Medical Equipment

Abstract

In a medical instrument that is inserted into a lesion or a tissue to perform treatment, a technology for delivering various drugs to a target site is required.　The present invention provides a medical instrument that is inserted into a lesion or a tissue to perform treatment, wherein a drug-loaded nanostructure is covalently bonded to the medical instrument via a photosensitive linker fixed to the surface of at least a portion of the medical instrument.

Description

[Technical field]

[0001] The present invention relates to a medical device that is inserted into an affected area or tissue to perform a treatment, and more particularly to a medical device that can release a substance such as a drug in a target affected area or tissue. [Background technology]

[0002] It is common to treat various medical conditions by inserting medical devices into biological lumens such as blood vessels, esophagus, airways, sinuses, trachea, colon, bile duct, urinary tract, prostate, intracerebral tract, etc. For example, medical devices such as stents, catheters, balloon catheters, etc. are used to treat vascular diseases.

[0003] Among them, percutaneous transluminal coronary angioplasty (PTCA) is one of the treatments for coronary artery disease. PTCA is a method of dilating the stenosis by passing a medical balloon through a blood vessel to the site of stenosis and inflating it. It is considered to be a less invasive and more immediate treatment compared to surgery or drug therapy. PTCA is broadly divided into two types, depending on whether it is performed by only inflating the balloon during dilatation or by placing a stent at the same time as inflation. It is known that the former is accompanied by the risk of restenosis, and the latter is accompanied by the risk of thrombus formation. In recent years, a drug-coated balloon (DEB; Drug Eluting Balloon) has been developed to reduce the risk of restenosis, aiming for treatment using only a balloon without leaving foreign matter in the body and with a low risk of thrombus formation. The surface of the DEB balloon is coated with a drug that suppresses cell proliferation. When the DEB comes into contact with the stenosis site during balloon inflation, the drug coated on the outer surface can be administered to the affected area, thereby suppressing restenosis. However, in the DEB currently used in clinical practice, the drug is only applied to the surface of the balloon, so it is easy to fall off, and it is known that the drug gradually flows out with the blood flow from the time the balloon is inserted into the blood vessel, and 60 to 70% of the drug falls off before reaching the affected area. In addition, 10 to 20% of the drug remains on the balloon even after the balloon is inflated. As a result, the amount of drug actually taken up by the cells is 50 to 60% of the initial applied amount, and in addition to the low drug delivery efficiency, there is a problem that a large amount of drug flows out into the blood (Patent Document 1: International Publication No. WO2014 / 163091). In addition, there is also a problem that some drugs cannot be applied to the balloon surface in the first place, and the drugs that can be loaded are limited. In addition, with existing DEBs, most of the loaded drugs fall off before being delivered to the target site, and it is difficult to control the drug remaining on the balloon after expansion / modification, so it is necessary to administer the drug by a single balloon expansion. However, the amount of drug that can be released by one balloon expansion is also limited by the time that blood flow can be stopped (estimated to be 0.5 to 1.0 min), making it difficult to increase the amount of drug delivered to the target site.

[0004] Studies are also being conducted to control the release of drugs from the coating layer of medical devices such as DEB. For example, Patent Document 2 (International Publication No. WO2014 / 152823) discloses a medical device having a coating modified with a photosensitive linker that covalently bonds a reagent, and describes that when the coating is exposed to light, the photosensitive bond is cleaved and the reagent is released in the immediate vicinity of the site. However, in this medical device, since the functional group of the reagent itself is covalently bonded to the photosensitive linker, there are problems in that the function or activity of the reagent may be impaired or that it is limited to reagents that can be covalently bonded. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. WO2014 / 163091 [Patent Document 2] International Publication No. WO2014 / 152823 Summary of the Invention

[0006] Under these circumstances, there remains a demand for technology that delivers a variety of drugs to target sites in medical devices that are inserted into affected areas or tissues to perform treatment.

[0007] The present invention is, for example, as follows. [1] A medical device that is inserted into an affected area or tissue to perform treatment, A medical device comprising a drug-loaded nanostructure covalently bonded to at least a portion of the surface of the medical device via a photolabile linker fixed thereto. [2] The medical device described in [1], wherein the size of the nanostructure is 20 nm to 500 nm. [3] The medical device according to [1] or [2], wherein the nanostructure is at least one selected from micelles, polymer micelles, liposomes, polymersomes, nanogels, nanoparticles, nanorods, and nanospheres. [4] The medical device according to any one of [1] to [3], wherein the drug includes at least one selected from a drug, a medicine, a diagnostic agent, and a nutritional agent.

[0008] [5] The medical device described in any of [1] to [4], wherein the drug is encapsulated within the nanostructure or physically or chemically bonded to the nanostructure. [6] The medical device according to any one of [1] to [5], wherein the drug is water-soluble or water-insoluble. [7] The medical device described in any of [1] to [6], wherein the photosensitive linker is cleaved or decomposed upon exposure to light to release the nanostructure. [8] The medical device described in [7], which comprises two or more photosensitive linkers that are cleaved or decomposed by light of different wavelengths. [9] The photolabile linker is selected from the group consisting of a double bond connecting two carbon atoms, an azo bond, a peroxide bond, a bond connecting a carbon atom and a nitrogen atom, and a bond represented by the following formula (I): [ka] (In the formula, * represents a linking site, and R1, R2, and R3 each independently represent a hydrogen atom, a lower alkyl, a lower alkoxy, an amino, a halogen atom (F, Cl, Br, I), a hydroxyl, or a cyano, or any two of adjacent R1, R2, and R3 taken together represent a methylenedioxy group.) The structure represented by The medical device according to any one of [1] to [8], comprising at least one selected from the following:

[10] A medical device according to any one of [1] to [9], which is used for delivering a drug to tissue.

[0009]

[11] The medical device according to any one of [1] to

[10] , wherein the tissue includes at least one selected from the coronary vascular system, the peripheral vascular system, the cerebrovascular system, the esophagus, the airway, the sinuses, the trachea, the colon, the bile duct, the urinary tract, the prostate, the intracerebral duct, and the lower limbs.

[12] The medical device according to any one of [1] to

[11] , wherein the medical device is selected from a balloon, a catheter, a stent, and a probe. Medical equipment.

[13] The medical device described in any of [1] to

[12] , further comprising a light source for exposing the photosensitive linker to light, the light source being selected from a light-emitting diode and a semiconductor laser.

[14] The medical device described in any of [1] to

[13] , further comprising a secondary medical device having an optical fiber or a photonic crystal fiber for exposing the photosensitive linker to light.

[15] The medical device described in any of [1] to

[14] , wherein the photosensitive linker is cleaved or decomposed upon exposure to light having a wavelength in the range of 200 to 1000 nm.

[0010] The medical device of the present invention has one or more of the following advantages. (1) The medical device of the present invention can be applied to a variety of drugs because the drug is delivered to the target site with the drug supported on the nanostructure. For example, it is possible to load a variety of drugs, such as low molecular weight compounds, polymeric drugs, hydrophobic and hydrophilic substances, poorly soluble and water-soluble substances. Furthermore, since it is not necessary to fix (covalently bond) the drug itself to the medical device, it is possible to suppress the decrease in the function and activity of the drug due to loading or delivery. (2) In the medical device of the present invention, the nanostructure is fixed to the surface of the medical device, so that the drug is prevented from falling off (detaching or falling off) during the delivery process to the target site, and the drug can be stably delivered to the target site. Therefore, the medical device of the present invention is capable of efficient drug transport to the target site. (3) In the medical device of the present invention, the photosensitive linker can be cleaved or decomposed by exposing it to light, thereby releasing the nanostructure and / or the drug supported on the nanostructure at the target site. In a preferred embodiment, the release behavior (speed, timing, etc.) of the nanostructure and / or the drug carried by the nanostructure can be controlled by adjusting the amount of light or wavelength of light to which the nanostructure is exposed. In particular, in the medical device of the present invention, the nanostructure and / or the drug carried by the nanostructure are released only upon light irradiation, and by adjusting the amount of light exposure and the wavelength of light, stepwise drug release is possible. By repeating light irradiation to perform multiple drug releases (for example, by repeating multiple times the time during which blood flow can be stopped (estimated to be 0.5 to 1.0 min)), reliable delivery of the drug to the target is possible. (4) By constructing the nanostructure from a material with excellent biocompatibility (eg, blood compatibility), the biocompatibility of the surface of the medical device can be improved. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a schematic cross-sectional view showing a balloon, which is a medical device according to one embodiment. [Diagram 2] Figures 2(A) and 2(B) are schematic diagrams showing the dissociation (release) behavior of nanostructures by light irradiation. Figure 2(B) shows a medical device in which the photosensitive portion of the photosensitive linker is photocleaved by light irradiation, causing the nanostructures to dissociate (release). [Figure 3A] Figure 3(A) shows a schematic diagram of a core-shell type polymer micelle encapsulating Cy5 as a model reagent, and a schematic diagram of the polymers that constitute the polymer micelle. [Figure 3B] FIG. 3(B) shows the reaction of latex beads (PC-Latex-1) with a photocleavable linker having a DBCO group on the surface introduced thereon, and polymer micelles. [Figure 3C] FIG. 3(C) shows latex beads (Micelle-PC-Latex-1) in which polymeric micelles were immobilized on the surface of the latex beads via a photocleavable linker. [Figure 3D] Figure 3(D) shows latex beads (Micelle-PC-Latex-1) in which polymer micelles are immobilized on the surface of the latex beads via a photocleavable linker. Figure 3(C) is an enlarged view of Figure 3(D). [Figure 4]FIG. 2 is a diagram showing the results of measuring the particle size distribution of the polymer micelles produced in Example 1 by dynamic light scattering (DLS). [Diagram 5] 5 shows confocal laser scanning microscope fluorescence images of Micelle-PC-Latex-1 obtained in Example 1. Fig. 5(A) shows a fluorescence image before irradiation with 365 nm laser light, and Fig. 5(B) shows a fluorescence image after irradiation with 365 nm laser light. [Figure 6] Fluorescence images of a confocal laser scanning microscope are shown to evaluate the uptake behavior of Cy5 released by light irradiation into cells. Figure 6 (A) shows a fluorescence image of a cell nucleus stained with a fluorescent dye (Hoechest33342) before light irradiation, Figure 6 (B) shows a fluorescence image of Cy5 taken up by cells before light irradiation, and Figure 6 (C) shows a bright-field image of a cell before light irradiation. Figure 6 (D) shows a fluorescence image of a cell nucleus stained with a fluorescent dye (Hoechest33342) after light irradiation, Figure 6 (E) shows a fluorescence image of Cy5 taken up by cells after light irradiation, and Figure 6 (F) shows a bright-field image of a cell after light irradiation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention will be described in detail below with reference to the following embodiments and examples, but the present invention is not limited to the following embodiments and examples, and can be modified as desired without departing from the scope of the present invention. All documents and publications described in this specification are incorporated herein by reference in their entirety, regardless of their purpose. The dimensional ratios in the drawings are exaggerated for the sake of explanation and may differ from the actual ratios.

[0013] "Nanostructure" refers to a structure having a size on the nanometer scale (e.g., 1 to 1000 nm). A structure refers to an assembly of substances having a two-dimensional or three-dimensional structure. The structure may be hollow (e.g., the inside of the core is hollow) or solid, and may be multi-layered with a hollow layer and a solid layer. The nanostructure can be used as a carrier (drug carrier) for drug delivery. In this specification, "for drug delivery" means that the carrier is biocompatible and can carry a drug. The material of the nanostructure is not particularly limited and may include various substances including polymers, lipids, metal materials, oxides, ceramics, magnetic materials, carbon, silica, surfactants, nanodiamonds, etc. The shape of the structure is not particularly limited and may be spherical, non-spherical, elliptical, rod-like, pyramidal, cubic, disc-like, wire-like, irregular, or lamellar. Polymers may generally include block copolymers, poly(lactic acid), poly(lactic-co-glycolic acid), polyethylene glycol (PEG), acrylic acid polymers, cationic polymers, and other polymers known in the art for use in making nanostructures. Lipids may include fats, waxes, sterols, cholesterol, fat-soluble vitamins, monoglycerides, diglycerides, phospholipids, sphingolipids, glycolipids, cationic or anionic lipids, derivatized lipids, and cardiolipin.

[0014] "Supported" refers to a state in which a drug is contained within a nanostructure and / or a state in which a drug is attached or bound to a nanostructure by chemical and / or physical means. A representative example of the above-mentioned chemical means is chemical bonding. Specific examples of chemical bonding include covalent bonds, metallic bonds, coordinate bonds, ionic bonds, hydrogen bonds, and intermolecular forces. As the above-mentioned physical means, any appropriate immobilization means other than chemical means can be adopted. Specific examples include adsorption, embedding, impregnation, etc.

[0015] The term "micelle" refers to a vesicle formed by one molecular membrane. Examples of micelles include micelles formed by amphiphilic molecules such as surfactants. "Polymer micelle" refers to a polymer aggregate formed by self-association of block copolymers (diblock or multiblock copolymers each having one or more blocks with different physicochemical properties) composed of polymer chains with different physicochemical properties such as hydrophilicity, hydrophobicity, and charge. Typically, it is a nanoparticle with a core-shell structure formed by autonomous multi-molecular association of block copolymers in which hydrophilic polymer chains and hydrophobic polymer chains are linked. Typically, in an aqueous medium, it is a particle with a particle diameter of about 10 to 100 nm, in which the hydrophobic part forms the core and the hydrophilic part forms the shell. The polymer micelles also include polyion complex micelles formed by electrostatic interactions as a driving force and micelles formed by metal complexes as a driving force. A "polyion complex" (hereinafter also referred to as "PIC") is a particulate polymer assembly formed by autonomously associating multiple molecules of a block copolymer in which a hydrophilic polymer chain and an anionic polymer chain are linked, and a block copolymer in which a hydrophilic polymer chain and a cationic polymer chain (e.g., polyglutamic acid, polyaspartic acid, etc.) are linked, by electrostatic interactions as a driving force. Specifically, in an aqueous medium, an ion layer formed between the anionic polymer chain and the cationic polymer chain of both block copolymers forms a core, and a hydrophilic portion forms a shell, forming a particulate assembly with a particle diameter of about several tens of nm. Polyion complexes are disclosed, for example, in JP-A-8-188541 and WO2006 / 118260.

[0016] The term "liposome" refers to a vesicle formed by two molecular membranes, usually a bilayer of phospholipids. The term "polymersome" refers to a closed endoplasmic reticulum, i.e., a vesicle, having a two-layer molecular membrane structure formed from an amphiphilic block copolymer (a diblock or multiblock copolymer having one or more hydrophobic and hydrophilic blocks).

[0017] "Nanogel" refers to nanoparticles having a hydrogel structure with a size on the nanometer scale (e.g., 1 to 1000 nm). They have a three-dimensional network structure of polymer chains crosslinked by electrostatic interactions, van der Waals forces, hydrophobic interactions, hydrogen bonds, covalent bonds, etc.

[0018] "Nanoparticle" means a fine particle having a diameter on the nanometer scale (e.g., 1 to 1000 nm, or 1 to 500 nm, or 1 to 100 nm, or 1 to 50 nm, or 1 to 30 nm, 20 nm to 500 nm, or 30 nm to 500 nm, or 20 nm to 200 nm, or 30 to 200 nm, or 20 nm to 100 nm, or 30 nm to 100 nm). A "nanorod" refers to a rod-shaped fine particle whose short axis length and long axis length are different. Typically, it is a particle with a short axis (diameter) of about 10 to 100 nm and a long axis (length) of about 10 to 1000 nm. The term "nanosphere" refers to nanoparticles formed by aggregation of polymers. Typically, these nanoparticles contain drugs or the like in a matrix based on a biocompatible polymer.

[0019] 1. Medical equipment One aspect of the present invention relates to a medical device that is inserted into an affected area or tissue to perform treatment, in which a drug-loaded nanostructure is covalently bonded to at least a portion of the surface of the medical device via a photosensitive linker fixed to the surface.

[0020] The medical device is not particularly limited as long as it is inserted into an affected area or tissue (hereinafter also simply referred to as a "target site") to perform treatment. Examples include balloons, catheters, stents, and probes. The affected area or tissue to be inserted is not particularly limited. For example, the inside of blood vessels or luminal cavity (e.g., lymphatic vessels, ducts such as bile ducts, digestive tracts, passages such as urinary tracts) in the body can be mentioned, and specifically, at least one selected from the coronary vascular system, peripheral vascular system, cerebrovascular system, esophagus, airway, sinus, trachea, colon, bile duct, urinary tract, prostate, intracerebral duct, and lower limbs (e.g., blood vessels in thighs, legs, etc.) can be mentioned. In one embodiment, the affected area or tissue is a tissue at risk of restenosis. In one embodiment, the medical device is configured to deliver at least one drug to the site at risk of restenosis. In one embodiment, the medical device is configured to deliver at least one drug to an intraluminal site, including a blood clot or an embolus. In one embodiment, the medical device is at least one angioplasty balloon, catheter, stent, and probe configured for temporary or permanent placement.

[0021] The drug is not particularly limited. For example, it may be a drug (e.g., a low molecular weight compound, a peptide, an antibody, a nucleic acid, etc.), a pharmaceutical (e.g., a low molecular weight drug, an antibody drug, a nucleic acid drug, a protein preparation, a vaccine, etc.), a diagnostic drug, or a nutritional supplement. The drug may be used alone or in combination of two or more kinds. The drug may be water-soluble or water-insoluble. In one embodiment, the drug is water-soluble. Conventionally, water-soluble drugs are difficult to deliver to a target site because they are easily released into the bloodstream or decomposed by enzymes. However, in this embodiment, the drug can be stably delivered to a target site by being supported (e.g., encapsulated or encapsulated) in a nanostructure.

[0022] The nanostructure is not particularly limited as long as it is capable of carrying a drug, and examples thereof include micelles, polymer micelles, liposomes, nanorods, nanogels, nanoparticles, and nanospheres. The form in which the drug is carried in the nanostructure is not particularly limited. In one embodiment, the drug is contained within the nanostructure. In one embodiment, the drug is attached or bound to the nanostructure by chemical and / or physical means. In one embodiment, the drug is encapsulated within the nanostructure or is physically or chemically bound to the nanostructure.

[0023] The size of the nanostructure is not particularly limited, but from the viewpoint of uptake into target cells, it is, for example, 500 nm or less, or 200 nm or less, or 100 nm or less, or 50 nm or less, and from the viewpoint of loading a required amount of drug, it is 20 nm or more, or 30 nm or more, or 50 nm or more, or 100 nm or more. In one embodiment, the size of the nanostructure is preferably 20 nm to 500 nm, preferably 30 nm to 500 nm, more preferably 30 to 200 nm, and even more preferably 30 to 100 nm. In this specification, the size of a nanostructure refers to its hydrodynamic diameter (average particle size). The hydrodynamic diameter (average particle size) can be measured by dynamic light scattering (DLS), and the volume average diameter is usually used.

[0024] The medical device according to one embodiment of the present invention is a balloon. Fig. 1 is a schematic diagram showing a balloon, which is a medical device according to one embodiment. Fig. 2(A) and Fig. 2(B) are schematic diagrams showing the behavior of dissociation (release) of a nanostructure from a medical device by light irradiation. The following description will be given using the balloons shown in these drawings as examples, but the medical device of the present invention is not limited to such forms. The medical device 1 has a photosensitive linker 12 fixed to a part of the outer surface. The nanostructure 11 is covalently bonded to the outer surface 13 of the medical device (balloon) via the photosensitive linker 12. In one embodiment, a covalent bond is formed between a functional group present on the outer surface 13 of the medical device (balloon) and a functional group present on the photosensitive linker 12, and further, a covalent bond is formed between a functional group present on the photosensitive linker 12 and a functional group present on the nanostructure 11. In this way, since the nanostructure 11 is fixed to the outer surface 13 of the medical device (balloon), the detachment and outflow of the nanostructure and / or drug due to blood flow or the like during the process of the medical device reaching the target site is suppressed or prevented, and the drug can be stably delivered to the target site.

[0025] The surface 13 of the medical device (balloon) may be coated to improve biocompatibility. Alternatively, the surface layer of the nanostructure 12 may be made of a material with excellent biocompatibility (e.g., polyethylene glycol (PEG)). In this form, the incorporation of the nanostructure is expected to improve biocompatibility, and the coating process for the medical device surface can be reduced or simplified.

[0026] The photosensitive linker 12 has a photosensitive portion 12a that is cleaved or decomposed by exposure to light. As shown in Fig. 2(A), by exposing the photosensitive linker 12 to light (hv), the photosensitive portion 12a is cleaved or decomposed as shown in Fig. 2(B). As shown in Fig. 2(B), the photosensitive linker 12 is cleaved by the cleavage or decomposition of the photosensitive portion 12a, and the nanostructure 11 and / or the drug (not shown) carried by the nanostructure 11 is released in the immediate vicinity of the site.

[0027] In one embodiment, the nanostructure is a polymer micelle. FIG. 3(A) shows a schematic diagram of a polymer micelle according to one embodiment. In FIG. 3(A), the left diagram shows a polymer micelle 21, and the right diagram shows each component of the polymer micelle 21. As shown in FIG. 3(A), the polymer micelle 21 includes a block copolymer 22. The block copolymer includes a hydrophilic polymer chain (PEG) and a polymer chain (PAsp or PDAP). The hydrophilic polymer chains are radially arranged on the outside to form a micelle, and a drug 24 is encapsulated in the core of the micelle. That is, the polymer micelle 21 has a core-shell structure in which the polymer chain and the drug 24 in the block copolymer 22 form the core, and the hydrophilic polymer chains in the polymer 22 extend outward to form a shell (outer shell). This polymer micelle 21 has excellent biocompatibility (stability in blood) because it has a hydrophilic polymer chain in the shell.

[0028] In the micelle shown in Fig. 3(A), some of the hydrophilic polymer chains of the block copolymer 22 are modified with functional groups 25, and the functional groups 25 are present on the surface of the micelle 21. As shown in Fig. 3(B) and Fig. 3(C), the polymer micelle 21 forms a covalent bond between the functional groups 25 on the surface and the functional groups of the photosensitive linker 32 fixed to the surface of the medical device 33, and can thereby be fixed to the surface of the medical device. The photosensitive linker 32 has a photosensitive portion 32a, and can be cleaved or decomposed by exposure to light (hν).

[0029] The block copolymer constituting the polymer micelle is not particularly limited, and any block copolymer generally known in the art can be used. One example of a block copolymer is one that is composed of a hydrophilic polymer chain and a polyamino acid. The hydrophilic polymer chain may be composed of any suitable hydrophilic polymer. Examples of the hydrophilic polymer include poly(ethylene glycol), polysaccharides, poly(vinylpyrrolidone), poly(vinyl alcohol), poly(acrylamide), poly(acrylic acid), poly(methacrylamide), poly(methacrylic acid), poly(methacrylic acid ester), poly(acrylic acid ester), polyhydroxyethyl acrylate, poly(hydroxyethyl methacrylate), polyamino acids, poly(malic acid), poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), poly(2-isopropyl-2-oxazoline), or derivatives thereof. Specific examples of polysaccharides include starch, dextran, fructan, galactan, etc. Among these, poly(ethylene glycol) (PEG) is preferably used because terminal reactive polyethylene glycols having various functional groups at the terminals are commercially available, and those with various molecular weights are also commercially available and can be easily obtained. The terminal of PEG (polyethylene glycol) may be methoxylated (MPEG; methoxy(polyethylene glycol)). These hydrophilic polymer chains may be used alone or in combination of two or more. Polyamino acids include polymers of amino acids selected from nonpolar amino acids such as leucine, isoleucine, phenylalanine, methionine, and tryptophan; acidic amino acids such as aspartic acid and glutamic acid; basic amino acids such as lysine, ornithine, arginine, homoarginine, and histidine; and derivatives thereof; and combinations thereof.

[0030] The polymer micelle can be formed by a known method using the above block copolymer and a conventionally known block copolymer. In the embodiment shown in Fig. 3(A), the drug 24 is fixed by modifying (binding) a part of the block copolymer 22, but the drug 24 does not have to be bound to the block copolymer 22.

[0031] For example, a polymer micelle carrying a drug can be produced by separately preparing a solution in which a drug is dissolved in a solvent such as alcohol and a solution in which a block copolymer is dissolved in a pH buffer solution, mixing the two solutions, and dialyzing them against PBS to produce a polymer micelle of a drug and a block copolymer (e.g., a polymer micelle in which a drug is encapsulated in the core). In the case of PIC micelles or liposomes, a mixed solution of a polymer solution that forms PIC micelles or liposomes and a drug is prepared, and the mixture is stirred and mixed, so that the drug is encapsulated in the PIC micelles or liposomes. Alternatively, a solution of a block copolymer can be stirred to form polymer micelles or PIC micelles, and then a solution in which a drug is dissolved can be added to the micelle solution to encapsulate the drug in the micelles.

[0032] The nanostructure is not limited to the polymer micelles composed of the block copolymers exemplified above, but also includes polymer micelles composed of lipid molecules, liposomes, polymersomes, nanogels, nanoparticles, nanorods, nanospheres, and the like.

[0033] The photolabile linker can be any suitable type that contains a photolabile moiety and can immobilize the nanostructure to the surface of the medical device, for example, via one or more covalent bonds. In one embodiment, the photosensitive linker has a photosensitive moiety, a functional group (hereinafter also referred to as "first functional group") capable of forming a covalent bond with a functional group present on the nanostructure, and a functional group (hereinafter also referred to as "second functional group") capable of forming a bond with a functional group present on the surface of the medical device. The nanostructure is fixed to the surface of the medical device via the photosensitive linker through the bond between the first functional group and the functional group present on the nanostructure and the bond between the second functional group and the functional group present on the surface of the medical device.

[0034] GovernmentFrom the viewpoint of reactivity between the nanostructure and the photosensitive linker, the functional group is preferably introduced to the surface of the nanostructure. The surface of the nanostructure may be modified after production to introduce the functional group, or a nanostructure having a functional group on the surface may be formed using a molecule modified with a functional group. For example, as in the polymer micelle shown in FIG. 3(A), a part of the block copolymer constituting the polymer micelle may be introduced at the end of the hydrophilic polymer chain. To the government The surface layer is made of a functionalized block copolymer. To the government Polymer micelles having functional groups can be formed.

[0035] The combination of the first functional group and the functional group of the nanostructure is not particularly limited as long as the nanostructure can be stably fixed by covalent bonding. For example, the combination of the first functional group and the functional group of the nanostructure can be a DBCO group and an azide group (-N3) group, a carboxyl group and an amino group, a thiol group and a maleimide group, etc.

[0036] The method of modifying the surface of a medical device with a functional group is not particularly limited and may be determined depending on the material of the surface of the medical device. For example, the surface of a medical device made of a polymer or rubber material may use a functional group, such as an amino group or an aldehyde group, created on the surface of the polymer by corona or plasma technology.

[0037] The combination of the second functional group and the functional group on the surface of the medical device is not particularly limited, and those generally used in the art can be used. Examples of the combination of the second functional group and the functional group on the surface of the medical device include a DBCO group and an azide group, a carboxyl group and an amino group, and a thiol group and a maleimide group.

[0038] The photosensitive moiety is a moiety that is cleaved or decomposed by exposure to light. In certain embodiments, the photosensitive linker (photosensitive moiety) is cleaved or decomposed by exposure to light in the wavelength range of 200 to 1000 nm. In one embodiment, the photosensitive linker (photosensitive moiety) is cleaved or decomposed by exposure to light in the wavelength range of 200 to 380 nm (ultraviolet light). In one embodiment, the photosensitive linker (photosensitive moiety) is cleaved or decomposed by exposure to light in the wavelength range of 380 to 700 nm (visible light). In one embodiment, the photosensitive linker (photosensitive moiety) is cleaved or decomposed by exposure to light in the wavelength range of 700 to 1000 nm (infrared light).

[0039] The number of photolabile linkers introduced onto the surface of the medical device is not particularly limited, and may be one, or two or more. The medical device may contain two or more photolabile linkers (photolabile moieties) that are cleaved or decomposed by light of different wavelengths, allowing for stepwise release of the nanostructure and drug, release of the nanostructure and drug at different target sites, or simultaneous or stepwise release of multiple drugs at different target sites.

[0040] The photosensitive linker is not particularly limited as long as it contains a photosensitive moiety, and examples thereof include those having the structure of the following formula (I) as the photosensitive moiety. [ka] In formula (I), * represents a linking site. In formula (I), R1, R2, and R3 each independently represent a hydrogen atom, a lower alkyl (e.g., a straight-chain or branched alkyl having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms)), a lower alkoxy (e.g., a straight-chain or branched alkoxy having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms)), amino, a halogen atom (F, Cl, Br, I), hydroxy, or cyano, or any two of adjacent R1, R2, and R3 taken together represent a methylenedioxy group. In one embodiment, R1, R2, and R3 are all hydrogen atoms. In one embodiment, any two of R1, R2, and R3 are hydrogen atoms, and the remaining one is a hydrogen atom, a lower alkyl, or a lower alkoxy.

[0041] The structure represented by the above formula (I) can dissociate the C-N bond in formula (I) by irradiation with light having a wavelength of, for example, 365 nm (deprotection of o-nitrobenzyl group). Therefore, when the structure represented by the above formula (I) is included, light having a specific wavelength range with a peak around 365 nm, for example, laser light or ultraviolet light having a wavelength region such as 360 to 370 nm, 355 to 375 nm, 350 to 380 nm, 345 to 385 nm, or 340 to 390 nm, can be used to cleave the photosensitive linker.

[0042] In one embodiment, the photolabile linker comprises a structure derived from a photolabile unit comprising 3-amino-3-(2-nitrophenyl)propanoic acid (ANP).

[0043] Other examples of photolabile linkers include at least one bond selected from a double bond connecting two carbon atoms, an azo bond, a peroxide bond, and a bond connecting a carbon atom and a nitrogen atom. For example, a photolabile (photolabile) protecting group containing the above bond can be used as the photolabile moiety. The photolabile linker is cleaved by deprotecting the protecting group by irradiation with light. Such photolabile protecting groups include, for example, one or more of α-substituted acetophenone, 3'-5'-dimethoxybenzoin, benzyl group, cinnamic acid ester, coumaryl-methyl-diethyl phosphate, o-nitrobenzyl ester, and analogs thereof. For example, deprotection of polycyclic aromatic hydrocarbons (aqmoc, mcmoc, phmoc) can be carried out at 350 nm or using a light source providing, for example, 345-355 nm, 340-360 nm, 335-365 nm, 330-370 nm, etc. Deprotection involving cis-trans isomerization for coumarin (366 nm), vinylphenol (254 nm), and vinylnaphthol (350 nm) can be used (wavelengths in parentheses are those which give maximum deprotection). Deprotection of the silyl group can be achieved using 204 nm and 254 nm light. Deprotection of the N-methyl-N-(o-nitro)carbamate can be achieved using 254 nm light. The deprotection of the 2-benzylbenzoic acid group can be carried out using light of 300 to 390 nm. Deprotection of 3,5-dimethoxybenzoin (3,5-DMB) derivatives is also available. Molecules with functional groups that are carboxylic acids can be protected by reaction with 3,5-DMB to give esters. Molecules with functional groups that are secondary amines can be protected by reaction with 3,5-DMB to give carbamates.

[0044] The photosensitive linker may be a commercially available product, such as 3-AMINO-3-(2-NITROPHENYL)PROPIONIC ACID manufactured by MARK.

[0045] The wavelength and intensity of the light irradiated to the photosensitive linker are not particularly limited as long as the photosensitive moiety is cleaved or decomposed by exposure to light, and are appropriately determined depending on the structure and type of the photosensitive moiety. For example, the intensity of the irradiated light is 0.01 to 0.02 mW / cm 2 , 0.02~0.05mW / cm 2 , 0.05~0.1mW / cm 2 , 0.1~0.2μW / cm 2 , 0.2~0.5μW / cm 2 , 0.5~1.0μW / cm 2 , 1.0~2.0μW / cm 2 , 2.0~5.0μW / cm 2 , 5.0~10μW / cm 2 , 10~20μW / cm 2 , 20~50μW / cm 2 , 50~100μW / cm 2, 100~200μW / cm 2 , 200~500μW / cm 2 , 500~1000μW / cm 2 , 1~2mW / cm 2 , 2~5mW / cm 2 , 5~10mW / cm 2 , 10~20mW / cm 2 , 20~50mW / cm 2 , 50~100mW / cm 2 , 100~200mW / cm 2 , 200~500mW / cm 2 , 500~1000mW / cm 2 and the like, and any combination thereof. The light may be continuous light or pulsed light. The irradiation time may be sufficient for the light exposure to cleave or decompose the photosensitive moiety, and may be, for example, about 0.01 milliseconds, about 0.02 milliseconds, about 0.05 milliseconds, about 0.1 milliseconds, about 0.2 milliseconds, about 0.5 milliseconds, about 1.0 milliseconds, about 2 milliseconds, about 5 milliseconds, about 10 milliseconds, about 20 milliseconds, about 50 milliseconds, about 100 milliseconds, about 200 milliseconds, about 500 milliseconds, about 1 second, about 2 seconds, about 5 seconds, about 10 seconds, about 20 seconds, about 50 seconds, about 100 seconds, about 1 minute, about 2 minutes, about 10 minutes, about 20 minutes, about 40 minutes, about 60 minutes, about 2 hours, about 4 hours, etc.

[0046] The medical device of the present invention further comprises a light source for exposing the photolabile linker to light. In one embodiment, the light source is selected from a light emitting diode and a semiconductor laser. These light sources can deliver light (side emission) effective for photocleavage of the photolabile linker at the target site. The light source can be used anywhere that light is delivered to the photolabile linker on the surface of the medical device. For example, the light source can be used at a target site near the photolabile linker, or at a tissue in the body different from the site where the photolabile linker is present, or outside the body to deliver light (side emission) effective for photocleavage of the photolabile linker. The light source is configured to produce light of any suitable wavelength. Examples of light of suitable wavelengths include light that is substantially ultraviolet, violet, blue, green, yellow, orange, red, infrared, or any combination of two or more thereof, for example, provided by separate optical cables or provided at different times.

[0047] The medical device of one embodiment of the present invention further comprises a secondary medical device for exposing the photolabile linker to light. The secondary medical device may, for example, include a secondary device having at least one optical fiber, photonic crystal fiber, which delivers light effective for photocleavage generated by a light source to the photolabile linker. Furthermore, one embodiment of the present invention is the above medical device present as an integral unit with the secondary medical device. One embodiment of the present invention is a kit including the above medical device and a secondary medical device having at least one optical fiber or photonic crystal fiber, which delivers light effective for photocleavage of the photolabile linker to the photolabile linker. In certain embodiments, the medical device is a balloon, and a kit is provided that includes the medical device and a secondary medical device having at least one optical fiber, which delivers light effective for photocleavage of the photolabile linker to the photolabile linker. In certain embodiments, the medical device is a balloon, and the nanostructures are configured to be in contact with the vessel wall upon balloon expansion.

[0048] 2. Manufacturing method of medical devices The medical device of the above embodiment can be manufactured by (1) fixing a photosensitive linker to the surface of the medical device, and (2) fixing a nanostructure to the photosensitive linker. The order of the above process (1) and process (2) is not particularly limited, and processes (1) and (2) may be performed simultaneously. For example, when (2) is carried out after (1) above, a medical device can be manufactured by the following steps. First, the second functional group of the photosensitive linker is reacted with and bonded to a functional group present on the surface of the medical device, thereby immobilizing the photosensitive linker on the surface of the medical device. The reaction is carried out, for example, by applying a solution containing the photosensitive linker to the surface of the medical device or by immersing the medical device in the solution. Then, the first functional group of the photosensitive linker fixed to the surface of the medical device is reacted with the functional group present on the nanostructure to form a covalent bond, for example, by applying a solution containing the nanostructure to the surface of the medical device or immersing the medical device in the solution.

[0049] 3. Use of medical equipment The medical device of the above embodiment may be used to deliver drug-loaded nanostructures and / or drugs to a target site. The medical device of the above embodiment can be used as a means to selectively and efficiently introduce a desired loaded drug to a target site. The medical device of the above embodiment is configured to be inserted into a target site and exposed to light at the site, where the photolabile linker is cleaved to release the nanostructure and / or the drug loaded thereon in the vicinity of the target site. In one embodiment, the medical device is configured to deliver at least one reagent to an intraluminal site or other site in the body. In the medical device of the embodiment, a drug is released by cleavage (cleavage or decomposition) of a photosensitive linker fixed to the surface by exposure to light. In one embodiment, the release of the drug depends on the intensity and wavelength of light. In a preferred embodiment, the release behavior (speed, timing, etc.) of the nanostructure and / or the drug carried by the nanostructure is controlled by adjusting the amount of light and the wavelength of light to which the nanostructure is exposed. The present invention encompasses the delivery of nanostructures, and delivery of drugs carried by nanostructures, for diagnostic or therapeutic purposes using the medical devices of the above embodiments. The medical device of the present invention is inserted into an affected area or tissue to perform treatment, and can be applied to various animals such as humans, mice, rats, rabbits, pigs, dogs, and cats, with no limitations on the subjects to be treated.

[0050] One aspect of the present invention provides a drug delivery device including the medical instrument of the above embodiment. The drug delivery device of the present invention can be used as a means for selectively and efficiently introducing a desired drug carried therein to a target site. Another aspect provides a method for releasing a desired drug carried therein at a target site using the medical instrument described above. One embodiment of the present invention is a method for delivering or releasing at least one drug to a diseased area or tissue using the medical device of the above embodiments, comprising the steps of placing the medical device at the diseased area or tissue (e.g., an intravascular site or lumen in the body) and irradiating with an amount of light effective to cleave (cleave or degrade) the photolabile linker. EXAMPLES

[0051] The present invention will be described in more detail below with reference to examples, production examples and test examples, but the present invention is not limited to these examples. In this specification, "room temperature" generally refers to about 10° C. to about 35° C. "%" refers to weight percent unless otherwise specified. As used herein, the term "about" can mean ±10%.

[0052] The abbreviations used in the examples are conventional abbreviations well known to those skilled in the art. Some abbreviations are listed below. FMOC: 9-fluorenylmethyloxycarbonyl FMOC-ANP: 3-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2-nitrophenyl)propanoic acid EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide DBCO: Dibenzocyclooctyne PEG: Polyethylene glycol PAsp: Polyaspartic acid PBS: Phosphate-buffered saline

[0053] The structures of FMOC-ANP and DBCO-PEG4-NH2 used in the examples are as follows: [ka]

[0054] The structures of N3-PEG-PAsp, MeO-PEG-PAsp-Cy5, and MeO-PEG-PDAP used in the examples are as follows: [ka]

[0055] [Example 1: Preparation of micelle-loaded photoresponsive latex beads (Micelle-PC-Latex-1)] Hereinafter, the manufacturing process of the micelle-supported photoresponsive latex beads (Micelle-PC-Latex-1) manufactured in Example 1 will be described with reference to Figures 3(A), 3(B), 3(C) and 3(D).

[0056] (1) Preparation of model micelle solution A model micelle solution was prepared by dissolving N3-PEG-PAsp, MeO-PEG-PAsp-Cy5, and MeO-PEG-PDAP in a molar ratio of 25 / 25 / 50 in 10 mM phosphate buffer (pH 7.4, 0 mM NaCl) to a solid concentration of 1 mg / mL. N3-PEG-PAsp is a block copolymer of a PEG chain modified with an azide group (N3-) at the end and a PAsp chain. MeO-PEG-PDAP is a block copolymer of a PEG chain modified with a methoxy group (MeO-) at the end and a PDAP chain. MeO-PEG-PAsp is a block copolymer of a PEG chain modified with a methoxy group (MeO-) at the end and a PAsp chain. A part (50%) of MeO-PEG-PAsp is modified with Cy5 at the N-terminus of the PAsp chain using sulfo-Cy5-NHS (manufactured by Lumiprobe). That is, MeO-PEG-PAsp-Cy5 is a block copolymer of a PEG chain modified with methoxy group (MeO-) at the α-terminus of PEG and with Cy5 at the PAsp terminus, and contains MeO-PEG-PAsp and MeO-PEG-PAsp at a molar ratio of 50:50. As shown in Figure 3(A), the obtained model micelle solution contained polymer micelles (21 in Figure 3(A)) consisting of a core formed from a PAsp block and a PDAP block encapsulating the model reagent Cy5 (24 in Figure 3(A)) in the micelle core, and a PEG shell having an azide group (N3-) (25 in Figure 3(A)) on the surface. Dynamic light scattering (DLS) measurements of the polymer micelles were performed using a Zetasizer (Malvern) with light at 633 nm, and the micelles had a size (average particle size) of 30 nm. Note that the size is a volume average value.

[0057] (2) Preparation of Micelle-PC-Latex-1 (i) Step 1: Introduction of photocleavable linker (PC) onto the latex bead surface [ka] [ka]

[0058] 100 μL of latex-NH2 beads (Micromod, product name: Micromer, NH2) were centrifuged, and FMOC-ANP (100 μL, 2.31 x 10 2 After adding 200 μL of 50% piperidine solution, the mixture was stirred for 8 hours. After purification, DBCO-PEG4-NH2 (100 μL, 1.91x10 -2 mM) and EDC (3 eq., 146 μL) were added and reacted for 24 hours. As a result, PC-Latex-1 (Figure 3(B)) was obtained, in which a photocleavable linker (DBCO-PEG4-ANP-COOH) (32 in Figure 3(B)) having a DBCO group on the surface was introduced onto the surface of a latex bead (33 in Figure 3(B)).

[0059] (ii) Step 2: Loading of micelles onto latex beads [ka]

[0060] The purified beads (PC-Latex-1) were added with a model micelle solution (100 μL, diluted 50-fold), lyophilized, and thawed at 4° C. After centrifugation and purification, the target product, Micelle-PC-Latex-1, was obtained (FIGS. 3(C)(D)). Specifically, as shown in FIG. 3(B)-(D), the DBCO group in the photocleavable linker 32 immobilized on the latex surface reacts with the azide group 25 present on the surface of the shell layer of the polymer micelle 21, and the polymer micelle 21 is covalently bonded to the latex bead surface 33 via the photocleavable linker 32 and immobilized.

[0061] Example 2: Photocleavage experiment A sample solution was prepared by dissolving Micelle-PC-Latex-1 obtained in Example 1 in 200 μL of H2O to a concentration of 0.01 mg / μL. Photocleavage was carried out by irradiating the sample with a 365 nm laser at 0.36 W for 40 minutes. Using a confocal laser scanning microscope (LSM800), fluorescence observation was performed on Cy5 (em: 633 nm), a model reagent encapsulated in micelles, before and after irradiation with laser light with a wavelength of 365 nm to confirm the introduction of Cy5-encapsulated micelles onto the latex surface and their photoresponsiveness (photocleavage). Specifically, the introduction of Cy5-encapsulated micelles to the latex surface was evaluated by observing the fluorescence of the micelles with a confocal scanning microscope before irradiation with a laser beam having a wavelength of 365 nm. If the micelles are supported on the latex surface, the fluorescence of Cy5 encapsulated in the micelles can be observed by irradiating with a 633 nm laser. A confocal laser scanning microscope fluorescence image of Micelle-PC-Latex-1 obtained in Example 1 (before irradiation with a laser beam having a wavelength of 365 nm) is shown in FIG. 5(A). As shown in FIG. 5(A), circular fluorescence was observed, confirming the introduction of micelles to the latex surface. Furthermore, the photoresponsiveness was evaluated by observing the fluorescence of the micelles with a confocal scanning microscope (LSM800) after irradiation with a 365 nm laser light for 40 minutes. This is because ANP, the photocleavable group (PC) used in this experiment, is cleaved at 365 nm. Figure 5(B) shows a fluorescence image of Micelle-PC-Latex-1 obtained in Example 1 after irradiation with a laser light having a wavelength of 365 nm, taken with a confocal laser scanning microscope. As shown in Figure 5(B), it is confirmed that the fluorescence observed before irradiation (Figure 5(A)) has disappeared. This result is considered to be due to the fact that ANP is cleaved by irradiation with a 365 nm laser light, and the micelles supported on the latex surface are dissociated, making it impossible to observe the fluorescence of Cy5 encapsulated in the micelles.

[0062] [Example 3: Cellular uptake experiment] To evaluate the uptake behavior of Cy released by cleavage upon irradiation, HeLa cells seeded on a 96-well plate were used. Specifically, Micelle-PC-Latex-1 obtained in Example 1 was purified with urea solution and PBS, and then dissolved in 200 μL of PBS to a concentration of 0.01 mg / μL. The resulting solution was irradiated with a 365 nm laser at 360 mW / cm. 2After irradiating with UV light for 1 minute, the solution containing the photocleaved micelles was collected. The collected solution was added to a well in which HeLa cells were cultured and incubated for 8 hours. The cell nuclei were washed with PBS and then stained with Hoechst 33342 fluorescent reagent (100 μL, 2.2 nM). The cellular uptake behavior of the obtained Cy5 was evaluated using a confocal laser scanning microscope (LSM800).

[0063] Specifically, the supernatants collected before and after 365 nm laser irradiation were added to HeLa cells, and fluorescence observation was performed after a certain period of incubation to examine the uptake behavior into cells. Figure 6 (A) shows a confocal laser scanning microscope fluorescence image of the cell nucleus stained with a fluorescent dye (Hoechest33342) before light irradiation, Figure 6 (B) shows a confocal laser scanning microscope fluorescence image of Cy5 taken up into the cells before light irradiation, and Figure 6 (C) shows a confocal laser scanning microscope bright-field image of the cells before light irradiation. Figure 6 (D) shows a confocal laser scanning microscope fluorescence image of the cell nucleus stained with a fluorescent dye (Hoechest33342) after light irradiation, Figure 6 (E) shows a confocal laser scanning microscope fluorescence image of Cy5 taken up into the cells after light irradiation, and Figure 6 (F) shows a confocal laser scanning microscope bright-field image of the cells after light irradiation. While no fluorescence was observed in Figure 6(B), fluorescence was observed in the cells in the image of Figure 6(E). This result confirmed that Cy5 dissociated from Micelle-PC-Latex-1 by light irradiation was taken up by the cells.

[0064] Micelle-PC-Latex-1 in the above Examples 1 to 3 is a model of a medical device (balloon) equipped with a polymer micelle carrying the model reagent Cy5. The results of the above Examples show the following. (i) Polymer micelles, nanostructures loaded with drugs (Cy5), were successfully immobilized onto the surface of latex beads, a model medical device, by covalent bonding via a photosensitive linker. (ii) When the photosensitive linker was photocleaved by irradiation with light, the nanostructured polymer micelles dissociated and the drug (Cy5) was released from the surface of the latex beads. (iii) The drug (Cy5) was cleaved and released upon irradiation with light, and was then taken up by cells. From the above results, it was confirmed that it is possible to deliver a drug supported on a nanostructure fixed on the surface of a medical device to a target site, and to release the nanostructure and drug by photocleaving the photosensitive linker at the target site. The type of reagent supported, the method of support, the type of nanostructure, the type of bond between the nanostructure and the medical device, the type of photosensitive linker, etc. can be appropriately changed by those skilled in the art using conventional methods, and the method is applicable to various nanostructures, drugs, and medical devices. [Industrial Applicability]

[0065] According to the present invention, it is possible to provide a medical device that can deliver a drug loaded on a nanostructure to a target site and release the nanostructure and / or the drug loaded thereon upon exposure to light at the target site. The medical device of the present invention is capable of efficient drug transport to the target site, as well as controlled release of the drug at the target site, and is therefore highly practical and useful.

[0066] All documents and publications mentioned in this specification are incorporated herein by reference in their entirety, regardless of purpose. This specification also incorporates the disclosures of the claims, specification, and drawings of U.S. Provisional Application No. 62 / 872,911 (filed July 11, 2019), from which this application claims priority. [Explanation of symbols]

[0067] 1, 26 Medical device (balloon) 11 Nanostructures 12, 32 Photolabile Linker 12a, 32a Photosensitive part 13 Surface of medical device (balloon) 21 Polymer Micelles 22 Block copolymers 24 Drugs 25 Functional group 33 Medical equipment (latex beads) hν light

Claims

1. A medical device that is inserted into an affected area or tissue to perform treatment, A drug-loaded nanostructure is covalently bonded to at least a portion of the surface of the medical device via a photolabile linker fixed thereto; the photolabile linker has a first functional group that forms a covalent bond with a functional group R present on the nanostructure; The photosensitive linker has the following formula (I): 【Chemistry 8】 (In the formula, * represents a linking site, and R 1 , R 2 , and R 3 each independently represent a hydrogen atom, a lower alkyl, a lower alkoxy, an amino, a halogen atom (F, Cl, Br, I), a hydroxyl, or a cyano, or any two of adjacent R 1 , R 2 , and R 3 taken together represent a methylenedioxy group.) The structure includes the nanostructure is a polymer micelle, the polymer micelle is composed of a block copolymer including a hydrophilic polymer chain and a polymer chain, has a core-shell structure having a core portion including the polymer chain and a drug and a shell portion including the hydrophilic polymer chain, a functional group R is introduced at an end of the hydrophilic polymer chain of a part of the block copolymer, the functional group R is present in a surface layer of the polymer micelle, and a covalent bond is formed between the first functional group and the functional group R, A medical device, wherein a combination of the first functional group of the photolabile linker and the functional group R is selected from a dibenzocyclooctyne (DBCO) group and an azide group, a carboxyl group and an amino group, and a thiol group and a maleimide group.

2. The medical device of claim 1, wherein the nanostructures have a size of 20 nm to 500 nm.

3. The medical device according to claim 1 or 2, wherein the drug includes at least one selected from the group consisting of medicines, pharmaceuticals, diagnostic agents, and nutritional agents.

4. The medical device of any one of claims 1 to 3, wherein the drug is encapsulated within the nanostructure or is physically or chemically bound to the nanostructure.

5. The medical device according to any one of claims 1 to 4, wherein the drug is water-soluble or water-insoluble.

6. The medical device of any one of claims 1 to 5, wherein the photolabile linker is cleaved or decomposed upon exposure to light to release the nanostructure.

7. The medical device of claim 6 , comprising two or more photolabile linkers that are cleaved or decomposed by light of different wavelengths.

8. The medical device according to any one of claims 1 to 7, which is used for delivering a drug to a tissue.

9. The medical device according to any one of claims 1 to 8, wherein the tissue comprises at least one selected from the coronary vasculature, the peripheral vasculature, the cerebrovascular system, the esophagus, the airway, the sinuses, the trachea, the colon, the bile duct, the urinary tract, the prostate, the intracerebral duct, and the lower limbs.

10. The medical device according to any one of claims 1 to 9, wherein the medical device is selected from a balloon, a catheter, a stent, and a probe.

11. The medical device of any one of claims 1 to 10, further comprising a light source for exposing the photolabile linker to light, the light source being selected from a light emitting diode and a semiconductor laser.

12. The medical device of any one of claims 1 to 11, further comprising a secondary medical device having an optical fiber or a photonic crystal fiber for exposing the photolabile linker to light.

13. The medical device of any one of claims 1 to 12, wherein the photolabile linker is cleaved or decomposed by exposure to light in the wavelength range of 200 to 1000 nm.

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