NIR Absorbing Capsules

Abstract

The capsules comprise a polymer shell surrounding a NIR absorber, the polymer shell comprising poly(amino acids) and obtainable by interfacial polymerization of N-carboxy-anhydride monomers according to the general structure (I). The capsules are suitable for optical medicine such as phototherapy including photothermal therapy (PTT), photodynamic therapy (PDT), photo-stimulated drug release, and medical fluorescence imaging. [Formula 1] TIFF2024514096000032.tif29166

Description

[Technical Field]

[0001] The present invention relates to the design of biocompatible organic nanocapsules and microcapsules for opto-medical applications such as phototherapy, including photothermal therapy (PTT), photodynamic therapy (PDT), light-stimulated drug release, and medical fluorescence imaging. [Background technology]

[0002] Background Field Near-infrared (NIR) laser technology is gaining importance in the noninvasive treatment and medical diagnosis of various diseases, including photothermal therapy, photodynamic therapy, fluorescence imaging, and photoacoustic imaging. Several of these technologies rely on NIR-absorbing nanoparticles, often inorganic nanoparticles, such as gold nanoparticles, carbon nanomaterials including carbon nanotubes, metal sulfides, metal oxides, and various upconverting nanoparticles. The use of inorganic photothermal conversion nanoparticles has been extensively reviewed (Non-Patent Document 1; Non-Patent Document 2). While these nanoparticles offer excellent NIR responses, they are not biodegradable and suffer from the risk of bioaccumulation and long body retention times, potentially increasing the likelihood of long-term toxicity. Therefore, nanoparticles based on biocompatible organic NIR absorbers appear to be highly desirable.

[0003] Although several classical organic NIR absorbers have been well documented for optical medicine applications, cyanine dyes are a particularly suitable class of NIR absorbers due to their high molar extinction coefficient. The high molar extinction of NIR laser light has the advantage of reducing the amount of NIR absorber required, enabling applications in in vitro and in vivo imaging and the treatment of deep-seated diseases, such as tumors. One of the best-known and FDA-approved cyanine dyes is indocyanine green.

[0004] NIR absorbers such as indocyanine green must be encapsulated to extend their lifetime in the body, to make them dispersible in the body's aqueous fluids, to prevent photobleaching, and to increase their tumor targeting ability.

[0005] Furthermore, encapsulation of NIR absorbers has other additional benefits. The spectral characteristics of some classes of NIR absorbers are highly dependent on their environment; for example, they can change as a function of pH and ionic strength, and these changes are caused by aggregation phenomena. Therefore, physically encapsulating NIR absorbers makes the spectral characteristics and photophysical properties of the absorbers independent of the external environment. This makes their response in physiological environments highly predictable. The adjustment of the laser response is easily achieved by adjusting the concentration of the NIR absorber in the capsule, avoiding the laborious synthesis of the NIR absorber each time.

[0006] Polypeptide-based materials, such as poly(amino acids), are attractive candidates for encapsulation due to their biocompatibility, biodegradability, high chemical functionality, tunable structural architecture, and ability to form nanocapsules or microcapsules.

[0007] Encapsulation of NIR absorbers by poly(amino acids) is generally achieved via coacervation or micelle formation. Poly(amino acids) are prepared by ring-opening polymerization of N-carboxy-anhydride monomers (NCAs).

[0008] Amphiphilic block copolymers containing poly(amino acid) blocks for the purpose of forming micelles The aggregates must be prepared separately and assembled into micelle-like capsules or transferred into capsules using a coacervation-type approach. The amphiphilic block copolymers can self-assemble into micelles to hold up the NIR absorbers.

[0009] In another approach, coacervation is achieved by combining anionic and cationic poly(amino acid) electrolytes together, as disclosed in Non-Patent Document 3. Coacervation always requires at least two polyelectrolytes, which limits the selection of useful poly(amino acids). The resulting capsule shells, held together by electrostatic forces between the polyelectrolytes, are susceptible to water penetration, thereby providing substantial water permeability toward the capsule core and, therefore, toward the encapsulated compound(s).

[0010] Both techniques result in capsules or micelles that have the disadvantage of having a shell that is much weaker than capsules with a polymer shell. In many systems, it becomes necessary to crosslink the shell of the micellar system to ensure biostability.

[0011] Poly(amino acids) can be prepared by polymerization of N-carboxyanhydride monomers (NCAs) in heterogeneous aqueous solvent systems. Non-Patent Document 4 described the preparation of glycopeptide microparticles using acylated chitosan as a starting material for the graft polymerization of NCAs in heterogeneous aqueous solvent systems. Emulsifying the aqueous phase into the solvent phase was particularly important, which limited the formation of large particles on the order of 100 to 800 microns, with shell thicknesses of around 50 microns. This particle size is completely outside the scope of many applications, including several biomedical applications where particles well below 1 micron are required. The disclosed microparticles were prepared using L-leucine as the amino acid and did not contain any specific core material. While the oil-in-water method has been preferred so far because it does not require complete evaporation before redispersion in water, converting the disclosed method to this method is far from obvious. In the proposed method, the compound to be encapsulated must be water-soluble, since water is the discontinuous phase. This method does not allow for the one-step encapsulation of more hydrophobic compounds, which can only be introduced by reloading the isolated capsules, making this type of encapsulation very laborious and economically unfeasible for many applications.

[0012] Biocompatible capsules or micelles for use in photothermal therapy, photodynamic therapy, light-stimulated drug delivery, and medical fluorescence imaging must possess stealth properties to avoid uptake by the reticuloendothelial system and to act, i.e., release drugs, only at the desired site in a controlled manner. Stealth properties can be introduced into carriers such as capsules and micelles through the incorporation of synthetic polymers with inherent stealth properties, such as poly(ethylene glycol) (PEG). The incorporation of PEG often requires laborious synthesis protocols of polyelectrolytes or amphiphilic block copolymers prior to encapsulation, which poses an obstacle to the simple and scalable preparation of NIR-absorbing poly(amino acid)-based capsules.

[0013] Micelle-like capsules often require a liquid medium to maintain their spherical structure, e.g., to retain the core material inside the micelle. Therefore, it is very difficult or impossible to isolate micelles in the dry state. Micelles and capsules obtained via coacervation, in contrast to capsules obtained by interfacial polymerization, are limited in the range of particle sizes that can be obtained. Furthermore, although amphiphilic block copolymer approaches allow good control of the polymer structure, the preparation of well-defined polymers requires extensive synthetic procedures, and therefore these approaches are not comparable to those based on interfacial polymerization. In contrast to technologies based on

[0014] Nano- and microcapsules can be prepared using both chemical and physical methods. For engineering applications, interfacial polymerization is a particularly preferred technique as it allows the most control in capsule design.

[0015] Patent Document 1 discloses capsules prepared by interfacial polymerization, which include a shell of vinylic urethane, vinylic amide, or vinylic urea units and a core that can contain a reactive chemical in combination with an IR-absorbing dye. The shell of vinylic urethane, vinylic amide, or vinylic urea units is not biodegradable.

[0016] Therefore, there is a need for an aqueous, single-step encapsulation technique that can directly access aqueous dispersions of poly(amino acid)-based capsules, encapsulate a range of compounds over a wide range of particle sizes, including submicron particle sizes, and contain shells that exhibit high mechanical strength, low water permeability, and that are biodegradable. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] WO2018 / 234179 [Non-patent literature]

[0018] [Non-Patent Document 1] Raza et al., Journal of Materials Research and Technology, 8(1), 1497-1509 (2019) [Non-patent document 2] Wang et al., International Journal of Nanomedicine, 15, 1903-1914 (2020) [Non-patent document 3] ACS Macro Lett. 2014, 3, 1088-1091 and in Chem. Lett. 2012, 41, 13541356 [Non-patent document 4] Wang et al. (International Journal of Biological Macromolecules Elsevier BV, NL, Volume 42, No. 1, p. 450-454) Summary of the Invention

[0019] The object of the present invention is to provide a solution to the above-mentioned problems, which is realized by an NIR absorber encapsulated in poly(amino acids) by an industrially and easily scalable technology as defined in claim 1.

[0020] A further aspect of the present invention is to provide an aqueous dispersion of capsules as defined in claim 1. The aqueous dispersion is defined in claim 10.

[0021] According to another aspect, the present invention comprises an industrially scalable method for encapsulating NIR absorbers in poly(amino acids), as defined in claim 13.

[0022] Other features, elements, steps, characteristics and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention. Specific embodiments of the invention are also defined in the dependent claims. DETAILED DESCRIPTION OF THE INVENTION

[0023] A. Capsule The object of the present invention is realized by a capsule with a core comprising a NIR absorber and a shell comprising an oligo- or poly(amino acid), the capsule being obtained by oligomerization or polymerization of at least one N-carboxy-anhydride monomer according to general formula I, [ka] During the ceremony n represents 0 or 1. R1, R2, and R3 are selected from the group consisting of hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkaryl groups, and substituted or unsubstituted aryl or heteroaryl groups. Any of R1, R2, and R3 can represent the atoms necessary to form a five- to eight-membered ring.

[0024] The particle size of the capsules of the present invention is preferably 0.05 μm to 10 μm, more preferably 0.07 μm to 5 μm, and most preferably 0.1 μm to 3 μm. Capsules according to the present invention with a particle size of less than 1 μm are particularly preferred, as they reduce the risk of capillary blockage in administration needles and tubing and prevent phagocytosis.

[0025] A.1. N-Carboxy-anhydride Monomers The object of the present invention is realized by capsules obtained by oligomerization or polymerization of at least one N-carboxy-anhydride monomer according to general structure I

[0026] In preferred embodiments, n represents 0. In particularly preferred embodiments, R3 represents hydrogen or an alkyl group, with hydrogen being most preferred.

[0027] In another preferred embodiment, R1 and R2 are selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, and a substituted or unsubstituted aryl group.

[0028] In a further preferred embodiment, the N-carboxy-anhydride monomer according to the general structure is selected from the group consisting of glycine derivatives, alanine derivatives, leucine derivatives, phenylalanine derivatives, phenylglycine derivatives, valine derivatives, glutamic acid derivatives, aspartic acid derivatives, lysine derivatives, ornithine derivatives, histidine derivatives, methionine derivatives, cysteine ​​derivatives, arginine derivatives, tryptophan derivatives, cysteine ​​derivatives, isoleucine derivatives, tyrosine derivatives, proline derivatives, and serine derivatives. Both D- and L-amino acid derivatives and mixtures thereof can be used.

[0029] Exemplary N-carboxy-anhydride monomers are provided in Table 1, but are not limited thereto. [Table 1-1] [Table 1-2]

[0030] N-Carboxy-anhydrides (NCAs) have been prepared using various synthetic methods, the earliest of which is known as the Leuchs method, which starts with the chloroformic acid acylation of an amino acid followed by its conversion to the corresponding NCA via its acid chloride. Several variations of this method have been published by Wessely and Katschalski, using the mixed anhydride method and PBr3-based conversion, respectively. Perhaps the best-known method is the Fuchs-Farting method, which uses phosgene for the direct conversion of an amino acid to the corresponding NCA. For safety reasons, phosgene has been replaced by diphosgene or triphosgene in subsequent studies. Over the years, several phosgene-free methods have been described, such as those by Secker et al. A review article has been published (Macromol. Biosci., 15, 881-891 (2015)).

[0031] A.2. NIR absorbers Any organic near-infrared (NIR) absorber known in the art can be used in the present invention as long as the NIR absorber is soluble in at least one water-immiscible solvent. A water-immiscible solvent is defined as a solvent that forms a two-phase system at room temperature when mixed with water in a 1:1 ratio. Esters and ketones are particularly suitable water-immiscible solvents.

[0032] Exemplary NIR absorbers can be selected from the group consisting of polymethylindolium, metal complex IR dyes, indocyanine green, polymethine dyes, croconium dyes, cyanine dyes, merocyanine dyes, squarylium dyes, chalcogenopyryloarylidene dyes, metal thiolate complex dyes, bis(calcogenopyrylo)polymethine dyes, oxiindolizine dyes, bis(aminoaryl)polymethine dyes, indolizine dyes, pyrylium dyes, quinoid dyes, quinone dyes, phthaloanine dyes, naphthalocyanine dyes, azo dyes, (metallated) azomethine dyes, and combinations thereof.

[0033] Cyanine dyes are a particularly suitable class of NIR absorbers due to their high extinction coefficients.

[0034] Cyanine dyes that are highly soluble in organic solvents are particularly suitable because they can be easily incorporated into the core of the capsules of the present invention by interfacial polymerization. Therefore, cyanine dyes according to general formula II are particularly suitable for designing nanoparticles according to the present invention. [ka] During the ceremony, A and A' independently represent a substituted or unsubstituted heterocyclic group that is covalently bonded to the polymethine chromophore via a carbon atom; R4 and R5 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkaryl groups, and substituted or unsubstituted aryl or heteroaryl groups; R4 and R5 can represent atoms necessary to form a five- to eight-membered ring; R6 and R7 are independently selected from the group consisting of a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, and a substituted or unsubstituted aryl or heteroaryl group.

[0035] In a further preferred embodiment, the NIR absorber represents a compound according to general formula III: [ka] During the ceremony, R4 and R5 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkaryl groups, and substituted or unsubstituted aryl or heteroaryl groups; R4 and R5 can represent atoms necessary to form a five- to eight-membered ring; R6 and R7 are independently selected from the group consisting of substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkaryl groups, and substituted or unsubstituted aryl or heteroaryl groups; R8 and R9 independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, and a substituted or unsubstituted aryl or heteroaryl group; Q represents atoms necessary to form a substituted or unsubstituted 5- or 6-membered heterocyclic ring.

[0036] In a more preferred embodiment, R4 and R5 represent the atoms necessary to form a substituted or unsubstituted five- or six-membered ring, with five-membered rings being most preferred.

[0037] In another preferred embodiment, R6 and R7 independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted aralkyl group, and a substituted or unsubstituted alkyl group is more preferred.

[0038] In a more preferred embodiment, A and A' are independently selected from the group consisting of substituted or unsubstituted indolinine, substituted or unsubstituted naphthinolinine, substituted or unsubstituted naphthostyryl, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted pyridine, and substituted or unsubstituted quinoline. Indolinine, naphthoindolinine, and naphthostyryl are particularly preferred.

[0039] In even more preferred embodiments, at least one, more preferably at least two of R6, R7, R8, and R9 represent a substituted or unsubstituted branched alkyl group.

[0040] A branched alkyl group is defined as an alkyl group substituted at a carbon atom other than the terminal end of the alkyl chain with at least a second group selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl, alkaryl, and aryl or heteroaryl groups. Particularly preferred branched alkyl groups are substituted with alkyl groups.

[0041] Exemplary, but non-limiting, examples of NIR absorbers according to the present invention are provided in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0042] The NIR absorber preferably has an absorption maximum between 700 nm and 1200 nm, more preferably between 750 nm and 1150 nm, and most preferably between 780 nm and 1100 nm.

[0043] The NIR absorber content in the dispersion is preferably 0.05% to 15% by weight, more preferably 0.1% to 10% by weight, most preferably 0.25% to 5% by weight, based on the total solid content of the dispersion.

[0044] A.3. Pharmaceutically Active Compounds The capsules of the present invention are also suitable for on-demand drug release, where the drug is released upon heating of the particles with a suitable NIR light source, such as a NIR laser. It is useful to incorporate pharmaceutical compounds to achieve this on-demand drug release.

[0045] In some cases, PTT or PDT may not completely destroy cancer cells, resulting in the survival of residual cells after photothermal therapy. Therefore, it is useful to incorporate anticancer drugs to enhance chemotherapy. Upon NIR light irradiation of the composite particles, the drug will be released due to the generated heat, resulting in synergistic chemo-photothermal therapy. The anticancer drug should preferably be dissolved in the water-immiscible solvent used to prepare the composite resin particles (see Section A.4.). Anticancer drugs suitable for incorporation into the particles of the present invention are cytostatic drugs. Cytostatic drugs for cancer treatment can be selected from the group consisting of alkylating agents, anthracyclines, cytoskeleton-disrupting agents, epothilones, histone deacetylase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, kinase inhibitors, nucleotide analogs, peptide antibiotics, platinum-based agents, retinoids, and vinca alkaloids and their derivatives. Alkylating agents can be bifunctional or monofunctional. Typical bifunctional alkylating agents are cyclophosphamide, mechlorethamine, chlorambucil, and melphalan. Typical monofunctional alkylating agents are dacarbazine, nitrosoureas, and temozolomide. Typical anthracyclines are daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin. Exemplary cytoskeletal disruptors include paclitaxel, docetaxel, Abraxane, and taxotere. Exemplary histone deacetylase inhibitors include vorinostat and romidepsin. Exemplary topoisomerase I inhibitors include irinotecan and topotecan. Exemplary topoisomerase II inhibitors include etoposide, teniposide, and tafluposide. Exemplary kinase inhibitors include bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, and vismodegib. Exemplary nucleotide analogs include azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, and thioguanine. Exemplary retinoids include tretinoin, alitretinoin, and bexarotene. Exemplary vinca alkaloids are vinblastine, vincristine, and vindesine.

[0046] A.4. Encapsulation Method The capsule of the present invention is prepared by ring-opening polymerization, more preferably by interfacial ring-opening polymerization.Interfacial ring-opening polymerization is preferably by the oil / solvent method in water, which is preferred because it does not require complete evaporation before redispersion in water.Another advantage of this method is that the compound to be encapsulated can be soluble in oil / solvent.Therefore, this method allows hydrophobic compounds to be encapsulated in one step.

[0047] The ring-opening polymerization of N-carboxyanhydrides has been reviewed by Cheng and Deming (Top. Curr. Chem., 310, 1-26 (2012)). Primary amines, and optionally secondary amines, are the most obvious initiators, and they are widely used to initiate ring-opening polymerization via nucleophilic initiation. Basic initiators can initiate ring-opening polymerization via an activated monomer mechanism, initiated by deprotonation of the NCA followed by ring-opening polymerization. When amine initiators are used, both mechanisms often proceed in parallel. Transition metal initiation is known to provide better control over polymerization. The use of hexamethyldisilazane as an initiator has also been disclosed to provide better control over polymerization.

[0048] In a further preferred embodiment, a mixture of N-carboxy-anhydrides derived from different amino acids is used. In yet a further embodiment, a mixture of different chiralities is used, preferably a mixture of D- and L-amino acids in a ratio of 9 / 1 to 1 / 9. In another preferred embodiment, a mixture of different chiralities and different amino acids is used. The mixture of D- and L-amino acids prevents the poly(amino acids) from forming secondary or tertiary structures, as peptides do in nature. The resulting polymer shell is therefore denser and more mechanically resistant.

[0049] In a particularly suitable interfacial ring-opening polymerization method for preparing capsules according to the present invention, an N-carboxy-anhydride monomer and an NIR absorber are dissolved in a water-immiscible solvent and emulsified in an aqueous solution containing a polymerization initiator. Upon emulsification and optional removal of the water-immiscible solvent, ring-opening polymerization is initiated at the interface. As it grows, a poly(amino acid) shell forms at the organic-water interface, creating a core-shell structure that encapsulates the NIR absorber. The resulting polymer shell is mechanically strong and stable, allowing the capsules to be isolated from the liquid in which they were prepared.

[0050] The particle size of the capsules of the present invention can be modified by modifying the emulsification technique, the use of a co-emulsifier during emulsification and the ratio of co-emulsifier to shell and core, the nature of the co-emulsifier, changing the viscosity of the continuous or dispersed phase, the ratio of the continuous and dispersed phases, the nature of the NIR absorber, and the nature of the shell monomer. High shear and ultrasonic techniques are particularly suitable as emulsification techniques. The particle size of the capsules of the present invention can be adjusted by adjusting the shear in high shear techniques or by changing the power and amplitude during ultrasonic treatment.

[0051] Difunctional or polyfunctional primary or secondary amines or mixtures thereof are particularly suitable initiators for the ring-opening polymerization of NCAs. The initiators are water-soluble and can be functionalized with additional hydrophilic functional groups. The additional hydrophilic functional groups are preferably selected from the group consisting of carboxylic acids or salts thereof, sulfonic acids or salts thereof, phosphonic acids or salts thereof, phosphoric esters or salts thereof, sulfuric esters or salts thereof, polyhydroxyl functional groups, poly(ethylene glycol), ammonium groups, sulfonium groups, and phosphonium groups.

[0052] Exemplary initiators are provided in Table 3, but are not limited thereto. [Table 3-1] [Table 3-2]

[0053] The incorporation of poly(ethylene glycol) functional groups is particularly useful for imparting stealth properties to the capsules of the present invention when used in the human or animal body, which is necessary to avoid uptake by the reticuloendothelial system.

[0054] Poly(ethylene glycol) can be incorporated using a variety of strategies, including the use of poly(ethylene glycol)-functionalized initiators, dispersing aids, and poly(ethylene glycol)-functionalized NCA monomers, or combinations thereof. In particularly preferred embodiments, monomers according to general structure I are used, where at least one of R1-R3 is functionalized with a poly(ethylene glycol) chain. In particularly preferred embodiments, the monomer is selected from the group consisting of cysteine ​​derivatives, lysine derivatives, ornithine derivatives, glutamic acid derivatives, and aspartic acid derivatives. Representative examples of ethoxylated N-carboxyanhydrides are provided in Table 4, but are not limited thereto. [Table 4]

[0055] The content of the ethoxylated N-carboxyanhydride monomer is preferably 5% by weight to 50% by weight, more preferably 10% by weight to 40% by weight of the total monomer composition.

[0056] In a further preferred embodiment, the capsule of the present invention further comprises a cross-linking agent. After biocompatibility and biodegradability, one of the most basic requirements for resin particles is stability in the medium in which they must function or be stored, for example, in the human body in the case of non-invasive therapy or diagnosis. Improved stability leads to improved storage stability, as well as increased blood circulation time and improved bioavailability. By using a cross-linking agent, the stability and mechanical resistance of the resin particles can be modified to meet the specifications of the system in which they are used. Can be decorated.

[0057] Any crosslinking agent known to crosslink amine-functionalized polymers can be used. Suitable crosslinking agents are selected from the group consisting of di- or multi-functional isocyanates, di- or multi-functional β-ketoesters, di- or multi-functional β-ketoamides, di- or multi-functional 1,3-diketones, di- or multi-functional epoxides or oxetanes, di- or multi-functional anhydrides, di- or multi-functional N-carboxyanhydrides, di- or multi-functional Michael reaction acceptors (e.g., acrylates, methacrylates, maleimides, vinyl sulfones, etc.), and di- or multi-functional five-membered cyclic carbonates.

[0058] Preferably, an additional emulsifier is used during the emulsification process. Typical emulsifiers are selected from stabilizing polymers and surfactants. The polymers and surfactants can be co-reactive polymers or surfactants, for example, functionalized with primary and secondary amines, which act as both initiators and emulsifiers, resulting in so-called self-dispersing capsules. The surfactants can be anionic, nonionic, cationic, or zwitterionic. Hydroxyl-functionalized polymers are particularly suitable as stabilizing polymers, preferably selected from polysaccharides and poly(vinyl alcohol) or poly(vinyl alcohol) copolymers or their derivatives. Poly- or oligo(ethylene oxide)-functionalized block or star copolymers are another class of particularly suitable polymeric emulsifiers.

[0059] In a further preferred embodiment, the NIR-responsive capsules according to the invention are core-shell particles, containing an additional functional compound in the core, which can be released upon NIR laser irradiation. The encapsulation technique according to the invention is of particular interest for the encapsulation of active pharmaceutical ingredients.

[0060] A particularly suitable interfacial ring-opening polymerization method comprises the steps of: a) dissolving a compound according to general structure I and an organic NIR absorber in a water-immiscible solvent; and b) dissolving a polymerization initiator in an aqueous liquid; and c) emulsifying the solution obtained in step (a) in an aqueous liquid to form a solvent-in-water emulsion; and d) optionally evaporating the water-immiscible solvent; and e) polymerizing a compound according to general structure I.

[0061] If an additional functional compound, such as a pharmaceutically active agent, is to be incorporated into the capsules of the present invention, this compound is preferably dissolved in a water-immiscible solvent. The ring-opening interfacial polymerization method according to the present invention is of particular interest for the incorporation of active pharmaceutical ingredients, such as anticancer drugs.

[0062] A particularly suitable method for preparing a dispersion of composite resin particles according to the present invention containing an additional functional compound, such as an active pharmaceutical ingredient, comprises the steps of: a) dissolving a compound according to general structure I, an organic NIR absorber, and an additional functional compound to be encapsulated in a water-immiscible solvent; and b) dissolving a polymerization initiator in an aqueous liquid; and c) emulsifying the solution obtained in step (a) in an aqueous liquid; and d) optionally evaporating the water-immiscible solvent; and e) polymerizing a compound according to general structure I.

[0063] B. Application Areas The composite resin particles according to the present invention are useful for imaging diseased organs in the human and / or animal body. Because they strongly absorb NIR light, they are also suitable for diffuse optical tomography and photoacoustic imaging.

[0064] When irradiated with an appropriate NIR laser, the NIR absorbers in the composite particles of the present invention can convert the absorbed photon energy into heat, directly ablating cancer cells while minimizing damage to surrounding healthy tissue, making these particles highly suitable for phototumor therapy (PTT).

[0065] The composite resin particles of the present invention are also useful in photodynamic therapy (PDT), where the NIR absorbers are excited with light of the appropriate wavelength to convert molecular oxygen into cytotoxic reactive oxygen species (ROS), such as singlet oxygen, which then damages cancer cells through oxidative stress and, as a result, induces cell death. [Example]

[0066] C. Working Example C.1. Material Mowiol 4 88 is a poly(vinyl alcohol) supplied by Kuraray. Marlon A365 is an anionic surfactant, supplied by Sasol Germany GMBH. Tris(2-aminoethyl)amine was supplied by TCI. Crosslinker 1 is a trifunctional β-ketoester according to the following structural formula, which can be prepared as disclosed by Speisschaert et al. (Polymer, 172, 239-246 (2019)). [ka] NIR-27 has the structure shown below and was supplied by FEW as S2025. [ka] NIR-7 is a NIR absorber and is prepared as follows: [ka] Synthesis of ureum(I) 146 g of n-butyl isocyanate was dissolved in 85 ml of toluene. 166 g of 2-heptylamine was added over 2 hours, while maintaining the temperature below 50° C. The reaction was continued at 50° C. for 30 minutes. The solvent and excess n-butyl isocyanate were removed under reduced pressure, and the crude ureum was used in the second step without further purification. Synthesis of barbituric acid derivatives (II) To 300 g of ureum(I) was added 206 g of acetic acid. The mixture was heated to 60°C. To 147 g of malonic acid was added a solution of ureum(I) in acetic acid at 60°C. This solution was added to 292 g of acetic anhydride. The reaction mixture was gently heated to 90°C and the reaction continued at 90°C for 2.5 hours. The reaction was allowed to cool to 50°C and 78 g of methanol was added. The mixture was refluxed for 45 minutes. The mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was redissolved in 311 g of methyl t-butyl ether and extracted three times with 2010 g of 5 wt % sodium chloride solution. The solvent was removed under reduced pressure. 35 ml of toluene was added followed by removal under reduced pressure for 4 hours. The crude barbituric acid derivative (II) was used without further purification. Synthesis of intermediate (III) To 240 g (0.85 mol) of the barbituric acid derivative (II), 84 g of cyclopentanone was added. 5 g of ammonium acetate was added, followed by 101 g of methanol. The reaction mixture was heated to reflux and continued at reflux for 4.5 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was removed at 50 mbar pressure and 95°C. 5 ml of toluene was added, followed by evaporation at 50 mbar and 100°C four times. The reaction mixture was allowed to cool to room temperature, and 92 g of toluene was added. 26 g of silica gel in 55 g of toluene was added, and the mixture was filtered. The silica gel was flushed with toluene. The pooled toluene fractions were treated twice with 26 g of silica gel in 55 g of toluene, filtered, and then the silica gel was flushed with toluene. All toluene fractions were pooled, followed by evaporation of the solvent under reduced pressure. 287 g of crude intermediate (III) (yield: 97%) was isolated. Synthesis of intermediate (V) 0.685 kg of intermediate (III) was dissolved in 0.334 kg of ethyl acetate. The solution was cooled to 10°C, and 18.9 g of acetic acid was added. 0.273 kg of N,N-dimethylformamide dimethyl acetal was added over 10 minutes, during which time the temperature rose to 20°C. The reaction was continued at room temperature for 30 minutes. The reaction mixture was heated to 45°C, and 0.604 kg of dimethylformamide dimethyl acetal was added over 15 minutes, followed by heating the reaction mixture to 65°C. The reaction was continued at 65°C for 25 minutes. The reaction mixture was allowed to cool to 47°C, followed by the addition of 1.06 kg of methyl t-butyl ether and 1.61 kg of n-hexane. The reaction mixture was cooled to 7°C. The crystallized intermediate V was isolated by filtration and washed with 160 g of ethyl acetate and 60 g of methyl t-butyl ether, followed by three washes with 160 g of ethyl acetate and 60 g of methyl t-butyl ether, and one wash with 400 g of heptane. The isolated intermediate (V) was dried. 335 g of intermediate (V) (yield: 37%) was isolated. Synthesis of intermediate (VI) Intermediate (VI) can be prepared as disclosed in WO2013037672. Synthesis of NIR-7: 621 g of intermediate (VI) was dissolved in 3.2 L of methyl acetate. The reaction mixture was heated to 40°C. 372 g of intermediate (V) was added, and the reaction was continued at 50°C for 2.5 hours. The reaction mixture was cooled to 20°C. The crystallized NIR-7 was isolated by filtration and washed with 284 mL of methyl acetate, 2.84 L of ethyl acetate, and 530 mL of methyl t-butyl ether. The crude NIR-7 was treated with 2.9 L of water, isolated by filtration, washed with 1.5 L of water, 142 mL of methyl acetate, 280 mL of ethyl acetate, and 800 mL of methyl t-butyl ether, and dried. 597 g of NIR-7 was isolated (yield: 87%). NIR-24 is a NIR absorber and is prepared as follows: [ka] The starting NIR dye (I) can be prepared as disclosed in Nagaoetal. (Dyes and Pigments, 73(3), 344-352 (2006). Synthesis of NIR-24 To 100 ml of acetonitrile was added 30 g of NIR starting material (I). 6.24 g of N,N'-dimethylbarbituric acid was added, followed by 5.5 ml (4.0 g) of triethylamine. The reaction was continued at room temperature for 3 hours. Crude NIR-24 was isolated by filtration and treated with refluxing methanol. NIR-24 was isolated by filtration of the warm methanol solution and dried. 19.7 g of NIR-24 was isolated (yield: 35%). NIR-25 is an NIR absorber and is prepared as follows: [ka] [ka] Synthesis of intermediate (I): Intermediate (I) can be prepared as disclosed in WO2010120058. Synthesis of intermediate (II): 292 g of N,N'-dicyclohexylbarbituric acid was dissolved in 1.5 L of trichloroethane. 156 mL of cyclohexanone, 12 mL of piperidine, and 15 mL of acetic acid were added, and the reaction mixture was heated to reflux. Water was removed by azeotropic distillation using a Dean-Stark trap. The reaction was continued for 24 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The residue was redissolved in 1 L of trichloroethane. The insoluble residue was removed by filtration. 100 mL of piperidine was added, and intermediate (II) crystallized from the solvent. Intermediate (II) was removed by filtration and dried. 302 g (yield: 67%) was isolated. Synthesis of NIR-25: 301.6 g of Intermediate (II) and 533 g of Intermediate (I) were dissolved in 1.05 L of N,N'-dimethylimidazolone. 186 mL of acetic anhydride and 366 mL of triethylamine were added, and the reaction mixture was heated to 100°C. The reaction was continued at 100°C for 30 minutes. The reaction mixture was allowed to cool to room temperature, and NIR-25 was crystallized from the reaction mixture. The crude NIR-25 was isolated by filtration and treated with 1.3 L of acetone, followed by 1.3 L of methyl t-butyl ether. The isolated NIR-25 was redissolved in a 1 / 1 mixture of dichloromethane and methanol. Remaining impurities were removed by filtration. 6.6 L of methyl t-butyl ether was added, and NIR-25 was crystallized from the solvent. The NIR-25 was removed by filtration and dried. 136 g of NIR-25 (yield: 28%) was isolated. NIR-26 is a NIR absorber and is prepared as follows: [ka] Synthesis of intermediate (I): 123.2 g of 1,1,2-trimethyl-1H-benzoindole and 234.1 g of n-decyl tosylate were dissolved in 173 g of sulfolane. A nitrogen flow was set to flow through the reactor, and the reaction mixture was heated to 123°C. The reaction was continued at 123°C for 6 hours. The reactor was cooled to 75°C, and 1350 ml of ethyl acetate was added with stirring to crystallize intermediate (I). The reaction mixture was allowed to cool to room temperature, and the crystallized intermediate (I) was isolated by filtration. 207 (yield: 69%) was isolated. Synthesis of intermediate (II): Intermediate (II) can be prepared as disclosed in EP889363. Synthesis of NIR-26: 2.14 g of intermediate (II) was dissolved in 10.9 ml of acetic anhydride at 40° C. 2.27 g of triethylamine was added at 40° C. After 15 minutes, 1 ml of dimethylacetamide was added at 55° C. A solution of 5.2 g of intermediate (I) in 20 ml of methanol was added at 55° C. The reaction was continued at 55° C. for 3 hours. The crystallized NIR-26 was isolated by filtration, washed with methanol, and subsequently treated with methanol at 50° C. and isolated by filtration. NIR-26 was dried under reduced pressure at 40° C. 3 g of NIR-26 (yield: 69%) was isolated. NIR-11 is a NIR absorber and is prepared as follows: [ka] Alkylation of 1,1,2-trimethyl-1H-benzoindole 31.4 g of 1,1,2-trimethyl-1H-benzoindole and 33.0 g of 1-bromo-3-methyl-butane were dissolved in 60 ml of acetonitrile. The reaction mixture was heated to reflux and the reaction was continued at reflux for 20 hours. The reaction mixture was allowed to cool, and 20 ml of acetonitrile was added. 100 ml of methyl t-butyl ether was added, and the precipitated intermediate (I) was isolated by filtration, washed with methyl t-butyl ether, and dried. 24.9 g of intermediate (I) (yield: 46%) was isolated. Synthesis of NIR-11 1 g of intermediate (I) and 0.636 g of intermediate (II) were dissolved in 15 ml of 1-methoxy-2-propanol. The reaction mixture was heated to reflux and the reaction was continued at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature. NIR-11 crystallized from the solvent. NIR-11 was isolated by filtration, washed with 1-methoxy-2-dowanol, and dried. 0.775 g (yield: 59%) of NIR-11 was isolated. NIR-28 is a NIR absorber and is prepared as follows: [ka] Alkylation of 2,3,3-trimethyl-indolenine 32 g of 2,3,3-trimethyl-indolenine and 25 g of 1-chloro-3-methyl-butane were dissolved in 80 ml of sulfolane. 40 g of potassium iodide was added. The reaction mixture was heated to 80°C and the reaction was continued at 80°C for 19 hours. The reaction mixture was allowed to cool to room temperature, and 30 ml of acetone was added. The precipitated potassium chloride was removed by filtration, and 600 ml of ethyl acetate was added to the filtrate. Intermediate (I) crystallized from the solvent. Intermediate (I) was isolated by filtration, washed with ethyl acetate and methyl t-butyl ether, and dried. 29.4 g of Intermediate (I) was isolated (yield: 41%). Synthesis of NIR-28 1 g of Intermediate (I) and 0.641 g of Intermediate (II) were dissolved in 15 ml of 1-methoxy-2-propanol. The reaction mixture was heated to reflux and the reaction was continued at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature. NIR-28 crystallized from the solvent. NIR-28 was isolated by filtration, washed with 1-methoxy-2-dowanol, and dried. 0.716 g (yield: 62%) of NIR-28 was isolated. L-phenylalanine N-carboxyanhydride, D-phenylalanine N-carboxyanhydride, and D,L-phenylalanine N-carboxyanhydride are N-carboxyanhydride monomers, which can be prepared according to standard methods as disclosed by Gabashvill et al. (Journal of Physical Chemistry B, 111(38), 11105-11110 (2007)) and Otake et al. (Angewandte Chemie, International Edition, 57(35), 11389-11393 (2018)). L-leucine N-carboxyanhydride, D-leucine N-carboxyanhydride, and D,L-leucine N-carboxyanhydride are N-carboxyanhydride monomers, which can be prepared according to standard methods as disclosed by Baars et al. (Organic Process Research and Development, 7(4), 509-513 (2003)). PEG-NCA-1 is an N-carboxy-anhydride monomer and is prepared as follows: [ka] Cysteine ​​addition to PEGylated methacrylate To 75 ml of water, 6.6 g of cysteine ​​was added. The pH was adjusted to 7.5 using 1N NaOH solution. 23.6 g of methacrylated mono-methoxy-poly(ethylene glycol) 350 was added, and the reaction was continued at room temperature for 24 hours. The salts in the aqueous solution were removed using chromatographic techniques. The aqueous solution was pumped onto a Flashpure C18 (40 μm, irregular) column (supplied by Büchi). Water was flushed through the column for several minutes, and then the cysteine ​​derivative was eluted with methanol. The methanol fraction was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 28 g of the intermediate product, in which cysteine ​​was attached to methacrylated mono-methoxy-poly(ethylene glycol) 350, was isolated as a white wax. Synthesis of PEG-NCA-1 100 ml of tetrahydrofuran was added to 10 g of the PEGylated cysteine ​​derivative. 2.7 g of triphosgene was added, and the reaction was continued at 60°C for 3 hours. During the reaction, the PEGylated cysteine ​​derivative gradually dissolved. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. 50 ml of n-hexane was added, and PEG-NCA-1 was isolated by decantation. The isolated PEG-NCA-1 was dissolved in 5 ml of tetrahydrofuran, precipitated with 50 ml of n-hexane, and isolated by decantation. This process was repeated three more times. The isolated PEG-NCA-1 was dried under reduced pressure. 10 g of PEG-NCA-1 (yield: 96%) was isolated as a viscous oil. PEG-NCA-2 is an N-carboxy-anhydride monomer and is prepared as follows: [ka] Cysteine ​​alkylation: To 75 ml of water, 6.06 g of cysteine ​​was added. 16.8 g of sodium bicarbonate was added, followed by tosylated poly(ethylene glycol) monomethyl ether (prepared from poly(ethylene glycol)-monomethyl ether 550 using standard tosylation conditions as described by Cia et al. (Macromolecules, 45(15), 6175-6184 (2012))). The reaction mixture was heated to 75°C, and the reaction was continued at 75°C for 6 hours. The reaction mixture was allowed to cool to room temperature. The aqueous solution was pumped onto a Flashpure C18 (40 μm, irregular) column (supplied by Büchi). Water was flushed through the column for several minutes, followed by elution of the cysteine ​​derivative with methanol. The methanol fraction was evaporated under reduced pressure. The residue was dissolved in methylene chloride. The methylene chloride solution was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 22 g (100% yield) of the PEGylated cysteine ​​derivative was isolated as a slightly colored wax. Synthesis of PEG-NCA-2: 100 ml of tetrahydrofuran was added to 10 g (15 mmol) of the PEGylated cysteine ​​derivative. 2.22 g (7.5 mmol) of triphosgene was added, and the mixture was heated to 60°C. The reaction was continued at 60°C for 3 hours. The PEGylated cysteine ​​derivative gradually dissolved during the reaction. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. 100 ml of n-hexane was added, and PEG-NCA-2 was isolated by decantation. The isolated PEG-NCA-1 was dissolved in 10 ml of tetrahydrofuran, precipitated with 100 ml of n-hexane, and isolated by decantation. This process was repeated two more times. The isolated PEG-NCA-2 was dried under reduced pressure. 10 g (yield: 95%) of PEG-NCA-2 was isolated as a viscous oil.

[0067] C.2. Method Capsule particle size was measured using a Zetasizer™ Nano-S (Malvern Instruments, Goffin Meyvis).

[0068] UV-VIS spectra were measured on an Agilent 8433 spectrophotometer up to 1100 nm. The more bathochromic dyes were measured on a Shimadzu UV2600 spectrophotometer. λ was measured by diluting the samples with water. max The absorbance of the sample at 1 was adjusted to 1.

[0069] C.3. Example 1 This example illustrates the encapsulation of various NIR absorbers by poly(amino acid) resins using anionic surfactants and polymeric emulsifiers as stabilizing systems.

[0070] Synthesis of INVRES-1 A first solution was prepared by dissolving 0.75 g of L-phenylalanine N-carboxyanhydride, 0.75 g of D-phenylalanine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, and 0.336 g of crosslinker 1 in 20 ml of methyl ethyl ketone. To this solution was added a solution of 75 mg of NIR-7 dissolved in 1 ml of dichloromethane. The solution was filtered through a 2.7 μm filter.

[0071] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0072] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 15,000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue for 24 hours at room temperature.

[0073] The average particle size was measured to be 253 nm. The dispersion had an absorption maximum at 1051 nm.

[0074] Synthesis of INVRES-2 A first solution was prepared by dissolving 0.75 g of L-phenylalanine N-carboxyanhydride, 0.75 g of D-phenylalanine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 0.336 g of Crosslinker 1, and 75 mg of NIR-26 in 26 ml of dichloromethane. The solution was filtered through a 2.7 μm filter.

[0075] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0076] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 18,000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was continued at room temperature for 24 hours.

[0077] The average particle size was measured to be 305 nm. The dispersion had an absorption maximum at 841 nm.

[0078] Synthesis of INVRES-3 A first solution was prepared by dissolving 1.5 g of D,L-phenylalanine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 0.336 g of Crosslinker 1, and 75 mg of NIR-24 in 26 ml of dichloromethane. The solution was filtered through a 2.7 μm filter.

[0079] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0080] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 15,000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue for 24 hours at room temperature.

[0081] The average particle size was measured to be 314 nm. The dispersion had an absorption maximum at 812 nm.

[0082] Synthesis of INVRES-4 A first solution was prepared by dissolving 1.5 g of D,L-phenylalanine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 0.336 g of Crosslinker 1, and 75 mg of NIR-27 in 26 ml of dichloromethane. The solution was filtered through a 2.7 μm filter.

[0083] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0084] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 15,000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue for 24 hours at room temperature.

[0085] The average particle size was measured to be 282 nm. The dispersion had an absorption maximum at 827 nm.

[0086] Synthesis of INVRES-5 A first solution was prepared by dissolving 1.5 g of D,L-phenylalanine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 0.336 g of Crosslinker 1, and 75 mg of NIR-25 in 26 ml of dichloromethane. The solution was filtered through a 2.7 μm filter.

[0087] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0088] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 15,000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue for 24 hours at room temperature.

[0089] The average particle size was measured to be 280 nm. The dispersion had an absorption maximum at 773 nm.

[0090] Synthesis of INVRES-6 A first solution was prepared by dissolving 1.5 g of D,L-phenylalanine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 0.336 g of Crosslinker 1, and 75 mg of NIR-11 in 26 ml of dichloromethane. The solution was filtered through a 2.7 μm filter.

[0091] Dissolve 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water. A second solution was prepared.

[0092] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 15,000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue for 24 hours at room temperature.

[0093] The average particle size was measured to be 330 nm. The dispersion had an absorption maximum at 838 nm.

[0094] Synthesis of INVRES-7 A first solution was prepared by dissolving 1.5 g of D,L-phenylalanine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 0.336 g of Crosslinker 1, and 75 mg of NIR-28 in 26 ml of dichloromethane. The solution was filtered through a 2.7 μm filter.

[0095] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0096] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 15,000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue for 24 hours at room temperature.

[0097] The average particle size was measured to be 310 nm. The dispersion had an absorption maximum at 803 nm.

[0098] C.4. Example 2 This example describes the synthesis of NIR-responsive submicron particles whose surfaces are functionalized with poly(ethylene glycol).

[0099] Synthesis of INVRES-8: A first solution was prepared by dissolving 1.5 g of D,L-phenylalanine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 1.380 g of PEG-NCA-1, 0.336 g of Crosslinker 1, and 121 mg of NIR-7 in 14 ml of ethyl acetate. The solution was filtered through a 2.7 μm filter.

[0100] A second solution was prepared by dissolving 0.968 g of Synperonic PE and 0.127 g of tris(2-aminoethyl)amine in 29 ml of water.

[0101] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 14,000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0102] The average particle size was measured to be 151 nm. The dispersion had an absorption maximum at 1051 nm.

[0103] ·INVRES-9 synthesis: In 14 ml of ethyl acetate, 1.5 g of D,L-phenylalanine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, 0.7 g of D-leucine N-carboxyanhydride A first solution was prepared by dissolving 5 g of PEG-NCA-2, 1.380 g of PEG-NCA-2, 0.336 g of crosslinker 1, and 121 mg of NIR-7. The solution was filtered through a 2.7 μm filter.

[0104] A second solution was prepared by dissolving 0.968 g of Synperonic PE and 0.127 g of tris(2-aminoethyl)amine in 29 ml of water.

[0105] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 14,000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0106] The average particle size was measured to be 162 nm. The dispersion had an absorption maximum at 1051 nm.

[0107] C.5. Example 3: This example illustrates the NIR reactivity of dispersions containing NIR-responsive submicron particles according to the present invention.

[0108] 1 mm thick coatings of a diluted dispersion of NIR nanoparticles according to the invention were exposed to a coherent laser combination equipped with three lasers emitting at 920 nm, 1064 nm, and 1150 nm, respectively. The degree to which different 1 mm thick coatings evaporated under laser exposure was evaluated. Samples were applied to a poly(propylene) substrate, Priplak (supplied by Antalis). The results are summarized in Table 5. [Table 5]

[0109] From Table 5 it is clear that the NIR-responsive nanoparticles according to the present invention exhibit high laser reactivity at various wavelengths.

Claims

1. 1. A method for preparing a dispersion of capsules, comprising: a) dissolving an N-carboxy-anhydride monomer according to general structure I and an NIR absorber in a water-immiscible solvent to obtain a solution; and b) dissolving a polymerization initiator in an aqueous liquid; and c) emulsifying the solution obtained in step a) in the aqueous liquid obtained in step b) in which a polymerization initiator has been dissolved; and d) evaporating the water-immiscible solvent; and e) polymerizing said N-carboxy-anhydride monomer according to general structure I; Including, 【Chemical 1】 During the ceremony, n represents 0 or 1; R 1 , R 2 , and R 3 is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, and a substituted or unsubstituted aryl or heteroaryl group; R 1 , R 2 , and R 3 can represent the atoms necessary to form a five- to eight-membered ring, and R 1 ~R 3 at least one of which is functionalized with a poly(ethylene glycol) chain; Said preparation method.

2. 10. The method for preparing a dispersion of capsules according to claim 1, wherein a surfactant or a stabilizing polymer is added to the aqueous liquid.

3. 3. A method for preparing a dispersion of capsules according to claim 1 or claim 2, wherein the polymerization initiator is a di- or polyfunctional primary or secondary amine containing a polyethylene glycol group.

4. A method for preparing a dispersion of capsules as described in claim 1 or 3, wherein a pharmaceutically active compound is dissolved in the water-immiscible solvent.

5. 1. A method for preparing a dispersion of capsules, comprising: a) dissolving an N-carboxy-anhydride monomer according to general structure I and an NIR absorber, which is a compound according to general formula II, in a water-immiscible solvent to obtain a solution; and b) dissolving a polymerization initiator in an aqueous liquid; and c) emulsifying the solution obtained in step a) in the aqueous liquid obtained in step b) in which a polymerization initiator has been dissolved; and d) evaporating the water-immiscible solvent; and e) polymerizing said N-carboxy-anhydride monomer according to general structure I; Including, 【Chemical 1】 During the ceremony, n represents 0 or 1; R 1 , R 2 , and R 3 is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, and a substituted or unsubstituted aryl or heteroaryl group; R 1 , R 2 , and R 3 may represent the atoms necessary to form a five- to eight-membered ring; 【Chemistry 2】 During the ceremony, A and A′ independently represent a substituted or unsubstituted heterocyclic group that is covalently bonded to the polymethine chromophore via a carbon atom; R 4 and R 5 are independently hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, and a substituted or unsubstituted aryl or heteroaryl group; Selected from the group R 4 and R 5 can represent the atoms required to form a five- to eight-membered ring. R 6 and R 7 are independently selected from the group consisting of substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkaryl groups, and substituted or unsubstituted aryl or heteroaryl groups; Said preparation method.

6. The NIR absorber is represented by the general formula III 【Chemistry 3】 During the ceremony, R 4 and R 5 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkaryl groups, and substituted or unsubstituted aryl or heteroaryl groups; R 4 and R 5 can represent the atoms required to form a five- to eight-membered ring. R 6 and R 7 are independently selected from the group consisting of substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkaryl groups, and substituted or unsubstituted aryl or heteroaryl groups; R 8 and R 9 independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, and a substituted or unsubstituted aryl or heteroaryl group; Q represents atoms necessary to form a substituted or unsubstituted 5- or 6-membered heterocyclic ring; is a compound according to 6. A method for preparing a dispersion of capsules according to claim 5.

7. R 1 ~R 3 7. A method for preparing a dispersion of capsules according to claim 5 or claim 6, wherein at least one of the following is functionalized with a poly(ethylene glycol) chain.

8. 6. A method for preparing a dispersion of capsules according to claim 5, wherein a surfactant or a stabilizing polymer is added to the aqueous liquid.

9. 8. A method for preparing a dispersion of capsules according to claim 5, claim 6 or claim 7, wherein the polymerization initiator is a di- or polyfunctional primary or secondary amine containing a polyethylene glycol group.

10. A method for preparing a dispersion of capsules according to claim 5, claim 6, claim 7 or claim 9, wherein a pharmaceutically active compound is dissolved in the water-immiscible solvent.

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