KR20170031637A - A drug delivery vehicle comprising a polymer or lipid,? -Lipoic acid and a photosensitizer - Google Patents

Abstract

The present invention relates to a drug delivery system comprising a polymer or lipid, a-lipoic acid, a photosensitizer, and a drug. More particularly, the present invention relates to a drug delivery system for generating an anoxic oxygen, Since it was confirmed that the generated anoxic oxygen was released while the alpha -lipoic acid contained in the drug delivery vehicle was cleared, the drug delivery vehicle simultaneously exhibited the antioxidant ability of alpha -lipoic acid and the active oxygen species production ability of photosensitizer It can be provided as a novel drug delivery system in which drug release is regulated by using selective generation and elimination of reactive oxygen species.

Description

The present invention relates to a drug delivery system comprising a polymer or lipid, a-lipoic acid and a photosensitizer,

The present invention relates to a drug delivery vehicle comprising a polymer or lipid,? -Lipoic acid and a photosensitizer.

Lipoic acid (LA) is an essential element of mitochondria and exists in various forms in animals and plants. It acts mainly as a coenzyme in enzymatic reactions in mitochondria. It is known that octanoic acid becomes a precursor of the C-8 fatty acid chain of lipoic acid, and cysteine becomes a source of sulfur and biosynthesis of lipoic acid occurs.

Dihydrolipoic acid, which is a form of reduced lipoic acid and lipoic acid, is well known as an antioxidant. It protects vitamin C, E and glutathione, enhances the effect, inhibits NF-kB, It functions to prevent damage.

Such lipoic acid has long been used as an important drug for a variety of diseases in the pharmaceutical field, including diabetes [Ziegler D. et al., Diabetologia, 38: 1425-1433, 1995], liver disease [Bode J. Ch. et al., DMW, 112 (9): 349-352, 1987], appetite suppression effect [German Patent No. 19,818,563], asthma [Korea Patent Publication No. 2004-97820], migraine [Korean Patent Publication No. 2002-60168 There is a report applied to the call.

However, due to the nature of highly reactive -SH (sulfhydryl) group-containing compounds, they are oxidized to produce disulfides, so that their solubility decreases and there is a problem in stability such as discoloration and decomposition. It is also soluble in ethanol, but it has low solubility in water, which affects bioavailability and is problematic in formulation due to its low melting point.

Photoensitizers produce cytotoxic substances such as unicellular oxygen, free radicals or peroxides by light stimulation, and these reactive oxygen species (ROS) destroy surrounding tissues , Can be used to treat malignant tumors. Such a photosensitizer may be administered locally to the site to be treated or selectively treated only at the affected site by locally irradiating the light source only to the affected site. The photosensitizer is also used for tumor diagnosis by imaging due to the generation of light of a specific wavelength by irradiation of a light source.

Accordingly, the present inventors have completed the present invention by preparing a novel drug delivery system capable of regulating drug release by selective generation of active oxygen species and elimination by simultaneously using the antioxidative capacity of alpha lipoic acid and the active oxygen species production ability of photosensitizer Respectively.

Korean Patent Publication No. 2008-0095182 (2008.10.28)

The present invention relates to a drug delivery system comprising an α-lipoic acid and a photosensitizer in a polymer or lipid. In the drug delivery system, the anoxic oxygen, which is an active oxygen species generated from a light-irradiated photosensitizer, And to provide a drug delivery system that releases the sealed drug by influencing the drug delivery system.

The present invention provides a drug delivery system comprising a polymer or lipid, a-lipoic acid, a photosensitizer, and a drug.

The drug delivery system may be a polymer or lipid, a-lipoic acid, a photosensitizer, and a drug, which are mixed with a polymer or a lipid and α-lipoic acid, a photosensitizer and a drug are encapsulated.

The drug delivery system chemically binds a polymer or lipid to? -Lipoic acid, mixes the? -Lipoic acid-bound polymer or lipid with the photosensitizer and the drug, encapsulates the photosensitizer and the drug into the polymer or lipid Lt; / RTI >

The drug delivery system may be one in which a photosensitizer is chemically bonded to a polymer or lipid, a polymer or lipid bound to the photosensitizer is mixed with a-lipoic acid and a drug to enclose the alpha-lipoic acid and the drug in the polymer or lipid .

The drug delivery system may be one in which a drug is mixed into a polymer or lipid by mixing a drug with a polymer conjugate modified with? -Lipoic acid and a photosensitizer, both of which are chemically bonded to a polymer or lipid chemically together with? -Lipoic acid and a photosensitizer .

The drug delivery system may include a first polymer conjugate having a polymer or lipid chemically bonded to? -Lipoic acid, a second polymer conjugate having a polymer or lipid chemically bonded with a photosensitizer, and a drug, It can be done.

According to the present invention, when a light source is irradiated to a drug delivery system containing a polymer or lipid,? -Lipoic acid, a photosensitizer, and a drug, the photosensitizer generates unidirectional oxygen, which is an active oxygen species, Since it is confirmed that the drug is released while the included? -Lipoic acid is cleaved, the drug delivery system can simultaneously exhibit the antioxidative ability of? -Lipoic acid and the active oxygen species production ability of the photosensitizer, Can be provided as a novel drug delivery system in which drug release is controlled by using the generation and elimination processes.

FIG. 1 is a schematic diagram showing a structural formula of pullulan-g-lipoic acid-g-chlorin e6 and a mechanism of action of the drug delivery system.
Fig. 2 shows a synthetic structural formula of pullulan-g-lipoic acid-chlorine e6.
3 is a graph of ¹ H NMR analysis of pullulan-g-lipoic acid-chlorine e6.
4 is a graph showing FT-IR analysis of pullulan-g-lipoic acid-chlorine e6.
Fig. 5 shows the results of absorbance analysis for the change of lipofusing activity of pullulan-g-lipoic acid-choline e6 according to irradiation with light, as a result of confirming the drug delivery system of pullulan-g-lipoic acid-choline e6 , Fig. 5 (b) shows the result of confirming the degree of production of anoxic oxygen by the presence or absence of lipoic acid, and Fig. 5 (c) shows the result of confirming the particle size change of the drug delivery vehicle of pullulan-g-lipoic acid- Fig. 5 (d) is a TEM image of a drug delivery vehicle of pullulan-g-lipoic acid-choline e6 according to a light source irradiation, and Fig. 5 And the drug release effect of the drug delivery system.
Fig. 6 shows the results of confirming the critical micelle concentration of pullulan-g-lipoic acid-chlorine e6 according to the light source irradiation, wherein Fig. 6 (a) is the critical micelle concentration before the light source irradiation, Fig. 6 (b) Michel concentration.
7 shows the results of confirming cell internalization of pullulan-g-lipoic acid-choline e6 drug delivery vehicle (D-SRN) encapsulating doxorubicin by pullulan. Fig. 7 (a) Fig. 7 (b) shows the cell internalization of lipofectamine-choline e6 drug delivery vehicle by pullulan of pullulan-g-lipoic acid-choline e6 drug transporter in liver cancer cells (HepG2) FIG. 7 (c) is a result of confirming receptor-mediated cellular internalization of pullulan-g-lipoic acid-choline e6 drug delivery system in liver cancer cells (HepG2) by confocal microscopy.
8 shows the results of confirming the ability of heparin-g-lipoic acid-choline e6 drug delivery vehicle (D-SRN) encapsulated with doxorubicin to produce an anoxic oxygen in the cells. As a result, D- The degree of oxygen production was confirmed by confocal microscopy.
9 shows the drug release effect of the drug delivery system of pullulan-g-lipoic acid-chlorine e6 according to the light source irradiation according to the cancer surrounding and intracellular acidity. Fig. 9 (a) 9 (b) is the result of confirming the intracellular acidity at pH 5.0.
10 (a) and 10 (b) show cervical cancer cells (HeLa) and cancer cells (HCT-116), respectively, as a result of confirming the internalization of cancer cells of the drug delivery system. Mediated cellular internalization by pullulan of the choline e6 drug delivery system.
11 (a) shows cervical cancer cells (HeLa), and Fig. 11 (b) shows the results of confirming the internalization of cancer cells of drug delivery vehicles. Confocal microscopy confirmed the receptor-mediated cellular internalization by pullulan in the chlorin e6 drug delivery system.
12 shows the results of confirming the photochemical internalization (PCI) of the drug delivery system of pullulan-g-lipoic acid-chlorine e6, and it has been found that the drug delivery system of pullulan-g-lipoic acid-choline e6 is treated in liver cancer cells (HepG2) Photochemical internalization (PCI) was confirmed before and after irradiation of the light source.
FIG. 13 shows the cytotoxicity of pullulan-g-lipoic acid-chlorine e6 drug transporter in liver cancer cells (HepG2).
Fig. 14 shows cytotoxicity of the drug delivery system. Fig. 14 (a) is cervical cancer cell (HeLa) and Fig. 14 (b) It is the result of confirming cytotoxicity of chlorin e6 drug delivery system.
Fig. 15 shows the result of confirming the anticancer effect of the drug delivery system. Fig. 15 (a) shows the fluorescence image of the drug delivery vehicle in a mouse transplanted with liver cancer cells (HepG2) (b) is a graph showing the effect of a pullulan-g-lipoic acid-choline e6 drug delivery vehicle (SRN) or a pullulan-g-lipoic acid-choline e6 drug delivery vehicle (D-SRN) containing doxorubicin in a mouse transplanted with hepatocarcinoma cells FIG. 15 (c) shows the results of histological (H & E) and immunohistological (TUNEL) analysis of cell death.
16 shows the results of confirming the degree of delivery and accumulation of drug carriers by organ. As a result, it was found that 6 hours after treatment of pullulan-g-lipoic acid-choline e6 drug delivery vehicle in mice transplanted with liver cancer cells (HepG2) .
FIG. 17 shows the result of confirming the physiological change by the drug delivery system. As a result, the body weight of the mouse transplanted with heparin cancer cell (HepG2) was examined after treatment with pullulan-g-lipoic acid-choline e6 drug delivery vehicle.
18 is a schematic diagram showing the mechanism of action of a drug delivery system in which mPEG-g-lipoic acid (mPEG-g-lipoic acid) and mPEG-g-chlorin e6 (mPEG-g-chlorin e6) are mixed.
19 shows the synthesis formula of mPEG-g-lipoic acid and mPEG-g-chlorin e6.
20 is a graph of ¹ H NMR analysis of mPEG-g-lipoic acid and mPEG-g-chlorin e6.
21 is a graph showing FT-IR analysis of mPEG-g-lipoic acid and mPEG-g-chlorin e6.
FIG. 22 shows the results of examining the particle size of the drug delivery vehicle in which mPEG-g-lipoic acid and mPEG-g-chlorin e6 were mixed at various ratios according to light irradiation.
23 is an SEM image of mPEG-g-lipoic acid and mPEG-g-choline e6 drug delivery vehicle according to light irradiation.
24 shows the result of confirming the anoxic-producing ability of a drug delivery vehicle in which mPEG-g-lipoic acid and mPEG-g-choline e6 are mixed. When mPEG-g-lipoic acid and mPEG-g- The results are as follows.
25 shows the results of confirming the lipophilization changes of the drug delivery vehicle in which mPEG-g-lipoic acid and mPEG-g-choline e6 were mixed. When mPEG-g-lipoic acid and mPEG-g- Lt; RTI ID = 0.0 >%< / RTI >
Fig. 26 shows the results of drug release effect of a drug delivery vehicle in which mPEG-g-lipoic acid and mPEG-g-choline e6 were mixed.
FIG. 27 shows the results of confirming the critical micelle concentration of mPEG-g-lipoic acid and mPEG-g-chlorin e6 according to light irradiation.
FIG. 28 is a schematic diagram showing the synthetic mechanism of Pluronic F68-g-Hematoporphyrin and the mechanism of action of the drug carrier in which lipoic acid is encapsulated therein.
29 is a graph of ¹ H NMR analysis of pluronic F68-g-hematoporphyrin.
30 is a graph showing FT-IR analysis of pluronic F68-g-hematoporphyrin.
FIG. 31 shows the result of confirming the effect of producing an anion oxygen of the F68-g-hematoporphyrin on the floronic F68-g-hematoporphyrin according to the presence or absence of lipoic acid and irradiation of light using DMA, It is the result of confirming the degree of oxygen production of porphyrin.
32 is a schematic diagram of a DPPC-Dipeptidylcholine-Pheophorbide a-lipoic acid and a drug delivery system.
33 is a schematic diagram showing the mechanism of action of a drug delivery system composed of DPPC-phiopoide a-lipoic acid.
34 (a) shows the result of confirming the particle size change of the DPPC-phopopone-alpha-lipoic acid drug delivery vehicle according to the light source irradiation, and Fig. 34 34 (b) is the absorbance of the DPPC-pyoporiboidal-lipoic acid according to the light source irradiation, and FIG. 34 (c) SEM image.
FIG. 35 is a graph showing the effect of a drug (hereinafter referred to as " DSPE-PEG2000-g-phiophorbide alpha (1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N- And the mechanism of action of the transporter.
Fig. 36 shows a synthetic structural formula of DSPE-PEG2000-g-phophorbide a.
FIG. 37 is a graph showing the 1H NMR analysis of DSPE-PEG2000-g-pyoprobide a.
FIG. 38 is a graph of TCE (Thin Layer Chromatography) analysis of DSPE-PEG2000-g-pyoporpide a.
FIG. 39 shows the result of confirming the particle size change of the DSPE-PEG2000-g-pyoporpide alpha drug delivery vehicle upon irradiation with a light source.
40 is a schematic diagram showing the mechanism of action of a drug delivery system in which DSPE-PEG2000-g-lipoic acid is mixed with piofoavide [alpha].
41 shows a synthetic structural formula of DSPE-PEG2000-g-lipoic acid.
Fig. 42 is a graph of? H NMR analysis of DSPE-PEG2000-g-lipoic acid.
Figure 43 is a graph of FT-IR analysis of DSPE-PEG2000-g-lipoic acid.
Fig. 44 shows the result of confirming the particle size change of the DSPE-PEG2000-g-lipoic acid drug delivery vehicle upon irradiation with light.

The present invention can provide a drug delivery system comprising a polymer or lipid, a-lipoic acid, a photosensitizer, and a drug.

The drug delivery system may be a polymer or lipid, a-lipoic acid, a photosensitizer, and a drug, which are mixed with a polymer or a lipid and α-lipoic acid, a photosensitizer and a drug are encapsulated.

The drug delivery system chemically binds a polymer or lipid to? -Lipoic acid, mixes the? -Lipoic acid-bound polymer or lipid with the photosensitizer and the drug, encapsulates the photosensitizer and the drug into the polymer or lipid Lt; / RTI >

The drug delivery system may be one in which a photosensitizer is chemically bonded to a polymer or lipid, a polymer or lipid bound to the photosensitizer is mixed with a-lipoic acid and a drug to enclose the alpha-lipoic acid and the drug in the polymer or lipid .

The drug delivery system may be one in which a drug is mixed into a polymer or lipid by mixing a drug with a polymer conjugate modified with? -Lipoic acid and a photosensitizer, both of which are chemically bonded to a polymer or lipid chemically together with? -Lipoic acid and a photosensitizer .

The drug delivery system may include a first polymer conjugate having a polymer or lipid chemically bonded to? -Lipoic acid, a second polymer conjugate having a polymer or lipid chemically bonded with a photosensitizer, and a drug, It can be done.

The polymer may be selected from the group consisting of pullulan, chondroitin sulfate, hyaluronic acid, glycol chitosan, starch, chitosan, dextran, pectin, pectin, curdlan, poly-L-lysine, polyaspartic acid, polylactic acid (PLA), polyglycolide (PGA), polycaprolactone (PCLA), poly (caprolactone-lactide) random copolymer (PCLA), poly (caprolactone-glycolide) random copolymer (PCGA) And may be one or more selected from the group consisting of polyethylene glycol, pluronic F-68 and pluronic F-127.

More preferably, it may be selected from the group consisting of pullulan, polyethylene glycol, and pluronic F-68.

The lipid may be 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol) Phosphatidylcholine, 1,2-dipalmitoyl-sn-phosphatidylcholine, N-[amino (polyethylene glycol) -2000], DSPE-PEG2000), Dipalmitoylphosphatidylcholine (DPPC), L- Glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (1,2-Dipalmitoyl- -Distearoyl-sn-glycero-3-phosphoethanolamine, and 1,2-Distearoyl-sn-glycero-3-phosphocholine ≪ / RTI >

The photosensitizer may be selected from the group consisting of a phorphyrins compound, a chlorins compound, a bacteriochlorins compound, a phthalocyanine compound, a naphthalocyanines compound, and a 5- 5-aminoevuline esters) compounds. Specifically, the porphyrin compound may be pyophorbide a, and the chlorine compound may be chlorin e6.

The drug is selected from the group consisting of paclitaxel, doxorubicin, gemcitabine, silolimus, etoposide, vinblastine, vinca alkaloids, docetaxel, cisplatin, glivec, adriamycin, cyclophosphamide, tenifoside, 5-fluorouracil, , Tamoxifen, anastrozole, fluoxuridine, lufurolide, flotamide, zoledronate, vincristine, streptozotocin, carboplatin, topotecan, velotecan, irinotecan, vinorelbine, hydoroxyurea , Valvocine, retinoic acid series, mesotrexate, mechlorethamine, chlorambucil, bisulfan, doxifluridine, prednisone, testosterone, mitosartron, aspirin, salicylate, ibuprofen, But are not limited to, corticosteroids, corticosteroids, progesterone, fenoprofen, indomethacin, phenylbutazone, cyclophosphamide, mcloethamine, dexamethasone, celecoxib, valdecoxib, nimesulide, cortisone, And anticancer agents, proteins, peptides, and genes selected from the group consisting of Lloyd and mitomycin C can be selected.

The mean particle size of the drug delivery vehicle may be between 10 nm and 100 mu m.

According to one embodiment of the present invention, a carbohydrate-g-lipoic acid-g of lipofuscin-g-lipoic acid of the present invention is produced in hepatic cancer cells by using carboxy-H ₂ DCFDA, which is a substance that turns into DCF (2-deoxycoformycin) -Chlorin e6 drug delivery system, it was found that when the light source was irradiated to the pullulan-g-lipoic acid-g-chlorin e6 drug delivery vehicle (D-SRN) encapsulating doxorubicin as shown in FIG. 8 , It was confirmed that DCF fluorescence expression was increased compared to a drug delivery vehicle in which the light source was not irradiated.

From the above results, it was confirmed that the drug delivery system of pullulan-g-lipoic acid-g-chlorine e6 effectively produced unilateral oxygen in cancer cells upon irradiation with light.

Therefore, the drug delivery vehicle can be applied as a photodynamic therapy agent.

The photodynamic therapy refers to treatment with a combination of photosensitizer, light, and oxygen. Specifically, when the photosensitizer is first administered to the human body, the photosensitizer is accumulated in the tumor, that is, the tumor tissue, and then irradiated with light to maximize the production of oxygen or free radicals, thereby selectively destroying the tumor.

The drug delivery system of the present invention comprises a polymer and a-lipoic acid and a photosensitizer to form a complex, which can generate active oxygen species such as oxygen during irradiation of a light source at the same time as the use of the drug delivery system. And the like.

The drug delivery system may be such that the photosensitizer generates active oxygen species upon irradiation with light and releases the encapsulated drug while the generated active oxygen species are cleared of? -Lipoic acid.

According to another embodiment of the present invention, in order to analyze the mobility and antitumor effect of the drug delivery vehicle of pullulan-g-lipoic acid-g-choline e6 prepared in Example 1, liver cancer cells were cultured in 6-week-old BALB / C An animal model subcutaneously injected into nude mice was prepared, and the drug delivery vehicle was administered via intravenous injection on days 0 and 3, and the light source was irradiated after 6 hours of drug delivery.

As a result, it was confirmed that the drug delivery system was well transferred to hepatocarcinoma cells as shown in FIG. 15 (a) and FIG. 16, and it was confirmed that the drug delivery system of Example 1 in which doxorubicin was enclosed as shown in FIG. It was confirmed that the size of the tumor tissue extracted from the light-irradiated mouse experimental group was most effectively reduced. In the H & E staining and TUNEL analysis of FIG. 15 (c), when the light source was irradiated to the drug delivery system of Example 1 in which the doxorubicin was encapsulated, it was confirmed that apoptosis was effectively induced.

According to another embodiment of the present invention, when a light source is irradiated to a drug carrier in which doxorubicin-encapsulated mPEG (polyethylene glycol) -g-lipoic acid is mixed with mPEG-g-chlorin e6. It was confirmed that the particle size was changed compared with the untransmitted drug delivery system.

From the above results, the drug delivery system in which mPEG-g-lipoic acid and mPEG-g-choline e6 are mixed is effective in reducing the size of alpha-lipoic acid by eliminating? -Lipoic acid due to an oxygen generated by the photosensitizer .

According to another embodiment of the present invention, when a light source is irradiated to a drug carrier in which mPEG-g-lipoic acid and mPEG-g-choline e6 mixed with doxorubicin are mixed. It was confirmed that the drug release was more effective than the drug delivery system in which the light source was not irradiated.

From the above results, it was confirmed that the drug delivery system in which mPEG-g-lipoic acid and mPEG-g-choline e6 were mixed effectively released the drug due to the elimination of? -Lipoic acid due to the unreacted oxygen generated by the photosensitizer upon irradiation of the light source .

According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising a DPPC, a phyopovid α, a drug carrier encapsulating lipoic acid, a drug carrier mixed with DSPE-PEG 2000 -peopoboid α and lipoic acid, and DSPE-PEG 2000- When a light source is irradiated to a drug delivery vehicle in which phytoopagus a is mixed, compared with a drug delivery vehicle in which a light source is not irradiated, the alpha-lipoic acid is erased due to an anoxic oxygen generated by the photosensitizer, It was confirmed that the size changes.

According to another embodiment of the present invention, in the case of the drug delivery system in which the phophophobia alpha and lipoic acid are encapsulated, the drug delivery vehicle is irradiated with the light source at 336 nm, which is the lipophilic absorption wavelength range of lipoic acid, It was confirmed that the absorbance was decreased and the structure of lipoic acid was changed.

The light irradiation may be irradiated to the drug carrier at a photon of 500 to 900 nm at a dose of 1 to 300 J / cm ² .

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

< Example  1> Pullulan -g-lipoic acid-g- Chlorine  e6 ( Pullulan -g- lipoic  acid-g-chlorin e6) synthesis and drug delivery

One. Pullulan -g-lipoic acid-g- Chlorine  e6 synthesis

G-lipoic acid-g-chlorine e6 (PuLACe6) was synthesized by the procedure shown in Fig.

Α-lipoic acid (1.94 mmol) was dissolved in dichloromethane (DCM) (3 mL), and dicyclohexylcarbodiimide (DCC) (1.2 molar times of lipoic acid) was dissolved in 2 mL of DCM And reacted for 24 hours to produce lipoyl anhydride. The precipitate formed in the solution was removed by filtration, and then about 1 mL of the DCM solution was concentrated, and then pullulan (0.01 mmol) and 4-dimethylaminopyridine (DMAP) (1.2 molar times of lipoic acid) And mixed in 19 mL of dissolved dimethyl sulfoxide (DMSO), followed by reaction for 2 days. The solution was precipitated in cold ethanol to obtain pullulan-g-lipoic acid (PuLA) and dried under reduced pressure. The PuLA (500 mg) and chlorin e6 (0.06 mmol) were dissolved in DMSO (20 mL) together with DCC (1.2 molar times of Ce6) and DMAP (1.2 molar times of Ce6) Lt; / RTI &gt;

The solution was precipitated in cold ethanol to obtain PuLA-g-Ce6 (PuLACe6). The PuLA-g-Ce6 (PuLACe6) was dried under reduced pressure.

Further, ¹ H NMR and FT-IR of the pullulan-g-lipoic acid-g-chlorine e6 (PuLACe6) compound were confirmed, and the characteristics of the compounds shown in FIGS. 3 and 4 were confirmed.

2. Pullulan -g-lipoic acid-g- Chlorine  e6 Drug Delivery Preparation

G-lipoic acid-g-choline e6 (10 mg) and doxorubicin (10 mg) dissolved in 5 mL of DMSO were added to prepare a drug carrier containing lipoic acid as an active ingredient in a self-assembled aqueous solution 1 mg) was dialyzed against distilled water for 24 hours.

< Example  2 > mPEG-g-lipoic acid and mPEG-g- Chlorine  e6 Synthesis and Drug Delivery with Mixed mPEG-g-Lipoic Acid and mPEG-g-Choline e6

1. mPEG-g-lipoic acid and mPEG-g- Chlorine  e6 synthesis

First, alpha-lipoic acid and chlorine (1.2 molar times of mPEG) were dissolved in 3 mL of DCM, and then DCC (1.2 molar times of Lipoic acid and Ce6) was dissolved in 2 mL of DCM and reacted for 24 hours. Hydride. The precipitate formed in the solution was removed by filtration, and then concentrated with about 1 mL of DCM solution, followed by addition of methoxy-polyethylene glycol (PEG) -AM (0.5 g) and DMAP (1.2 molar amount of lipoic acid and Ce6) Dissolved in 20 mL of DMF, and reacted by blocking light for 24 hours. The solution was precipitated in ether to give mPEG-g-lipoic acid and mPEG-g-Ce6, and the mPEG-g-lipoic acid and mPEG-g-Ce6 were dried under reduced pressure.

The mPEG-g-lipoic acid and mPEG-g-Ce6 compounds were characterized by ¹ H NMR and FT-IR, and the characteristics of the compounds shown in FIGS. 20 and 21 were confirmed.

2. mPEG-g-lipoic acid and mPEG-g- Chlorine  Preparation of drug carrier mixed with e6

To prepare a drug delivery system containing lipoic acid as an active ingredient in a self-assembled aqueous solution, mPEG-g-lipoic acid (10 mg) and mPEG-g-choline e6 dissolved in 5 mL of DMSO (1 mg ) And doxorubicin (1 mg) were dialyzed against distilled water for 24 hours.

< Example  3> Puluronic  F68-g- Hematoporphyrin  ( Pluronic  F68-g-hematoporphyrin synthesis and drug delivery

One. Puluronic  F68-g- Hematoporphyrin  synthesis

20 mL of DMSO was mixed with Pluronic F68 (100 mg), hematoporphyrin (HPP) (30 mg), DCC (1.2 molar times of HPP) and DMAP (1.2 molar times of HPP) Light was blocked and reacted. The solution was dialyzed against distilled water for 24 hours and lyophilized.

¹ H NMR and FT-IR were confirmed for the PULURRONIC F68-g-hematoporphyrin compound, and the characteristics of the compound were confirmed as shown in FIGS. 27 and 28.

2. Puluronic  F68-g- Hematoporphyrin  Drug delivery

To prepare a drug delivery system containing lipoic acid self-assembled in aqueous solution as an active ingredient, pululonic F68-g-hematoporphyrin (10 mg), paclitaxel (1 mg) and lipo Iksan (1 mg) was dialyzed against distilled water for 24 hours.

< Example  4> DPPC , Piofoboid  Production of drug carrier containing α, lipoic acid

One. DPPC - Piofoboid  alpha-lipoic acid inclusion

A thin-film hydration method was used to prepare a drug delivery system containing lipoic acid self-assembled in aqueous solution as an active ingredient. After dissolving DPPC-pyopovide α-lipoic acid (50: 1: 30 mg) sufficiently in 5 mL of CHCl 3, the solvent was removed by a rotary evaporator. Then, it was sufficiently hydrated with 25 mL of 1 mM ammonium sulfate buffer, and then the particles were pulverized in a state of being shielded from light for 3 minutes by using an ultrasonic wave sonicator.

< Example  5> DSPE - PEG2000 - Piofoboid  alpha ( DSPE - PEG2000 -g- Pheophorbide  α) synthesis and drug delivery

One. DSPE - PEG2000 - Piofoboid  alpha synthesis

DSPE-PEG2000-phophorbide alpha was synthesized by the procedure shown in FIG.

The solution was dissolved in 5 mL of CHCl3, and the solution was poured into a solution of DCC (1.5 molar times of piophoboid α) dissolved in 5 mL of CHCl₃. Nitrogen pressure (N 2 purge ) To produce the anhydride. The precipitate formed in the solution was removed by filtration, and the CHCl3 solution was mixed with 10 mL of CHCl3 in which DSPE-PEG2000 (0.05 g) and NHS-Hosu (1.5 molar times of the phophoboid alpha) were dissolved and reacted for 48 hours. The solution was subjected to Sephadex G-25 Size Exclusion Chromatography (SEC) to obtain DSPE-PEG2000-Piophobide alpha, and the DSPE-PEG2000-Piophobide alpha was dried under reduced pressure.

1H NMR and TLC (Thin Layer Chromatography) were confirmed for the DSPE-PEG2000-pyoporpide alpha compound, and the characteristics of the compounds shown in FIGS. 6 and 7 were confirmed.

2. DSPE - PEG2000 - Piofoboid  Preparation of Drug Delivery System Mixed with α and Lipoic Acid

A thin-film hydration method was used to prepare a drug delivery system containing lipoic acid self-assembled in aqueous solution as an active ingredient. After sufficiently dissolving DSPE-PEG2000-phophorbide alpha (10.2 mg), L-alpha-phosphatidylcholine (Egg, Chicken) 2.3 mg) and lipoic acid (0.21 mg) in 5 mL of CHCl3, To remove the solvent. Then, it was sufficiently hydrated with 10 mL of a 250 mM ammonium sulfate buffer solution, and the particles were pulverized in a state of being shielded from light for 10 minutes by using an ultrasonic grinder. The drug carrier was extruded 5 times with a polycarbonate membrane (PC membrane) having a diameter of 0.2 μm and 5 times with a polycarbonate membrane having a diameter of 0.1 μm to extrude the drug carrier to a small size.

< Example  6> DSPE - PEG2000 -Lipoic acid synthesis and drug delivery

One. DSPE - PEG2000 - lipoic acid synthesis

DSPE-PEG2000-lipoic acid was synthesized by the procedure shown in FIG.

First, alpha lipoic acid (1.5 molar times of DSPE-PEG2000) was dissolved in 3 mL of DCM, and the reaction was carried out by dropping DCC (1.5 molar times of lipoic acid) in 2 mL of DCM and reacting for 24 hours. Respectively. The precipitate formed in the solution was removed by filtration, and the DCM solution was mixed with another DCM solution (3 mL) in which DSPE-PEG2000 (0.1 g) was dissolved and reacted for 48 hours. The solution was precipitated in ether to give DSPE-PEG2000-lipoic acid, which was dried under reduced pressure.

The DSPE-PEG2000-lipoic acid compound was confirmed by 1H NMR and FT-IR, and the characteristics of the compounds shown in FIGS. 12 and 13 were confirmed.

2. DSPE - PEG2000 - Lipoic acid and Piofoboid  Preparation of Drug Delivery System Mixed with?

A thin-film hydration method is used to prepare a drug delivery system containing lipoic acid self-assembled in an aqueous solution as an active ingredient. After dissolving DSPE-PEG2000-lipoic acid (10 mg), L-α-phosphatidylcholine (Egg, Chicken) 5.2 mg) and phophoboid α (0.6 mg) in 5 mL of CHCl 3, To remove the solvent. Then, it was sufficiently hydrated with 10 mL of a 250 mM ammonium sulfate buffer solution, and the particles were pulverized in a state of being shielded from light for 10 minutes by using an ultrasonic grinder. The drug carrier was extruded to a small size by repeating 5 times with a polycarbonate membrane of 0.2 μm in diameter and 5 times with a polycarbonate membrane of 0.1 μm in diameter.

< Experimental Example  1> of lipoic acid REPOILING  Confirm change

UV-Vis spectrometry (UV-2450; Shimadzu, Japan) was used to dilute the drug carrier prepared in Examples 1, 2 and 4 on DMSO and irradiate the light source with time, And the absorbance was confirmed at 336 nm. Lipoylation of lipoic acid showed the absorbance at 336 nm and the change of lipofilling was observed using the property that the absorbance disappears when the structure of lipoic acid changes.

As a result, it was confirmed that the absorbance at 336 nm decreased when the light source was irradiated to the drug delivery system of Example 1 as shown in FIG. 5 (a), and the drug delivery vehicle of Example 2 and Example 4 was also shown in FIGS. It was confirmed that the absorbance decreases as shown in Fig. 34 (a).

< Experimental Example  2> Singlet oxygen Scatters  Confirm

Dimethylanthracene (DMA), a reagent for detecting unidentified oxygen, one of the active oxygen species, was used to confirm the ability of lipoic acid to erase the active oxygen species generated by the photosensitizer.

The DMA, which is a material whose fluorescence is canceled by atmospheric oxygen, was mixed and finally the DMA concentration was adjusted to 20 μM. When irradiating the light source to each drug delivery solution for time-varying oxygen production, the presence of lipoic acid was analyzed using a spectrofluorophotometer (RF-5301; Shimadzu, Japan).

As a result of examining the amounts of change in DMA concentration of the drug delivery vehicle prepared in Examples 1, 2 and 3, it was found that the decrease of DMA concentration in the experimental group in which the drug carrier and lipoic acid were administered together as shown in FIG. 5 (b), FIG. 23, It was confirmed that the number of drug delivery vehicles was smaller than that of the drug delivery vehicle administered alone.

From the above results, it was confirmed that lipoic acid competitively cleans oxygen with DMA, and that lipoic acid in the drug delivery system effectively cleans active oxygen species generated by the photosensitizer.

< Experimental Example  3> Confirmation of particle size distribution change

The particle size distribution was measured by dynamic light scattering (DLS; ZetasizerNano ZS, Malvern Instruments Ltd., U.K.) when light was not irradiated to the drug carrier prepared in the above example or irradiation was performed over time.

As a result, as shown in FIG. 5 (c), the drug delivery system of pullulan-g-lipoic acid-g-chlorine e6 prepared in Example 1 had a size distribution of 10-400 nm and an average size of 120 nm. 28 mW, and the size distribution after irradiating the light source becomes wider.

As shown in FIG. 22, the mPEG-g-lipoic acid and mPEG-g-chlorine e6 mixed drug carrier prepared in Example 2 had a size distribution of 80 to 800 nm and an average size of 190 nm. 100 nm to 120 nm.

As shown in FIG. 34 (b), the DPPC-phophoboidal alpha-lipoic acid drug carrier prepared in Example 4 had a size distribution of 100 to 700 nm and an average size of 240 nm, I can confirm that it is going to disappear.

 As shown in FIG. 39 (a), the DSPE-PEG2000-phophorbide alpha drug delivery vehicle without lipoic acid prepared in Example 5 had a size distribution of 60 to 600 nm and an average size of 170 nm, There was no size distribution after irradiation. In contrast, as shown in FIG. 39 (b), the DSPE-PEG2000-phophoboid alpha, lipoic acid mixed drug carrier prepared in Example 5 had a size distribution of 40-500 nm and an average size of 157 nm. The posterior size distribution was found to be wider.

 As shown in FIG. 44, the DSPE-PEG2000-lipoic acid peptoid alpha mixed drug carrier prepared in Example 6 had a size distribution of 7 to 700 nm, an average size of 143 nm, and a size distribution after irradiation And it was confirmed that it became broad.

< Experimental Example  4> Morphological confirmation

The particle morphology was confirmed using a transmission electron microscope (TEM) (JEM1010, Jeol, Japan) and a field emission scanning electron microscope (FE-SEM; Hitachi s-4800, Japan).

Briefly, the particles prepared in the above examples were irradiated with no light or irradiated, and then cast on a cover glass to prepare a sample. After dried in a vacuum, the shape of each sample was imaged by TEM and FE-SEM Respectively.

As a result, the drug delivery vehicle of pullulan-g-lipoic acid-g-chlorine e6 prepared in Example 1 exhibited a uniform particle size distribution before irradiation with light, as shown in FIG. 5 (d) It can be seen that it collapsed unstably.

34 (c), the DPPC-phophoboidal? -Lipoic acid drug delivery vehicle prepared in Example 1 exhibited a uniform particle size distribution before the light source irradiation, but after the light source irradiation, the particles unstably collapsed .

< Experimental Example  5> Confirm drug efficacy

The drug carrier prepared in Example 1 was placed in a dialysis membrane and then placed in phosphate buffer saline (PBS) or phosphate-citrate buffer (pH 7.4, 6.5, 5.0) Emission test. The buffer was replaced at every fixed time, and the result of illuminance measurement at 3 hours was diluted to 8: 2 in DMSO and confirmed using a fluorescence multi-plate reader (TecanGenios, NC, U.S.A.).

As a result, as shown in FIG. 5 (e), in the experimental group in which the light source was not irradiated to the drug delivery vehicle of pullulan-g-lipoic acid-g-chlorine e6 prepared in Example 1, 20 to 25% , And in the experimental group irradiated with the light source, the drug release amount was increased to 35 to 45% for 12 hours.

Also, the mPEG-g-lipoic acid and mPEG-g-choline e6 mixed drug carrier prepared in Example 2 were also examined for drug release amount in a phosphate buffer solution of pH 7.4 in the same manner as described above. As a result, In the untreated drug delivery group, about 60% of the drug was released in 24 hours, but in the drug delivery group irradiated with the light source, it was confirmed that the drug release amount increased to about 80 to 90% over 24 hours.

< Experimental Example  6 > Critical Micelle Concentration; CMC ) Confirm

When the concentration of Hoechst 33342 fluorescent substance was sealed in the drug delivery system, the drug delivery vehicle could not be formed and fluorescence was observed. When the drug delivery material was formed at a certain concentration or more, the fluorescence of Hoechst 33342 disappears and the critical micelle concentration was confirmed .

The drug carriers prepared in the above examples were respectively diluted with distilled water to a concentration of 0.00025 to 1 g / L depending on whether light sources were irradiated or not, and then the diluted drug carrier solution was taken and the degree of fluorescence was confirmed using a spectrofluorephotometer.

As a result, as shown in FIG. 6, the cumulus-g-lipoic acid-g-chlorine e6 drug delivery vehicle prepared in Example 1 had an increase in the CMC from 0.014 g / L to 0.037 g / L after irradiation of the light source.

< Experimental Example  7> Confirmation of drug delivery into cancer cells

In order to investigate the specific introduction of cancer cells into the drug carrier prepared in the above examples, the following experiment was conducted on cancer cells cultured in vitro.

Hepatocellular carcinoma cells (HepG2), cervical cancer cells (HeLa), and colon cancer cells (HCT-116) were cultured in order to confirm intracellular inflow of the drug delivery vehicle prepared in Example 1, Was treated for 1 hour, washed with buffer solution, analyzed for intracellular influx of the drug delivery vehicle using a fluorescence multi-plate reader and flow cytometer, and analyzed under the same conditions with 4% paraformaldehyde Cells were fixed and the distribution of intracellular drug delivery system was visually confirmed using a confocal microscope.

In order to compare the cell internalization effects of pullulan, which is known as a polymer specifically binding to liver cancer cells, and the drug delivery system of Example 1, pullulan was administered to hepatocarcinoma cells together with the drug delivery system of Example 1 as a competitive control And the degree of cell entry into the drug delivery system was confirmed.

As a result, as shown in FIG. 7 (a), it was confirmed that the influx of the drug transporter relative to liver cancer cells was increased compared to other cancer cells, and that the drug transporter was introduced into hepatocellular carcinoma cells at a level similar to that of pullulan.

As a result of flow cytometry analysis to confirm the above results, the cell internalization of the drug delivery system of Example 1 was confirmed in liver cancer cells as shown in FIG. 7 (b). In addition, it was confirmed that the drug carrier of Example 1 was efficiently internalized in liver cancer cells as shown in Fig. 7 (c), which is a result of confocal microscopy.

From the above results, it was confirmed that the drug delivery system of Example 1 exhibited cell internalization effect through receptor mediated action using pullulan.

Also, as shown in FIGS. 10 and 11, it was confirmed that the drug delivery system of Example 1 was effectively introduced into the cells of cervical cancer cells (HeLa) and colon cancer cells (HCT-116).

< Experimental Example  8> In cancer cells of drug delivery Singlet oxygen Generation  Confirm

The following experiments were performed on hepatocarcinoma cells cultured in vitro in order to confirm the degree of production of oxygen in the hepatocarcinoma cells by specifically introducing the drug carrier prepared in Example 1 into hepatocarcinoma cells.

The drug delivery system of Example 1 was filled with doxorubicin, treated with the cultured liver cancer cells, and washed with the buffer solution 1 hour later. Carboxy-H ₂ DCFDA (25 μM) was then treated and Hoechst 33342 (1 μM) was treated for the last 5 minutes. After 30 minutes, the cells were washed with buffer solution, fixed with 4% paraformaldehyde, and visually confirmed by the confocal microscope.

Carboxy-H ₂ DCFDA was transformed into DCF (2-deoxycoformycin) by a singlet oxygen and exhibited fluorescence. Irradiation of the drug carrier with a light source of 1.2 J / cm ² and confirming the degree of DCF fluorescence expression, Respectively.

As a result, when the light source was irradiated to the drug delivery vehicle (D-SRN) of Example 1 in which doxorubicin was encapsulated as shown in FIG. 8, it was confirmed that the DCF fluorescence expression was increased as compared with the drug delivery vehicle in which the light source was not irradiated.

From the above results, it was confirmed that the drug delivery system of Example 1 efficiently produced unilateral oxygen in cancer cells upon irradiation with a light source.

< Experimental Example  9> Confirmation of photochemical cytoplasmic internalization of drug delivery system

In order to confirm that the drug carrier prepared in Example 1 was specifically introduced into hepatocellular carcinoma cells to induce photochemical cytoplasmic internalization, the following experiment was conducted on liver cancer cells cultured in vitro.

After the liver cancer cells were cultured, the drug carrier prepared in Example 1 was treated for 2 hours and washed with a buffer solution. The ribosomes of cells Lysotracker Green DND-26 were stained using (Molecular Probes, Inc., Eugene, OR, USA), the stained cells confocal microscope (LSM 710 Meta; Zeiss, Germany ) in 1.2 J / cm ² As shown in Fig.

As a result, the fluorescence of the cell ribosome was clearly observed before the irradiation of the light source as shown in FIG. 12, but it was confirmed that the fluorescence of the ribosome was decreased after the irradiation of the light source.

From the above results, it was confirmed that the photochemical cellular internalization of the drug delivery system appeared.

< Experimental Example  10> Cytotoxicity of Drug Delivery System

The drug delivery vehicle prepared in Example 1 was subjected to a cytotoxicity test with or without light source irradiation. (HepG2), cervical cancer cells (HeLa), and colorectal cancer cells (HCT-116) cultured in vitro were subjected to the following experiments.

The cultured cells were each divided into 96-well cell culture dishes, cultured for 12 hours, treated with doxorubicin at a concentration of 10 μg / mL or the drug carrier of Example 1 alone, or with a drug containing the same concentration of doxorubicin And then cultured for 4 hours.

Thereafter, the culture medium was removed, irradiated with a light source of 1.2 J / cm ² , and cultured for 48 hours. Finally, cell viability was analyzed by MTT assay (Biomaterials, 2013, 34 (36) 9277-9236).

As a result, it was confirmed that when the liver cancer cells treated with the drug delivery vehicle (D-SRN) of Example 1 in which doxorubicin is encapsulated as shown in FIG. 13 were irradiated with a light source, the cell viability was reduced to 50% or less, There was no apparent toxicity in cervical cancer and colorectal cancer cells.

< Experimental Example  11> Antitumor effect of drug delivery system

In order to analyze the antitumor effect of the drug delivery vehicle prepared in Example 1, an animal model in which liver cancer cells were subcutaneously injected into 6-week-old BALB / C nude mice was prepared. The number of cells inoculated was 4 × 10 ^6, and inoculated on a culture medium without 100 μL of serum. The size of the tumor was calculated as major axis × minor axis × minor axis × 0.5 (unit = mm ³ ).

To confirm the antitumor effect of the nanoparticles on the above animal model, mice were randomly divided into 6 experimental groups and the following experiment was carried out. Each drug delivery vehicle was administered intravenously on days 0 and 3, and the light source was examined 6 hours after drug delivery. The amount of irradiated light was 100 J / cm ² , and fluorescence images were taken using Image Station 4000 MM (Kodak, USA).

H & E staining was also performed for histological analysis.

In detail, the tumor tissue extracted from the mouse was fixed with 4% paraformaldehyde for 24 hours, followed by deparaffinization, and then the tissue was divided into 5-μm-thick sections and stained with hematozolin and eosin.

Immunohistochemical analysis was performed by TUNEL assay.

Specifically, the tumor tissue extracted from the mouse was fixed with 4% paraformaldehyde for 24 hours, and then the tissue was divided by paraffin section to a thickness of 5 탆. The tissue was washed twice with PBS and placed in a 0.2% Triton X-100 solution at room temperature for 10 minutes. The tissues were then stained with the TUNEL assay kit (Promega Corp., WI, USA).

As a result, it was confirmed that the drug delivery system of Example 1 was well transferred to liver cancer cells as shown in Fig. 15 (a) and Fig. 15 (b), in the animal model in which the drug carrier of Example 1 in which doxorubicin was encapsulated was administered at a dose of 5 mg / kg, the size of the tumor tissue extracted from the light-irradiated mouse test group was most effective And the results of H & E staining and TUNEL analysis of FIG. 15 (c) showed that apoptosis was effectively induced when the light source was irradiated to the drug delivery system of Example 1 in which the doxorubicin was encapsulated.

On the other hand, as shown in FIG. 17, when the drug transporter of Example 1 was administered to the mice transplanted with liver cancer cells, there was no change in the weight of the mice when the light source was irradiated.

From the above results, it was confirmed that the drug delivery vehicle of the present invention was able to effectively kill cancer cells by releasing the drug selectively without tumor toxicity, thus confirming that it is a drug delivery system having excellent biosafety and liver cancer treatment effect.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (14)

A polymer or lipid, a-lipoic acid, a photosensitizer, and a drug. [Claim 2] The drug carrier according to claim 1, wherein the drug delivery vehicle comprises a mixture of a polymer or lipid, a-lipoic acid, a photosensitizer, and a drug, and encapsulating the α-lipoic acid, the photosensitizer and the drug into the polymer or lipid. The drug delivery system according to claim 1, wherein the drug delivery vehicle chemically binds a polymer or lipid to α-lipoic acid, mixes the α-lipoic acid-bound polymer or lipid with a photosensitizer and a drug to form a photosensitizer And the drug is encapsulated. [2] The drug delivery system according to claim 1, wherein the drug delivery vehicle chemically binds a polymer or lipid to a photosensitizer, and the polymer or lipid bound to the photosensitizer is mixed with a-lipoic acid and a drug to form a polymer or lipid, A drug delivery system characterized in that a drug is encapsulated. [2] The drug delivery system according to claim 1, wherein the drug delivery vehicle is a drug delivery system comprising a polymer or a lipid and a photosensitizer chemically bonded to the polymer or lipid, Wherein the drug delivery system comprises a drug delivery system. [4] The drug delivery system according to claim 1, wherein the drug delivery vehicle comprises a first polymer conjugate having a polymer or lipid chemically bonded to? -Lipoic acid, a second polymer conjugate having a polymer or lipid chemically bonded with a photosensitizer, A drug delivery system characterized in that a drug is enclosed in lipids. The method of claim 1, wherein the polymer is selected from the group consisting of pullulan, chondroitin sulfate, hyaluronic acid, glycol chitosan, starch, chitosan, dextran dextran, pectin, curdlan, poly-L-lysine, polyaspartic acid, polylactic acid (PLA), polyglycolide (PGA) (PCLA), poly (caprolactone-glycolide) random copolymers (PCLA), poly (caprolactone-lactide) random copolymers One or more selected from the group consisting of PLGA, polyethylene glycol, pluronic F-68 and pluronic F-127. &Lt; / RTI &gt; 3. The composition of claim 1, wherein the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol) Phosphatidylcholine, L-alpha-phosphatidylcholine, 1,2-di (diethylene glycol) 3-phosphoethanolamine, 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl- Glycero-3-phosphoethanolamine and 1,2-distearoyl-sn-glycero-3-phosphocholine ) Or a pharmaceutically acceptable salt thereof.
2. The composition of claim 1, wherein the photosensitizer is selected from the group consisting of a phorphyrins compound, a chlorine compound, a bacteriochlorins compound, a phthalocyanine compound, a naphthalocyanines compound, Wherein the compound is selected from the group consisting of 5-aminoevuline esters compounds. The pharmaceutical composition of claim 1, wherein the medicament is selected from the group consisting of paclitaxel, doxorubicin, gemcitabine, silorimus, ethofoside, vinblastine, vinca alkaloid, docetaxel, cisplatin, glivec, adriamycin, cyclophosphamide, But are not limited to, thyroxine, thyroxine, thyroxine, thyroxine, thyroxine, oeruracil, camptothecin, tamoxifen, anastrozole, fluoxuridine, lufurolide, flotamide, zoledronate, vincristine, streptozotocin, But are not limited to, serotonin, serotonin, serotonin, serotonin, serotonin, serotonin, serotonin, serotonin, serotonin, serotonin, serotonin, But are not limited to, lutein, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, cyclophosphamide, mechlorethamine, dexamethasone, celecoxib, valdecoxib, A protein, a peptide, and a gene selected from the group consisting of cytosine, thysole, corticosteroid, and mitomycin C. The drug delivery system according to claim 1, wherein the drug delivery vehicle has an average particle diameter of 10 nm to 100 μm. The drug delivery system according to claim 1, wherein the drug delivery vehicle is applied as a photodynamic therapy. [Claim 2] The drug delivery system according to claim 1, wherein the drug delivery vehicle generates an active oxygen species upon irradiation with light, and releases the encapsulated drug while the generated active oxygen species are cleared of? -Lipoic acid. [Claim 16] The drug carrier according to claim 13, wherein the light irradiation is performed by irradiating the drug carrier with photons having a wavelength of 500 to 900 nm at 1 to 300 J / cm &lt; ^{2 &} gt ;.

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