 and pHPMA-b-piG-PMA 12: (i) ACVA, acetate buffer (pH 5) / EtOH, 70 °C, 24 h; (ii) ACVA, DMF / H2O or l,4-dioxane / H2O, 75 °C, 24 h. pHPMA can represent a second end of the first polymer and a second end of the second polymer, wherein the second end each comprises monomers that are not covalently linked to a nucleobase (= nucleobase-free region of the first and second polymers). The nucleoside-based block copolymer pHPMA-b-piCPMA 11 can represent a first polymer and the nucleoside-based block copolymer pHPMA-b-piGPMA 12 can represent a second polymer of the mixture according to the invention.

[0043] Figure 2D shows a reaction scheme for acidic deprotection of the acetonide function of pHPMA-b-piCPMA 11 and pHPMA-b-piGPMA 12: (i) TFA, H2O, rt, 2 h (11: 53%, 12: 81%) to establish OH groups at the C2 and C3 atoms of the ribose residue. This measure can increase the solubility of pHPMA-b-piCPMA 11 and pHPMA-b-piGPMA 12 in water.

[0044] Figure 3 shows analytical data of piCPMA 5 and piGPMA 6, i.e. of a portion (e.g. piCPMA 5) of a first polymer (e.g. pHPMA-b-piGPMA) and of a portion (e.g. piGPMA 6) of a second polymer (e.g. pHPMA-b-piGPMA) of a mixture according to the invention.

[0045] Figure 4 shows analytical data of pHPMA-b-piCPMA 11 and pHPMA-b-piG-PMA 12, i.e. of a first polymer (e.g. pHPMA-b-piCPMA) and of a second polymer (e.g. pHPMA-b-piGPMA) of a mixture according to the invention.

[0046] Figure 5A shows SEM image, size distribution, and hydrodynamic size distribution by DLS of pHPMA-b-pCPMA 13. Figure 5B shows SEM image, size distribution, and hydrodynamic size distribution by DLS of pHPMA-b-pGPMA 14.

[0047] Figure 6A shows SEM image, size distribution and hydrodynamic size distribution by DLS of a mixture of pHPMA-b-pCPMA 13 and pHPMA-b-pGPMA 14 at room temperature (25 °C) before heating to > 37 °C (100 °C).

[0048] Figure 6B shows SEM image, size distribution and hydrodynamic size distribution by DLS of the same mixture from Figure 5A, only after heating to > 37 °C (100 °C) for 30 min and subsequent cooling to room temperature (25 °C).

[0049] Figure 7 shows a UV-Vis spectrum of the average of the individual polymer 13 and polymer 14 (lineshape: - - - -), a mixture of polymer 13 and polymer 14 at room temperature (25 °C) before heating to > 37 °C (100 °C) (lineshape: - ) and the mixture of polymer 13 and polymer 14 after heating to > 37 °C (100 °C) for 30 minutes and subsequent cooling to room temperature (25 °C) (lineshape: - ).

[0050] Figure 8 shows a reaction scheme of another possible RAFT polymerization for producing a first polymer or a second polymer of a mixture according to the invention.

[0051] Figure 9 schematically shows a self-assembly of branched first polymers and second polymers which the mixture according to the invention may contain.

[0052] Example 1 - Basics for the assembly of the polymers of the mixture

[0053] In 1976, Israelachvili et al. presented their theory on the self-assembly of amphiphilic molecules and introduced the concept of the critical packing parameter (P c ) to predict the formation of supramolecular structures from amphiphilic molecules (Israelachvili, JN et al., Theory of selfassembly of hydrocarbon amphiphiles into micelles and bilayers., Journal of the Chemical Society-Faraday Transactions, 72:1525-1568 (1976). The critical packing parameter is defined as

[0054] P c = v / aolc where v: volume of the hydrophobic portion, ao: area occupied by the hydrophilic head group, l c : Contour length of the molecule.

[0055] The critical packing parameter thus describes the shape of the molecule, which is related to the curvature at the hydrophobic-hydrophilic interface and thus enables a prediction of the self-assembled structure

[0056] Pc values ​​below 0.5 (especially < 0.33) result in highly curved aggregates such as spherical and cylindrical micelles (single-layer arrangement). Pc values ​​from 0.5 to 1 result in the formation of vesicles (bilayer arrangement). P c -Values ​​of >1 result in the formation of inverse micelles.

[0057] In the present case, the first polymer and the second polymer of the mixture according to the invention do not have one hydrophilic region (portion) and one hydrophobic region (portion), but rather two hydrophilic regions (portions). Strictly speaking, therefore, the first polymer and the second polymer of the mixture according to the invention are not amphiphilic molecules.

[0058] Nevertheless, the theory of self-assembly developed by Israelachvili et al. is also applicable to the first polymer and the second polymer of the inventive mixture (see, for example, Polymer Vesicles, DE Discher & A. Eisenberg; Science, 297:967-973). The "hydrophobic" region in the amphiphilic molecules of the theory corresponds in the polymers of the inventive mixture to a region of the first polymer and the second polymer that contains the monomers that are each covalently bonded to a nucleobase. This region of the first polymer and the second polymer leads to the assembly of the first and second polymers into micelles or vesicles via hybridization of complementary nucleobases between the first and second polymers in an aqueous medium at a temperature of <37°C.This favored interaction leads to a microphase separation of the non-functionalized hydrophilic part and the other hydrophilic part, which assembles with its complementary counterpart through the formation of hydrogen bonds and pi-stacking. As a result, the two polymer parts are not uniformly miscible, but rather cause a phase separation through demixing, which is responsible for the supramolecular structure formation.

[0059] This type of assembly is comparable to the assembly of the hydrophobic region of lipids, which is driven by the hydrophobic effect. However, unlike the assembly of lipids via the hydrophobic effect, the assembly of the polymers in the mixture according to the invention can be broken by raising the temperature to a temperature in the range of > 37°C, causing assembled micelles or vesicles to disassemble, i.e., lose their micellar or vesicular structure.

[0060] The region (portion) of the first polymer and the second polymer that does not contain nucleobase-linked monomers (e.g., a region containing or consisting of PEG) may be suitable for promoting phase separation. Advantageously, this region (compartment) is more hydrophilic than the region (portion) of the first and second polymers that contains the nucleobase-linked monomers.

[0061] Since the theory of self-assembly developed by Israelachvili et al. is also applicable to the first polymer and the second polymer of the mixture according to the invention, the critical packing parameter for the first polymer and the second polymer of the mixture according to the invention can be defined as:

[0062] P c= v / aolc where v: volume of the region of the polymer which has monomers each bound to a nucleobase (nucleobase-containing region), ao: area formed by the region of the polymer which has no monomers bound to

[0063] Nucleobase-bound monomers (ie nucleobase-free region) l c : Contour length of the polymer molecule.

[0064] The P c should be essentially the same for the first polymer and the second polymer (deviation preferably maximum 10%). Common P c Values ​​below 0.5 (especially < 0.33) cause an assembly of the first and second polymers into spherical and cylindrical micelles, whereas common P c Values ​​in the range of 0.5 to 1 cause the first and second polymers to assemble into vesicles. Common P c -values ​​of >1 can cause assembly into inverse micelles. According to the invention, P cValues ​​in the range 0.5 to 1 are preferred, since in this range vesicles are formed and the formation of vesicles represents a preferred embodiment of the invention.

[0065] Example 2 - Linking of nucleobases with monomers

[0066] Nucleosides were used as protected 2',3'-acetonide forms to address the 5'-position. For stability reasons, methacrylamide-functionalized ribonucleosides were preferred over methacrylate derivatives, which can be synthesized enzymatically. The synthesis of the cytidine- (1) and guanosine-based monomers (2) (see Figure 2B) was carried out in a two-step process involving the oxidation of the primary hydroxyl group and subsequent amide coupling with / V-(3-aminopropyl)-methacrylamide (see Figure 2A). Despite the higher nucleophilicity of the exocyclic -NH2 group, in contrast to enzymatic esterification, no protection step of this functionality was required.

[0067] To oxidize commercially available 2',3'-isopropylidene-cytidine and 2',3'-isopropylidene-guanosine to their carboxylic acid derivatives, the acetal-protected ribonucleosides were briefly oxidized with TEMPO and BAIB in the presence of NaHCO3. After filtration of the precipitate, oxidized cytidine (3) was obtained in 44% yield, while the yield of oxidized guanosine (4) was quantitative as a white powder (see Figure 1A). Compounds 1 and 2 (see Figure 2B) were obtained after amide coupling of compounds 3 and 4 (see Figure 2A) with / V-(3-aminopropyl)methacrylamide hydrochloride using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) in 44% and 52% yield, respectively (see Figure 2A). The chemical structure was confirmed by NMR spectroscopy and ESI-MS analyses.

[0068] Compound 2 showed lower solubility than compound 1, but both ribonucleoside methacrylamide-based monomers showed reasonable solubility in nonpolar solvents such as chloroform and diethyl ether, as well as in polar solvents such as dichloromethane, acetone, and dimethylformamide as aprotic solvents, and water, methanol, and ethanol as protic solvents. This solubility property can be explained by the simultaneous formation of hydrogen bonds and hydrophobic moieties within one molecule. Due to the high solubility of the two monomer molecules, further deprotection of the nucleoside monomers was omitted for the polymerizations.

[0069] Example 3 - Preparation of a nucleobase-containing section of the polymers

[0070] RAFT-mediated polymerization is one of the most important and well-known polymerization techniques involving a radical initiator and a chain transfer agent (CTA). Here, the dithioester-based CTA 4-cyano-4-(phenylcarbonothioylthio)pentanoic acid (CPADB) was chosen because it has been described for the polymerization of methacrylamide-based monomers.

[0071] Compounds 1 and 2 (see Figure 2B) were homopolymerized by RAFT polymerization using ACVA as a thermal initiator at 75 °C. Polymerizations of nucleoside-based monomers were performed with a [M0]:[CTA0]:[l0] ratio of 75:3:1. Observation of solvent mixtures of 8:2 DMF / H2O and 9:1 l,4-dioxane / H2O showed different effects depending on the nucleoside type. The use of a 9:1 1,4-dioxane / FhO mixture resulted in high conversion (94%) of the G-based polymer (piGPMA), whereas the conversion of the cytidine-based polymer (piCPMA) was reduced to 34% using the same solvent mixture. On the other hand, in 8:2 DMF / H2O, the conversion of piCPMA was increased to 40% and that of piGPMA was decreased to only 70%.

[0072] The polymerizations of the nucleoside homopolymers and their monomer conversions were determined by comparing the integrals of the typical C-4 protons of piCPMA (δ 4.43 ppm) and piGPMA (δ 4.50 ppm) with the integrals of the monomeric vinyl peaks of iCPMA (δ 5.64 ppm and 5.30 ppm) and iGPMA (δ 6.39 ppm and 5.61 ppm). The theoretical molecular weights (Mn, theory, NMR) are summarized in Figure 3.

[0073] The acetonide protecting groups of the homopolymers of both ribonucleosides were removed under acidic conditions with trifluoroacetic acid (see Figure 2D) to improve the hydrophilicity due to the demanding solubility properties.

[0074] Example 4 - Preparation of polymers of mixtures according to the invention

[0075] Polymers according to the invention, specifically block copolymers with nucleosides (pHPMA-b-piCPMA 11 and pHPMA-b-piGPMA 12), were prepared using the RAFT-mediated polymerization technique.

[0076] Specifically, a nucleobase-free polymer was first prepared. Poly(V-(2-hydroxypropyl)methacrylamide) (pHPMA) was selected due to its biocompatibility. For this purpose, an HPMA macroinitiator was first prepared via RAFT-mediated polymerization according to S. Perrier (50th Anniversary Perspective, RAFT Polymerization—A User Guide, Macromolecules, 2017, 50, 7433–7447). The monomer conversion to pHPMA was 75%, resulting in a theoretical Mn of 7.8 kDa.

[0077] Subsequently, compound 1 or compound 2 (see Figure 2B) was polymerized to the pHPMA via RAFT-mediated polymerization to produce polymers (block copolymers) according to the invention. These were synthesized with a low "live" rate. "Live" is a property that enables chain extension. It indicates how many "live" chains remain intact for further block copolymerizations. Low "live" leads to high amounts of dead ends, resulting in nucleobase-based polymers lacking the phenyl Z group, which can interfere with UV-Vis spectroscopy analysis. The calculated "live" rates were kept low and are 36.0% for polymer 11, while they were 15.6% for polymer 12.

[0078] The polymerization of compound 1 and compound 2 was carried out in the solvent system most suitable for the homopolymers: compound 1 in 8:2 DMF / H2O, compound 2 in 9:1 l,4-dioxane / H2O. The pyrimidine-based compound 2 resulted in a higher conversion and thus a higher molecular weight than the purine-based compound 1 (see Figure 4). The monomer conversion was determined by comparing the integrals of the monomer peak (1: δ 5.30 ppm; 2: δ 5.61 ppm) with the peak of the nucleoside-based polymer (b-piCPMA δ 4.37 ppm or b-piGPMA δ 6.14 ppm). The monomer conversion for polymer 11 was 68%, while for polymer 12 it was 78% (see Figure 4).

[0079] The two nucleoside-based block copolymers 11 and 12 showed low solubilities in water due to the integrated nucleobases.

[0080] The block copolymers were removed by acidic deprotection of the acetal functionalities with trifluoroacetic acid (Figure 2D). Successful deprotection was confirmed by the disappearance of the two singlets in the upfield, originating from the acetal protecting groups of polymer 11 (δ 1.46 ppm and 1.28 ppm) and polymer 12 (δ 1.48 and 1.33 ppm), in the 1H NMR spectroscopy analysis. Shaking for a total of 2 hours yielded polymer 13 and polymer 14 (Figure 4D), which represent polymers according to the invention and exhibit improved solubility in water. Example 5 - Assembly of the Polymers into Vesicles

[0081] To investigate vesicle formation (see Figure 1) due to hydrogen bonding interactions between the purine and pyrimidine functionalities, SEM and DLS analyses were performed (Figures 5 and 6).

[0082] The SEM images show that pHPMA-b-pCPMA 13 forms large network structures in aqueous solution. These structures result from stronger C–C interactions with a broad size distribution and an average size of 280 nm. This broad size distribution was also determined by DLS, with a polydispersity index (PDI) of 0.421. The average hydrodynamic diameter of polymer 13 is 507 nm. However, SEM images of pHPMA-b-pGPMA 14 show small particles due to G–G interactions with an average size of 86 nm. The size distribution was smaller according to DLS, with an average hydrodynamic diameter of approximately 144 nm (PDI = 0.213) (Figure 5).

[0083] Blending the two complementary block copolymers resulted in particles with an average hydrodynamic diameter of approximately 165 nm and a PDI of 0.3. Heating this mixture to 100 °C for 30 minutes and subsequent cooling resulted in a narrower size distribution and a smaller average size of 266 nm and a hydrodynamic diameter of 136 nm (Figure 6).

[0084] This observation could be explained by the breaking of the strong C–C and G–G hydrogen bonds at higher temperatures and the restoration of C–G interactions upon cooling to room temperature (rt). Sonication of polymers 13, 14 and the blend of both polymers 13, 14 did not result in any change in morphology, indicating high stability.

[0085] Nucleobases exhibit strong UV absorption due to hydrogen bonds and n-n interactions. Base pairing interactions of nucleobase derivatives lead to changes in UV-Vis spectroscopy. Spectrophotometric measurements were performed to investigate the hydrogen bond interactions of the complementary nucleoside-containing polymers 13 and 14 (Figure 7).

[0086] The UV absorption spectra of the individual polymers 13 and 14 were compared with the spectrum of the blend after heating. The average values ​​of the individual polymers pHPMA-b-pCPMA 13 and pHPMA-b-pGPMA 14 agree with the absorption values ​​of the blend of both polymers at the same concentrations, which is due to the hydrogen bonds of the individual polymers.

[0087] After heating the polymer mixture to a temperature of > 37°C (100°C) for 30 minutes, a decrease in absorption was observed (hypochromism), resulting from the reassembly of the complementary CG interactions after heating and cooling.

[0088] The hypochromism at a wavelength of 260 nm is considered to indicate dsDNA-like structures, which exhibit lower absorption compared to ssDNA. This demonstrates that the targeted assembly of polymers 13 and 14 into vesicles via hybridization of their nucleobases was successful.

[0089] Example 6 - Alternative preparation of polymers of mixtures according to the invention

[0090] Example 4 provided a first example of how polymers according to the invention, ie, polymers of a mixture according to the invention, can be prepared. An alternative preparation process, which is also based on RAFT-mediated polymerization, is given below (see also Figure 8).

[0091] Monomers of ( / V-(2-hydroxypropyl)methacrylamide (HPMA) are attached to a homopolymer, whose monomers each have an active ester, via RAFT-mediated polymerization, so that a block copolymer is formed, the first block of which is formed by the homopolymer, whose monomers each have an active ester, and the second block of which is formed by poly-( / V-(2-hydroxypropyl)methacrylamide (pHPMA). If this block copolymer is then coupled and deprotected with a nucleobase that is bound to a hydrophilic spacer with an amino group, the active ester of the monomers of the first block of the block copolymer reacts with the amino group of the spacer bound to the nucleobase, whereby a nucleobase is bound to a monomer of the first block of the block copolymer via its hydrophilic spacer and via an amide bond.This creates a block copolymer whose first block consists of monomers, each of which has a nucleobase bound (via a hydrophilic linker), and whose second block consists of pHPMA.

[0092] Example 7 - Assembly of branched polymers

[0093] The first polymer and the second polymer may each be a branched polymer, ie a polymer with at least three arms (e.g. 3-arm PEG or 4-arm PEG).

[0094] In this case, it is advantageous if the first polymer and the second polymer have at least six nucleobases, each covalently bonded to a respective monomer of the polymer, distributed at a first end and a second end of the first polymer and the second polymer, respectively. For example, the first polymer has six monomers, each covalently bonded to a nucleobase, at a first end and six monomers, each covalently bonded to a nucleobase, at a second end (see Figure 9: oligo block 1), and the second polymer has six monomers, each covalently bonded to a nucleobase, at a first end and six monomers, each covalently bonded to a nucleobase, at a second end (see Figure 9: complementary oligo block 2).

[0095] The branching in the first polymer and the second polymer can be realized in such a way that a monomer of the first polymer and of the second polymer, which is not (directly) linked to a nucleobase and is located between the first and second ends of the first and second polymers, respectively (in particular in their middle), is linked to another polymer (e.g., PEG), optionally via a spacer (or linker, e.g., a polymer linker). In this case, the other polymer branches off from the first and second polymers, so that the first and second polymers form a type of "fork structure" (see Figure 9). The other polymer is advantageously suitable for effecting phase separation after the first polymers have been linked to the second polymers in an aqueous phase at a temperature in the range of <37°C (see Figure 9: polymer block for phase separation).

[0096] If the mixture according to the invention contains two branched polymers, it is advantageous for assembly into micelles or vesicles if the volume fraction of the region of the first polymer and the second polymer that assembles in aqueous solution (i.e. the region that has the monomers that are each attached to a nucleobase) is as similar as possible to the volume fraction of the region of the first polymer and the second polymer that does not assemble in aqueous solution (i.e. the region that has the monomers that are each not attached to a nucleobase).

[0097] The first polymer and the second polymer can each comprise a 4-arm PEG (e.g., with a molar mass of 5000 g / mol), with at least two arms of the 4-arm PEG comprising the monomers (preferably at their ends), each covalently bonded to a nucleobase. These monomers can represent an oligomer consisting of monomers bound sequentially to nucleobases (e.g., each arm has four or six such monomers). The oligomer can be configured as an oligonucleotide.

Claims

Claims: A mixture comprising a) a first polymer having at least six nucleobases, wherein each nucleobase is covalently linked to each monomer of the polymer; and b) a second polymer having at least six nucleobases, wherein each nucleobase is covalently linked to each monomer of the polymer, wherein the at least six nucleobases of the second polymer are complementary to the at least six nucleobases of the first polymer; characterized in that the first polymer and the second polymer are suitable, via their mutually complementary nucleobases, to assemble into micelles or vesicles in an aqueous solution at a temperature of < 37°C by forming hydrogen bonds between their complementary nucleobases, and not to assemble into micelles or vesicles at a temperature of > 37°C due to the absence of hydrogen bonds between their complementary nucleobases.A mixture according to the preceding claim, characterized in that the mixture further contains an active ingredient, wherein the active ingredient is preferably selected from the group consisting of medically active substances, cosmetic substances, sensor substances, lubricants, coolants, adhesives and combinations thereof, wherein the active ingredient is particularly preferably selected from the group consisting of medically active substances, perfumes, antiperspirants, UV protectants, coolants, lubricants, adhesives and combinations thereof. A mixture according to one of the preceding claims, characterized in that the i) first polymer contains at least 20, preferably at least 50, particularly preferably at least 100, most preferably at least 200, in particular at least 500, monomers or consists thereof; and / or ii) second polymer contains at least 20, preferably at least 50, particularly preferably at least 100, most preferably at least 200, in particular at least 500, monomers or consists thereof.A mixture according to one of the preceding claims, characterized in that i) the first polymer comprises at least ten, preferably at least twelve, particularly preferably at least 14, in particular at least 16, optionally a maximum of 18, nucleobases, wherein each nucleobase is covalently linked to each monomer of the first polymer; and ii) the second polymer comprises at least ten, preferably at least twelve, particularly preferably at least 14, in particular at least 16, optionally a maximum of 18, nucleobases, wherein each nucleobase is covalently linked to each monomer of the second polymer, wherein the nucleobases of the second polymer are complementary to the nucleobases of the first polymer.Mixture according to one of the preceding claims, characterized in that in the i) first polymer, between two successive monomers, each linked to a nucleobase, a maximum of three monomers, preferably a maximum of two monomers, particularly preferably a maximum of one monomer, in particular no monomer, are arranged which are not each covalently linked to a nucleobase; and / or. ii) a second polymer, in which a maximum of three monomers, preferably a maximum of two monomers, particularly preferably a maximum of one monomer, and in particular no monomer, are arranged between two successive monomers, each linked to a nucleobase, and each monomer is not covalently linked to a nucleobase. A mixture according to one of the preceding claims, characterized in that the nucleobases in i) the first polymer are nucleobases containing or consisting of cytosine, isocytosine, and / or adenine, preferably cytosine; and / or ii) the second polymer are nucleobases containing or consisting of guanine, isoguanine, and / or thymine, preferably guanine.A mixture according to one of the preceding claims, characterized in that the nucleobases of i) the first polymer are linked to the monomer of the first polymer via a ribose residue, wherein preferably the nucleobase is linked to the Cl atom of the ribose residue and the monomer is linked to the C5 atom of the ribose residue; ii) the nucleobases of the second polymer are linked to each of the monomers of the first polymer via a ribose residue, wherein preferably the nucleobase is linked to the Cl atom of the ribose residue and the monomer is linked to the C5 atom of the ribose residue.Mixture according to one of the preceding claims, characterized in that the monomers of the first polymer and / or the second polymer, each of which is linked to a nucleobase, i) each contain or consist of a residue selected from the group consisting of amino acid residue, sugar residue, ribose phosphate residue, methacrylamide residue, and combinations thereof, wherein the residue is preferably selected from the group consisting of ribose phosphate residue, methacrylamide residue. and combinations thereof, wherein the residue is particularly preferably selected from the group consisting of ribose-5-phosphate residue, / V-(3-aminopropyl)-methyarylamide residue and combinations thereof; and / or ii) form a homopolymer, wherein the homopolymer is preferably selected from the group consisting of polypeptide, polysaccharide, polyribose phosphate, polymethacrylamide and combinations thereof, wherein the homopolymer is particularly preferably selected from the group consisting of poly-ribose phosphate, polymethacrylamide and combinations thereof, wherein the homopolymer is particularly preferably selected from the group consisting of poly-ribose-5-phosphate, poly-( / V-(3-aminopropyl)-methyarylamide and combinations thereof;and / or iii) are covalently linked to the nucleobase via a bond, optionally via a ribose residue selected from the group consisting of ester bonds, thioester bonds, ether bonds, and amide bonds, wherein the bond is preferably an amide bond, particularly preferably an amide bond to a ribose residue covalently linked to the nucleobase, and in particular an amide bond to a C5 atom of a ribose residue covalently linked to the nucleobase at the Cl atom of the ribose residue. Mixture according to one of the preceding claims, characterized in that monomers of the first polymer and / or second polymer, each not linked to a nucleobase, i) each contain or consist of a residue selected from the group consisting of ( / V-(2-hydroxypropyl)methacrylamide residue, vinylamine residue, butadiene residue, ethylene oxide residue, acrylic acid residue, amino acid residue, sugar residue, and combinations thereof;and / or ii) form a homopolymer, a block copolymer or a heteropolymer, wherein the homopolymer is preferably selected from; a mixture consisting of poly( / v-(2-hydroxypropyl)methacrylamide, polyvinylamine, polyethylene oxide, polypeptide, polysaccharide, and combinations thereof, particularly preferably poly( / v-(2-hydroxypropyl)methacrylamide, and / or the block copolymer is preferably selected from the group consisting of polybutadiene polyethylene oxide, polyvinylamine polyethylene oxide, polyglutamic acid polyethylene oxide, polyacrylic acid, and combinations thereof, and / or the heteropolymer is preferably selected from the group consisting of polypeptide, polysaccharide, and combinations thereof. A mixture according to any one of the preceding claims, characterized in that the mixture does not contain an organic solvent. A mixture according to any one of the preceding claims for use in medicine, preferably for the thermal release of an active ingredient, particularly preferably for the thermal release of an active ingredient for the treatment of cancer.An aqueous solution containing a mixture according to any one of the preceding claims, wherein the first polymer and the second polymer are at least partially assembled into micelles or vesicles. An aqueous solution according to claim 12, characterized in that the micelles and / or vesicles have an average hydrodynamic radius, determined by dynamic light scattering, in the range of 30 nm to 300 nm, preferably in the range of 50 nm to 200 nm, optionally in the range of 100 nm to 150 nm. An aqueous solution according to claim 12 or 13, characterized in that the micelles and / or vesicles contain an active ingredient in an interior space, wherein the active ingredient is preferably selected from the group consisting of medically active substances, cosmetic substances, sensor substances, lubricants, coolants, and combinations thereof, wherein the active ingredient is particularly preferred. The substance is selected from the group consisting of medically active substances, fragrances, antiperspirants, UV protectants, coolants, lubricants, and combinations thereof. Use of an aqueous solution according to any one of claims 12 to 14 for the thermal release of an active ingredient, preferably for Release of an active ingredient selected from the group consisting of medically active substances, cosmetic substances, sensor substances, lubricants, coolants and combinations thereof, wherein the active ingredient is particularly preferably selected from the group consisting of medically active substances, perfumes, antiperspirants, UV protectants, coolants, lubricants, adhesives and combinations thereof.

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