Near infrared absorbing composite resin particles

Abstract

Composite resin particles comprising a near infrared absorber according to general formula I and a resin selected from the group consisting of poly(amino acids), polyphosphazenes, polysaccharide derivatives, poly(esters), poly(orthoesters), poly(cyano-acrylates), and copolymers thereof. The composite resin particles are suitable for photomedical applications such as phototherapy including photothermal therapy (PTT), photodynamic therapy (PDT), chemical photodynamic nanotherapy, and fluorescence medical imaging. (General formula I) [Formula 1] TIFF2024511856000016.tif47166

Description

[Technical field]

[0001] The present invention relates to the design of biocompatible organic nano- and microparticles for photomedical applications such as phototherapy, including photothermal therapy (PTT), photodynamic therapy (PDT), chemo-photodynamic therapy, and fluorescence medical imaging. [Background technology]

[0002] Near infrared (NIR) laser technologies are becoming increasingly important in the non-invasive treatment and medical diagnosis of various diseases, including photothermal therapy, photodynamic therapy, fluorescence imaging, and photoacoustic imaging. Some of these technologies rely on NIR-absorbing nanoparticles, often inorganic nanoparticles, such as gold nanoparticles, carbon nanoparticles (including carbon nanotubes), metal sulfides, metal oxides, and various upconversion nanoparticles. The use of inorganic photothermal conversion nanoparticles has been widely reviewed (Non-Patent Document 1, Non-Patent Document 2). Although these nanoparticles provide excellent NIR responses, they are non-biodegradable, have a risk of bioaccumulation, and have a long persistence time in the body, which could potentially increase the possibility of their long-term toxicity. Nanoparticles based on biocompatible organic NIR absorbers would therefore be highly desirable.

[0003] Although there are several classical organic NIR absorbers that have been well reported for photomedical applications, cyanine dyes are a particularly preferred 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 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) need to be incorporated into nanoparticles to increase their body persistence, render them dispersible in aqueous body fluids, prevent photobleaching, and improve their tumor targeting capabilities.

[0005] The integration of NIR absorbers into nanoparticles also has other additional advantages. It is known that the spectral properties of some classes of NIR absorbers are highly dependent on their environment and can change, for example, depending on pH and ionic strength due to aggregation phenomena. Therefore, the physical integration of NIR absorbers into nanoparticles makes their spectral properties and photophysics independent of the external environment. As a result, their response in physiological environments becomes easily predictable. The tuning of the laser response is performed simply by matching the concentration of the NIR absorber in the nanoparticles, which avoids the need for laborious NIR absorber synthesis on a case-by-case basis.

[0006] Several nanoparticle designs have been proposed in the prior art and have been reviewed recently (Non-Patent Document 3, Non-Patent Document 4, Non-Patent Document 5, Non-Patent Document 6). The proposed nanoparticle designs often require laborious synthesis protocols, which makes it difficult to easily tailor the nanoparticles for different applications. Therefore, there is a need for near-infrared responsive nanoparticles that can be utilized via simple and scalable industrial techniques. One such simple and scalable industrial technique is solvent evaporation.

[0007] On the other hand, cyanine dyes (such as indocyanine green) can be combined with biocompatible nanoparticles. Indocyanine green is often incompatible with readily scalable industrial techniques (such as solvent evaporation) for physical integration into aqueous solutions. Indocyanine green has no or very limited solubility in the solvents currently used in solvent evaporation techniques. Indocyanine green dye is partially soluble in water and decomposes in water, and therefore needs to be fully encapsulated to avoid any contact with water. This requirement further limits the feasibility of using the techniques to prepare fully encapsulated indocyanine green nanoparticles and microparticles.

[0008] Therefore, there is a need to integrate organic NIR absorbers with high molar extinction coefficients into biocompatible nanoparticles using industrial solvent evaporation techniques without requiring complete encapsulation of the NIR absorber. [Prior art documents] [Non-patent literature]

[0009] [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] Zhu et al.Biomater.Sci,6,746-765(2018) [Non-Patent Document 4] Zhu et al.,Current Medicinal Chemistry,26,1389-1405(2019) [Non-Patent Document 5] Hg.Et al.,Chemical reviews,115,11012-11042(2015) [Non-Patent Document 6] Shao et al.,RSC Nanoscience & Nanotechnology,40,125-157(2016) Summary of the Invention

[0010] One of the objectives of the present invention is to provide a specific class of NIR absorbers that can be integrated with biocompatible polymers and converted into composite resin particles as defined in claim 1 via easily scalable industrial techniques.

[0011] Yet another aspect of the present invention is to provide biocompatible polymeric nano- or microcapsules comprising the specific non-ionic NIR absorber according to claim 4.

[0012] Another aspect of the present invention is to provide an aqueous dispersion of composite resin particles as claimed in claim 1. The aqueous dispersion is as claimed in claim 8.

[0013] According to another aspect, the present invention comprises a scalable industrial method of integrating a specific class of NIR absorbers with a biocompatible polymer as claimed in claim 14.

[0014] 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. Particular embodiments of the invention are also defined in the dependent claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The object of the present invention is realized by a composite resin particle comprising a NIR absorber and a biocompatible resin. The NIR absorber is a compound according to general formula I (see below).

[0016] A. Composite resin particles A.1. NIR absorbers The NIR absorber present in the composite resin particles of the present invention has the general formula I [ka] This is due to During the ceremony, A and A' independently represent a substituted or unsubstituted heterocyclic group covalently bonded to the polymethine chromophore through a carbon atom; R 1 and R 2 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 1 and R 2 may represent the atoms necessary to form a 5- to 8-membered ring; R 3 and R 4 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.

[0017] In a preferred embodiment, the NIR absorber has the general formula II: [ka] is a compound according to During the ceremony, R 1 and R 2 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 1 and R 2 may represent the atoms necessary to form a 5- to 8-membered ring; R 3 and R 4 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkaryl groups, and substituted or unsubstituted aryl or heteroaryl groups; R 5 and R 6 represent independently 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 the atoms necessary to form a substituted or unsubstituted 5- or 6-membered heterocycle.

[0018] In another preferred embodiment, R 1 and R 2 represents the atoms necessary to form a substituted or unsubstituted 5- or 6-membered ring, with 6-membered rings being most preferred.

[0019] In another preferred embodiment, R 3 and R 4 independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, and a substituted or unsubstituted aralkyl group, with a substituted or unsubstituted alkyl group being most preferred.

[0020] In another preferred embodiment, A and A' are independently selected from the group consisting of substituted or unsubstituted indolinine, substituted or unsubstituted naphtinolinine, substituted or unsubstituted naphthostyryl group, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted pyridine, and substituted or unsubstituted quinolone. Indolinine, naphtindolinine, and naphthostyryl are particularly preferred.

[0021] In yet another preferred embodiment, R 3 , R 4 , R 5 , and R6 At least one, and more preferably at least two, of represent a substituted or unsubstituted branched alkyl group.

[0022] A branched alkyl group is defined as an alkyl group in which a non-terminal carbon atom of the alkyl chain is substituted with at least a second group selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, an alkaryl group, and an aryl or heteroaryl group. Most preferably, the branched alkyl group is substituted with an alkyl group.

[0023] Table 1 gives typical, non-limiting examples of NIR absorbers according to the present invention. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0024] The NIR absorber preferably has an absorption maximum in the range of 700 to 1200 nm, more preferably 750 to 1150 nm, and most preferably 780 to 1100 nm.

[0025] In a preferred embodiment of the present invention, the NIR absorber is non-ionic. The non-ionic nature of such NIR absorbers makes them highly soluble in the solvents used in the solvent evaporation technique. Therefore, the concentration of the NIR absorber in the resin particles can be increased. Non-ionic NIR absorbers also have low solubility in water. Due to their low solubility in water, complete encapsulation by the resin in the composite resin particles is not necessary.

[0026] When the composite resin particles are dispersed in an aqueous medium, the NIR absorbent content in the dispersion is preferably 0.05 wt.% to 15 wt.%, more preferably 0.1 wt.% to 10 wt.%, and most preferably 0.25 wt.% to 5 wt.%, based on the total solid content in the dispersion.

[0027] A.2. Biocompatible resins The biocompatible resin present in the composite resin particles according to the present invention is preferably soluble in a substantially water-immiscible solvent, which 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 preferred as water-immiscible solvents.

[0028] Biodegradable Polymers, The resin may be selected from those discussed in PBM Series, Volume 2 (Citus Books 2003, ISSN 1479-1285). The resin according to the present invention is selected from the group consisting of poly(amino acids), polyphosphazenes, polysaccharide derivatives, poly(esters), poly(orthoesters), poly(cyano-acrylates), and copolymers thereof, with poly(amino acids) and poly(esters) being more preferred.

[0029] The poly(ester) is preferably poly(caprolactone), poly(lactic acid), poly(L-lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), poly(L-lactic acid-co-glycolic acid), poly(D,L-lactide), and any derivatives and / or combinations thereof.

[0030] A.3. Pharmaceutically Active Compounds The composite resin particles are also suitable for on-demand drug release, with the drug being released upon heating of the particles by a suitable NIR light source (such as a NIR laser), and it is therefore useful to include a pharmaceutical compound to achieve this on-demand drug release.

[0031] PTT or PDT may not completely destroy cancer cells, leading to survival of residual cells after photothermal therapy. It is therefore useful to include an anticancer drug to enhance chemotherapy. The drug will be released due to the heat generated upon application of NIR light to the composite particles, resulting in synergistic chemo-photothermal therapy. The anticancer drug should preferably be soluble in the water-immiscible solvent used in the preparation of the composite resin particles (see Section B).

[0032] Anticancer drugs suitable for inclusion in the particles of the present invention are cytostatic drugs. Cytostatic drugs for the treatment of cancer 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 drugs, retinoids, and vinca alkaloids, and derivatives. Alkylating agents can be bifunctional or monofunctional. Exemplary bifunctional alkylating agents are cyclophosphamide, mechlorethamine, chlorambucil, and melphalan. Exemplary monofunctional alkylating agents are dacarbazine, nitrosoureas, and temozolomide. Exemplary anthracyclines are daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin. Exemplary cytoskeletal disrupting agents are paclitaxel, docetaxel, abraxane, and taxotere. Exemplary histone deacetylase inhibitors are vorinostat and romidepsin. Exemplary topoisomerase I inhibitors are irinotecan and topotecan. Exemplary topoisomerase II inhibitors are etoposide, teniposide, and tafluposide. Exemplary kinase inhibitors are bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, and vismodegib. Exemplary nucleotide analogs are azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, and thioguanine. Exemplary retinoids are tretinoin, alitretinoin, and bexarotene. Exemplary vinca alkaloids are vinblastine, vincristine, and vindesine.

[0033] B. Preparation of Composite Resin Particles and Composite Particle Dispersion The composite resin particles according to the present invention comprise a biocompatible resin, which is preferably soluble in a water-immiscible solvent, selected from the group consisting of poly(amino acids), polyphosphazenes, polysaccharide derivatives, poly(esters), poly(orthoesters), poly(cyano-acrylates), and copolymers thereof, poly(amino acids), and poly(esters), and at least one and a NIR infrared dye according to the present invention (see section A.1).

[0034] The resin according to the invention can be functionalized with a functional group that renders the resin self-dispersible in water, provided that the functionalization does not render the resin completely water-soluble.Typical functional groups that render the resin self-dispersible are selected from the group consisting of poly(ethylene oxide), carboxylic acid or salts thereof, sulfonic acid or salts thereof, phosphonic acid or salts thereof, phosphoric acid monoester or salts thereof, sulfuric acid monoester or salts thereof, ammonium groups, sulfonium groups, and phosphonium groups.

[0035] The inclusion of poly(ethylene glycol) functional groups is particularly useful for imparting stealth properties to the composite resin particles of the present invention within the human or animal body, which are required to avoid rapid uptake by the reticuloendothelial system and ensure that they are retained only at the site of need.

[0036] In a preferred embodiment, the resin according to the present invention is not functionalized with functional groups that would render the resin self-dispersing.

[0037] The use of a dispersant in the preparation of the aqueous dispersion of composite resin particles is particularly preferred. This allows the surface properties to be adjusted without the need for special resin design. Standard biocompatible resins can be used in the preparation of the resin particles. The dispersant can be a surfactant or a stabilizing polymer. The surfactant can be nonionic, anionic, cationic, or zwitterionic. Nonionic ethoxylated block copolymer surfactants are preferred. EO-PPO-EO triblock copolymers are even more preferred. The block copolymers not only provide the particles of the invention with stealth properties, but also reduce the particle size. As the stabilizing polymer, a hydroxyl-functionalized polymer is particularly preferred, preferably selected from polysaccharides and poly(vinyl alcohol) or poly(vinyl alcohol) copolymers, or derivatives thereof.

[0038] In a preferred embodiment, the particle size of the composite resin particles according to the present invention is 0.03 μm to 3 μm, more preferably 0.05 μm to 1 μm, and most preferably 0.07 μm to 0.5 μm. It is particularly preferred that the particle size of the composite resin particles according to the present invention is less than 0.25 μm.

[0039] A particularly preferred method for preparing the composite resin particle dispersion according to the present invention is 1. Dissolving the resin according to the invention and the NIR absorber according to the invention in a water-immiscible solvent; 2. Dissolving a dispersant in water; 3. Emulsifying a solution of resin and NIR absorber in an aqueous solution of a dispersant; 4. Evaporating the water-immiscible solvent; Includes.

[0040] The composite particles can be isolated via separation techniques (centrifugation, freeze-drying, etc.) to provide the composite resin particles in a dry state, if desired.

[0041] If an additional functional compound (such as a medicamentously active agent) needs to be incorporated into the composite resin particles, this compound is preferably soluble in a water-immiscible solvent. The solvent evaporation technique according to the present invention is particularly preferred for the inclusion of active pharmaceutical ingredients (such as anticancer drugs).

[0042] A particularly preferred 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) is to 1. Dissolving a resin according to the invention, a NIR absorber according to the invention and a functional compound in a solvent that is substantially immiscible with water; 2. Dissolving a dispersant in water; 3. Emulsifying a solution of resin, NIR absorber, and functional compound in an aqueous solution of a dispersant; 4. Evaporating the substantially water-immiscible solvent; Includes.

[0043] The composite resin particles can be obtained by the same method as described above.

[0044] C. Application Areas The composite resin particles according to the invention are suitable for imaging diseased organs in the human and / or animal body. Due to their strong absorption of NIR light, the composite resin particles according to the invention are also suitable for diffuse optical tomography and photoacoustic imaging.

[0045] 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, thereby directly eliminating cancer cells while minimizing the damage to the surrounding healthy tissue, making the particles highly suitable for phototherapy treatment of tumors (PTT).

[0046] The composite resin particles of the present invention are also useful in photodynamic therapy (PDT), in which the NIR absorbers are excited with light of a wavelength suitable for the conversion of oxygen molecules into cytotoxic reactive oxygen species (ROS) (such as singlet oxygen), which then damage cancer cells via oxidative stress, ultimately inducing cell death. EXAMPLES

[0047] D. Working Example D.1. Materials: Mowiol4 88 is a poly(vinyl alcohol) supplied by Kuraray. · Synperonic PE / F68-FL is a PEO-PPO-block copolymer surfactant supplied by Croda Chemicals International Ltd. Natureworks Polylactide Resin 4060D is a poly(lactide) supplied by Evans Chemetics. · Resomer RG503H is a poly(D,L-lactide-co-glycolide) supplied by Evonik Industries.

[0048] 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 keeping the temperature below 50° C. The reaction was continued for 30 minutes at 50° C. 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.

[0049] -Synthesis of barbiturates(II) 206 g of acetic acid was added to 300 g of ureum (I). The mixture was heated to 60° C. The acetic acid solution of ureum (I) was added to 147 g of malonic 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 was continued at 90° C. for 2.5 hours. The reaction was cooled to 50° C. and 78 g of methanol was added. The mixture was refluxed for 45 minutes. The mixture was cooled 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 and then removed under reduced pressure four times. The crude barbituric acid derivative (II) was used without further purification.

[0050] -Synthesis of intermediate (III) 84 g of cyclopentanone was added to 240 g of barbituric acid derivative (II). 5 g of ammonium acetate was added, followed by 101 g of methanol. The reaction mixture was heated to reflux and the reaction was continued under reflux for 4.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed at 95° C. under 50 mbar pressure. 5 ml of toluene was added and evaporated at 100° C. under 50 mbar for 4 times. The reaction mixture was cooled to room temperature and 92 g of toluene was added. 55 g of toluene containing 26 g of silica gel was added and the mixture was filtered. The silica gel was flushed with toluene. The pooled toluene fractions were treated twice with 55 g of toluene containing 26 g of silica gel, filtered, followed by flushing of the silica gel with toluene. After pooling all the toluene fractions, the solvent was evaporated under reduced pressure. 287 g (yield: 97%) of crude intermediate (III) was isolated.

[0051] - 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 while the temperature was raised 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, after which the reaction mixture was heated to 65° C. The reaction was continued at 65° C. for 25 minutes. The reaction mixture was cooled to 47° C., after which 1.06 kg of methyl t.-butyl ether and 1.61 kg of n.-hexane were added. 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 washing three times with 160 g of ethyl acetate and 60 g of n.-hexane, and once with 400 g of heptane. The isolated intermediate (V) was dried. 335 g (yield: 37%) of intermediate (V) was isolated.

[0052] - Synthesis of intermediate (VI): Intermediate (VI) can be prepared as disclosed in WO2013037672.

[0053] -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 (yield: 87%) of NIR-7 was isolated.

[0054] NIR-24 is a NIR absorber and is prepared as follows: [ka] The starting NIR dye (I) can be prepared as disclosed by Nagao et al. (Dyes and Pigments, 73(3), 344-352 (2006).

[0055] Synthesis of -NIR-24 30 g of NIR starting material (I) was added to 100 ml of acetonitrile. 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 methanol at reflux. NIR-24 was isolated by filtering the warm methanol solution and dried. 19.7 g (yield: 35%) of NIR-24 was isolated.

[0056] NIR-25 is a NIR absorber and is prepared as follows: [ka] - Synthesis of intermediate (I): Intermediate (I) can be prepared as disclosed in WO2010120058.

[0057] - Synthesis of intermediate (II): 292 g of N,N'-dicyclohexylbarbituric acid were dissolved in 1.5 liters of trichloroethane. 156 ml of cyclohexanone, 12 ml (0.12 mol) 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 cooled to room temperature and the solvent was removed under reduced pressure. The residue was redissolved in 1 liter of trichloroethane. Undissolved residue was removed by filtration. 100 ml of piperidine was added and intermediate (II) was crystallized from the medium. Intermediate (II) was isolated by filtration and dried. 302 g (yield: 67%) was isolated.

[0058] 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 cooled to room temperature and NIR-25 was crystallized from the reaction mixture. 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. Residual impurities were removed by filtration. 6.6 l of methyl t.butyl ether was added. Ether was added and NIR-25 crystallized from the medium. NIR-25 was isolated by filtration and dried. 136 g (yield: 28%) of NIR-25 was isolated.

[0059] D.2. Method Capsule particle size was measured using a Zetasizer™ Nano-S (Malvern Instruments, Goffin Meyvis).

[0060] The UV-VIS spectra were measured on an Agilent 8433 spectrophotometer to obtain spectra up to 1100 nm. For the more bathochromic NIR absorbers, measurements were performed on a Shimadzu UV2600 spectrophotometer. The λ range was increased by diluting the samples with water. max The absorption of the sample at was adjusted to 1.

[0061] D.3. Example 1 This example illustrates the preparation of a PLA-based submicron particle dispersion according to the present invention.

[0062] -Preparation of COMPOSITE-RES-1 A first solution was prepared by dissolving 4.651 g of Natureworks polylactide resin 4060D in 51.86 g of ethyl acetate. A solution of 117 mg of NIR-7 in 2 ml of dichloromethane was added and the solution was stirred for an additional 30 minutes.

[0063] A second solution was prepared by dissolving 2.33 g of Mowiol 4 88 in 93 g of water.

[0064] The first solution was added to the second solution over a period of 15 minutes while stirring at 18000 rpm using an Ultra Turrax T25 (IKA). After addition was complete, stirring at 18000 rpm was continued for a further 10 minutes while maintaining the temperature below 32° C.

[0065] The solvents (ethyl acetate and dichloromethane) were removed under reduced pressure at 35° C., gradually decreasing the pressure from 950 mbar to 85 mbar. The weight of the dispersion was adjusted to 100 g by dilution with water if necessary.

[0066] The average particle size measured was 282 nm. The dispersion had an absorption maximum at 1036 nm.

[0067] D.4. Example 2 This example illustrates the preparation of a PLGA-based composite resin particle dispersion according to the present invention.

[0068] Preparation of -COMPOSITE-RES-2 A first solution was prepared by dissolving 4.651 g of Resomer RG503H in 61.86 g of ethyl acetate. A solution of 116 mg of NIR-7 in 2 ml of dichloromethane was added and the solution was stirred for an additional 30 minutes.

[0069] A second solution was prepared by dissolving 4.651 g of Synperonic PE / F68-FL in 90.58 g of water.

[0070] The first solution was added to the second solution over a period of 15 minutes while stirring at 13000 rpm using an Ultra Turrax T25 (IKA). After addition was complete, stirring at 13000 rpm was continued for a further 10 minutes while maintaining the temperature below 32° C.

[0071] The solvents (ethyl acetate and dichloromethane) were removed under reduced pressure at 35° C., gradually decreasing the pressure from 950 mbar to 85 mbar. The weight of the dispersion was adjusted to 100 g by dilution with water if necessary.

[0072] The measured average particle size was 167 nm. The dispersion had an absorption maximum at 1036 nm.

[0073] Preparation of -COMPOSITE-RES-3 A first solution was prepared by dissolving 4.651 g of RESOMER RG503H and 0.116 g of NIR24 in 92 g of methylene chloride.

[0074] A second solution was prepared by dissolving 2.33 g of Mowiol 4 88 in 93 g of water.

[0075] The first solution was added to the second solution over a period of 15 minutes while stirring at 10000 rpm using an Ultra Turrax T25 (IKA). After addition was complete, stirring at 10000 rpm was continued for a further 10 minutes while maintaining the temperature at 21° C.

[0076] The solvent was removed under reduced pressure at 35° C., gradually decreasing the pressure from 950 mbar to 85 mbar. The weight of the dispersion was adjusted to 100 g by dilution with water, if necessary.

[0077] Particle size was measured using an optical microscope. The average particle size was 2 microns. The dispersion had an absorption maximum at 772 nm.

[0078] -Preparation of COMPOSITE-RES-4: A first solution was prepared by dissolving 4.651 g of RESOMER RG503H and 0.116 g of NIR25 in 92 g methylene chloride.

[0079] A second solution was prepared by dissolving 2.33 g of Mowiol 4 88 in 93 g of water.

[0080] The first solution was added to the second solution over a period of 15 minutes while stirring at 10000 rpm using an Ultra Turrax T25 (IKA). After addition was complete, stirring at 10000 rpm was continued for a further 10 minutes while maintaining the temperature at 21° C.

[0081] The solvent was removed under reduced pressure at 35° C., gradually decreasing the pressure from 950 mbar to 85 mbar. The weight of the dispersion was adjusted to 100 g by dilution with water, if necessary.

[0082] Particle size was measured using an optical microscope. The average particle size was 2 microns. The dispersion had an absorption maximum at 810 nm.

[0083] D.5. Example 3: This example illustrates the NIR response of a dispersion containing NIR-responsive submicron particles according to the present invention.

[0084] A 1 mm thick coating of a dilute dispersion of NIR nanoparticles according to the invention was applied to a 300 nm laser equipped with three lasers (emitting light at 920 nm, 1064 nm, and 1150 nm, respectively). The samples were exposed to laser radiation from a Coherent laser combination. The extent to which different coatings of 1 mm thickness evaporated under laser exposure was evaluated. The sample coatings were applied on Priplak, a poly(propylene) substrate supplied by Antalis. A summary of the results is shown in Table 2. [Table 2] From Table 2, it is clear that the NIR-responsive nanoparticles according to the present invention exhibit high laser response.

Claims

1. General formula I 【Chemistry 1】 and a resin selected from the group consisting of poly(amino acids), polyphosphazenes, polysaccharide derivatives, poly(esters), poly(orthoesters), poly(cyano-acrylates), and copolymers thereof, During the ceremony, A and A' independently represent a substituted or unsubstituted heterocyclic group covalently bonded to the polymethine chromophore through a carbon atom; R １ and R ２ 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 １ and R ２ may represent the atoms necessary to form a 5- to 8-membered ring; R ３ and R ４ is 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 group or heteroaryl group.

2. 2. The composite resin particle of claim 1, wherein the poly(ester) is selected from the group consisting of poly(caprolactone), poly(lactic acid), poly(L-lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), poly(L-lactic acid-co-glycolic acid), poly(D,L-lactide), and any derivatives and / or combinations thereof.

3. The near infrared absorbing agent is represented by the general formula II 【Chemistry 2】 This is due to During the ceremony, R １ and R ２ 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 １ and R ２ may represent the atoms necessary to form a 5- to 8-membered ring; R ３ and R ４ 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 ５ and R ６ 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; 2. A composite resin particle according to any preceding claim, wherein Q represents the atoms necessary to form a substituted or unsubstituted 5- or 6-membered heterocyclic ring.

4. 2. The composite resin particle of claim 1, wherein the NIR absorber is non-ionic.

5. 10. The composite resin particle according to any of the preceding claims, wherein the average particle size of said composite resin particle according to the present invention is between 0.03 μm and 3 μm.

6. 10. The composite resin particle of any preceding claim, further comprising a pharma- ceutical active compound.

7. The composite resin particle of claim 6, wherein the pharma- ceutical active compound is a cytostatic agent selected from the group consisting of alkylating agents, anthracyclines, cytoskeletal disrupting agents, epothilones, histone deacetylase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, kinase inhibitors, nucleotide analogs, peptide antibiotics, platinum-based drugs, retinoids, and vinca alkaloids, and derivatives.

8. An aqueous dispersion comprising the composite resin particles according to any one of claims 1 to 7 and a stabilizing polymer or surfactant.

9. 9. The aqueous dispersion of claim 8, wherein the surfactant is a non-ionic ethoxylated block copolymer surfactant.

10. 9. The aqueous dispersion of claim 8, wherein the stabilizing polymer is a polysaccharide, poly(vinyl alcohol), or a poly(vinyl alcohol) copolymer, or a derivative thereof.

11. A pharmaceutical composition comprising the dispersion according to any one of claims 8 to 10 and a pharmaceutical carrier or pharmaceutical additive.

12. A pharmaceutical composition comprising the dispersion of claims 8 to 10 for use in cancer treatment.

13. A pharmaceutical composition comprising a dispersion according to claims 8 to 10 for use in medical imaging methods.

14. a) (The group consisting of poly(amino acids), polyphosphazenes, polysaccharide derivatives, poly(esters), poly(orthoesters), poly(cyano-acrylates), and copolymers thereof) and a NIR absorber according to the general formula in a substantially water immiscible solvent; b) dissolving a dispersant in water; c) emulsifying the solution of the resin and the near infrared absorbing agent obtained in step a) into the aqueous solution of the dispersant obtained in step b); d) evaporating the substantially water-immiscible solvent; A method for preparing the aqueous dispersion according to claims 8 to 10, comprising:

15. 15. The method for preparing an aqueous dispersion according to claim 14, wherein in step a) a pharma- ceutical active compound is added to the substantially water-immiscible solvent.

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