KR20220029810A - Ultrasound guided drug delivery system using an ultrasonic contrast agent comprising biomaterials on which drugs are conjugated via ester bond - Google Patents

Abstract

The present invention relates to: an ultrasound-guided drug delivery system including biomaterials on which drugs are conjugated via ester bonds, phospholipids, and PEGylated phospholipids; a drug delivery composition including the drug delivery system; and a method for preventing or treating diseases, comprising the steps of administering the composition to a non-human subject and releasing the drug by irradiating ultrasound to a site where the composition is administered. In the present invention, the ultrasound-guided drug delivery system including biomaterials on which drugs are conjugated via ester bonds, phospholipids, and PEGylated phospholipids forms micro/nano bubbles and drug release is accelerated by promoting hydrolysis of ester bonds due to physical stimulation and collapse of bubbles when irradiated with ultrasound, thus delivering drugs to a target site with high efficiency.

Description

Ultrasound guided drug delivery system using an ultrasonic contrast agent comprising biomaterials on which drugs are conjugated via ester bond

The present invention relates to an ultrasound-guided drug delivery system comprising a biomaterial to which a drug is bound through an ester bond, a phospholipid, and a PEGylated phospholipid; A composition for drug delivery comprising the drug delivery system; It relates to a method for preventing or treating a disease, comprising administering the composition to a subject other than a human and releasing a drug by irradiating ultrasound to the site to which the composition is administered.

The drug delivery system selectively delivers a drug to a target site and optimizes the effective blood concentration for a long time according to the disease, thereby maximizing the therapeutic efficacy and effect, and minimizing side effects of the drug. In order to increase the target delivery efficiency of such a drug delivery system, studies to maximize drug delivery, such as binding various target ligands, controlling the drug release rate through near-infrared irradiation, or improving the penetration ability by ultrasound, have been conducted in various fields. is being carried out, and there is still a need to develop an excellent drug delivery technology for controlling the release of an appropriate amount of drug to a target site.

Accordingly, the inventors of the present invention made diligent efforts to develop a drug delivery system capable of maximizing the effect of a drug by releasing an appropriate amount of the drug with high efficiency. As a result, the biomaterial (hyaluronic acid), phospholipid and The present invention was completed by confirming that the ultrasonically induced drug delivery system containing PEGylated phospholipids forms micro/nano bubbles, and the drug release is accelerated by the collapse of the bubbles and the acceleration of hydrolysis of the ester bond during ultrasonic irradiation. .

SUMMARY OF THE INVENTION The present invention aims to solve the above problems and other problems related thereto.

An exemplary object of the present invention is to provide an ultrasound-guided drug delivery system comprising a biomaterial to which a drug is bound through an ester bond, a phospholipid, and a PEGylated phospholipid.

Another exemplary object of the present invention is to provide a composition for drug delivery, including the drug delivery system.

Another exemplary object of the present invention is to provide a method for preventing or treating a disease comprising administering the composition to a subject other than a human and releasing the drug by irradiating ultrasound to the site where the composition is administered. .

The technical problem to be achieved according to the technical idea of the invention disclosed in this specification is not limited to the problem for solving the above-mentioned problems, and another problem not mentioned can be clearly understood by those skilled in the art from the description below. There will be.

This will be described in detail as follows. Meanwhile, each description and embodiment disclosed in the present application may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present application fall within the scope of the present application. In addition, it cannot be seen that the scope of the present application is limited by the detailed description described below.

One aspect of the present invention for achieving the above object provides an ultrasound-guided drug delivery system comprising a biomaterial to which a drug is bound through an ester bond, a phospholipid, and a PEGylated phospholipid. In the present invention, the biomaterial to which the drug is bound through the ester bond may be selectively attached to the interface of micro/nano bubbles together with phospholipids after preparation.

In the present invention, the term "biomaterial" includes all materials, surfaces, and structures that interact with organ systems, and the biomaterial of the present invention has a chemical structure capable of binding to a drug or a fluorescent dye through an ester bond. , For example, it may include a hydroxy group or a carboxy group, and may have a structure suitable for forming a drug delivery system in the form of micro/nano bubbles. Specifically, the biomaterial may be a protein or a biocompatible polymer, for example, the protein is gelatin, collagen, fibrin, gluten, elastin, or bovine serum albumin. (BSA), human serum albumin (HSA)), and more specifically, albumin, but is not particularly limited thereto. In addition, the biocompatible polymer is alginic acid (alginic acid), pectin (pectin), chitin (chitin), carrageenin (carrageenin), gellan gum (gellan gum), carboxymethyl cellulose (carboxymethyl cellulose), dextran (dextran), poly(caprolactone) (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(vinyl alcohol) (PVA), poly(acrylic acid) (PAA), or hyaluronic acid and the like, and more specifically, may mean hyaluronic acid, but is not particularly limited thereto.

In the present invention, in particular, the drug linked to hyaluronic acid by an ester bond undergoes a hydrolysis reaction very slowly under physiological conditions (pH 7.1 to 7.4), so that the released drug cannot show an effect. When irradiated, the hydrolysis reaction is accelerated and the drug release rate is 10-100 times higher due to physical stimulation and elevated high temperature/high pressure, so that the drug can be discharged to a sufficient extent to show a significant effect on the desired site.

In the present invention, the term "phospholipid" is a type of lipid containing phosphorus as a major component of a biological membrane, and has a structure in which two fatty acids and one phosphate group are bonded to glycerol. The type varies depending on the type of organic material bonded to the phosphoric acid group, and the direction in which the fatty acid is bonded indicates hydrophobicity, and the direction in which the phosphoric acid group is bonded indicates hydrophilicity.

Specifically, in the present invention, the phospholipids include dipalmitoylphosphatidylcholine (DPPC), dioleoyl phosphatidylcholine (DOPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), didecanoylphosphatidylcholine (DDPC) , Dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE), distearoyl phosphatidylethanolamine (DSPE), dioleyl phosphatidylethanolamine (DOPE) , diarachidoyl phosphatidylethanolamine (DAPE), dilinoleyl phosphatidylethanolamine (DLPE), dipalmitoylphosphatidylglycerol (DPPG), dilauroyl phosphatidylglycerol (DLPG), distearoyl phosphatidylglycerol (DSPG) ), dioleoyl phosphatidylglycerol (DOPG), phosphatidylcholine (PC), and egg phosphatidylcholine (EPC) may be at least one selected from the group consisting of, more specifically dipalmitoylphosphatidylcholine (DPPC) or distearoyl phosphatidyl It may be ethanolamine (DSPE), but is not particularly limited thereto.

In the present invention, the term "ultrasound" is a sound wave with a frequency exceeding 20 kHz, and for the purpose of the present invention, it is irradiated to the micro/nano bubble drug delivery system to collapse the bubble and generate physical stimulation and high temperature/high pressure to release the drug or fluorescent dye It is not particularly limited as long as it can facilitate

In addition, the drug delivery system of the present invention comprises a biomaterial to which a drug is bound through an ester bond, a phospholipid, and a PEGylated phospholipid, and forms microbubbles or nanobubbles with a diameter of 0.2 to 10 μm. In the case of irradiating ultrasonic waves to the drug carrier, the drug release is accelerated by the generation of high temperature/high pressure due to physical stimulation and the collapse of the bubble, and thereby promoting the ester bond hydrolysis between the biomaterial and the drug. do.

In the present invention, "drug" may mean including all compounds, protein drugs, peptide drugs, nucleic acid molecules for gene therapy, nanoparticles, functional cosmetic active ingredients or cosmetically used active ingredients, for the purpose of the present invention As long as it can bind to the biomaterial through an ester bond, it is not particularly limited thereto. Specifically, in the present invention, the drug is directly bonded through an ester bond with a hydroxy group or a carboxy group of the biomaterial constituting the drug delivery system, or a person skilled in the art is an ester between the biological material and the drug The binding may be by introducing an appropriate linker compound in the art that enables binding.

When the drug of the present invention is a hydrophobic drug, the drug can be loaded inside the drug carrier according to the difference in hydrophilicity/hydrophobicity according to the direction of the phospholipid, and the drug carrier of the present invention stably supports the majority of hydrophobic drugs. and has the characteristics of being able to be transmitted.

More specifically, the drug is, for example, an anti-cancer agent, an anti-inflammatory agent, an analgesic agent, an anti-arthritic agent, an antispasmodic agent, an anti-depressant agent, an anti-psychotic agent, an anti-anxiety agent, an anti-anxiety agent, an opioid antagonist, an anti-Parkin's disease drug, a cholinergic agonist, an anti-angiogenesis agent Depressant, immunosuppressant, antiviral, antibiotic, appetite suppressant, analgesic, anticholinergic, antihistamine, antimigraine, hormone, coronary, cerebrovascular or peripheral vasodilator, contraceptive, antithrombotic, diuretic, antihypertensive, cardiovascular Treatments for diseases, cosmetic ingredients (eg, anti-wrinkle agents, skin aging inhibitors and skin whitening agents), etc., but are not limited thereto. For example, the drug is doxorubicin, paclitaxel, vincristine, daunorubicin, vinblastine, actinomycin-D, docetaxel, etoposide (etoposide), teniposide, bisantrene, homoharringtonine, Gleevec (STI-571), cisplatin, 5-fluorouracil, adriamycin (adriamycin), methotrexate, busulfan, chlorambucil, cyclophosphamide, melphalan, nitrogen mustard, nitrosourea ) or a drug such as camptothecin, but is not particularly limited thereto.

In addition, the drug delivery system may additionally introduce a targeting agent (targeting material) to the surface of a biomaterial or phospholipid, thereby further increasing the efficiency of drug release according to ultrasonic irradiation. In the present invention, the "targeting agent" is a molecule specific for a target, and may be an antibody or antibody fragment specific for a specific target, or an aptamer. The targeting agent is designed to specifically bind to a target, including a receptor, including an organ, tissue, cell. Therefore, the targeting agent specifically binds to a receptor that is expressed in association with a specific disease, so that the drug carrier of the present invention can specifically bind to the target, and the drug bound by ester binding is released and delivered into the target. can be

Another aspect of the present invention for achieving the above object provides a composition for drug delivery, comprising the drug delivery system. The terms biomaterial, phospholipid, ultrasound and drug are the same as described above.

Another aspect of the present invention for achieving the above object is the prevention of a disease comprising administering the composition to an individual other than a human and irradiating ultrasound to the site to which the composition is administered to release the drug provide a treatment method.

In the present invention, the term "individual" refers to all animals, including humans, to which the drug delivery system or composition for drug delivery of the present invention can be administered for the prevention or treatment of diseases, and specifically, it may be any mammal including humans. This is not particularly limited.

In the present invention, the term "administration" means introducing the drug delivery system or composition for drug delivery to an individual in an appropriate way, and the administration route can be administered through any general route as long as it can reach the target site. Specifically, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration may be administered, but are not particularly limited thereto.

In the present invention, the term "disease" may refer to various brain diseases including brain tumors and all malignant tumors (cancer) in the human body, but is not particularly limited thereto. Specifically, the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal Cell cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain tumor, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse giant B-cell lymphoma , Enlarged Barter cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, Esophageal cancer, glioma, neuroblastoma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, primary site Unknown cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer , mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, It may be anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer or thymus cancer, but is not particularly limited thereto.

In the present invention, the ultrasonically induced drug delivery system comprising a biomaterial to which a drug is bound through an ester bond, a phospholipid, and a PEGylated phospholipid can form micro/nano bubbles, and physical stimulation and The drug release is accelerated due to the acceleration of hydrolysis of the ester bond due to the collapse, and it is characterized in that the drug is delivered with high efficiency to the target site.

However, effects according to an embodiment of the technology disclosed in the present specification are not limited to those mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the following description.

In order to more fully understand the drawings cited herein, a brief description of each drawing is provided.
1 is a diagram showing that when the drug delivery system of the present invention is irradiated with ultrasound, the hydrolysis of the ester bond between the biomaterial (hyaluronic acid, HA) and the drug is accelerated due to the occurrence of physical stimulation and high temperature and high pressure, thereby accelerating drug release It is a schematic diagram showing the process.
2 shows a chemical structure in which a biomaterial (hyaluronic acid, HA) and a drug (methotrexate, paclitaxel, doxorubicin) or a model drug (rhodamine B) are linked through an ester bond in the drug delivery system of the present invention.
3 shows a three-dimensional structure of a protein (albumin) and a structure in which a drug (doxorubicin) or a model drug (Fluorescein) is linked through an ester bond in the drug delivery system of the present invention.
4A schematically shows the synthesis method of a biomaterial (hyaluronic acid, HA) to which a drug (methotrexate) is bound through an ester bond in the present invention, and FIG. 4B is an NMR and post-synthesis NMR of the biomaterial UV-vis analysis data.
5A schematically shows the synthesis method of a biomaterial (hyaluronic acid, HA) to which a model drug (rhodamine B) is bound through an ester bond in the present invention, and FIG. 5B is a before/after synthesis of the biomaterial NMR and UV-vis analysis data.
6 is a drug carrier (experimental group, MB-ERHA) containing a biomaterial (hyaluronic acid) to which a model drug (rhodamine B) is bound through an ester bond and a biomaterial to which a model drug (Fluorescein) is bound through an amide bond; It shows an optical microscope and a confocal microscopy photograph of a drug delivery system (control) containing a model drug (Nile Red) without hyaluronic acid.
7 is a drug delivery system (experimental group, MB-ERHA) containing a biomaterial (hyaluronic acid) to which a model drug (rhodamine B) is bound through an ester bond, and a biomaterial to which a model drug (Fluorescein) is bound through an amide bond. The size of the microbubble-based contrast medium of the drug delivery system containing (control group 1, MB-AFHA) and the drug delivery system containing the model drug (nile red) without hyaluronic acid (control group 2, MB-NR) was analyzed through a DLS particle size analyzer one result is shown.
8 shows a solution in which only a biomaterial (control, ERHA) to which a model drug (rhodamine B) is bound through an ester bond and a biomaterial to which a model drug (rhodamine B) is bound through an ester bond is prepared with microbubbles Shows the results of comparing the release amount of the model drug through UV-vis analysis when the drug delivery system (experimental group, MB-ERHA) was irradiated with ultrasound.
9 is a drug delivery system (experimental group) containing a biomaterial (hyaluronic acid) to which a drug is bound through an ester bond with respect to an agarose gel and a drug carrier (control group) containing a biomaterial to which a drug is bound through an amide bond. It is a schematic diagram showing the drug diffusion test during ultrasonic irradiation.
10 is a drug delivery system (experimental group) containing a biomaterial (hyaluronic acid) to which a drug is bound through an ester bond and a drug carrier (control group) containing a biomaterial to which a drug is bound through an amide bond. Shows the results of confirming the degree of diffusion with confocal microscopy.
11 shows the results of in-vitro biotoxicity experiments of a model drug and a biomaterial to which a model drug (rhodamine B) is bound through an ester bond.
12 is a drug delivery system comprising a biomaterial to which a model drug (rhodamine B) is bound through an ester bond (experimental group, MB-ERHA) and a drug carrier comprising a biomaterial to which a model drug (Fluorescein) is bound through an amide bond (Control group, MB-AFHA) shows the results of comparing the in-vitro cell uptake according to the presence or absence of ultrasound irradiation.

Hereinafter, the present invention will be described in more detail through the following examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples only.

Example 1: Preparation of microbubble drug delivery system

Disperse and dissolve a mixture of 1-10 mg of PEG-conjugated phospholipid DSPE-PEG (2000) and 5-30 mg of phospholipid (DSPC) in 2-5 mL of chloroform in a 30 mL vial. . After dispersing and dissolving 1-10 μg of a biomaterial (hyaluronic acid, HA) bound to a drug by ester bonding in 1-3 mL of a 40% aqueous ethanol solution, it is mixed with the prepared phospholipid solution. Remove the organic solvent and water from the vial containing the mixed solution using a rotary concentrator, and make a vial coated with an opaque phospholipid film. Add 3-5 mL of sodium chloride (0.9%) aqueous solution and 1 mL of liquid gas (2H,3H-Decafluoropentane) to the film-coated vial, and apply ultrasound for 0.5-2 minutes using a tip sonicator to prepare a microbubble drug delivery system. . After the prepared aqueous solution is cooled slowly, the solution in the upper layer where the residue remains is removed, and the bubbled drug delivery system is recovered as a precipitated microbe. The microbubble solution thus prepared is confirmed through NTA, DLS, Confocal, and SEM.

As a result, in the case of a drug delivery vehicle (experimental group, MB-ERHA) containing a biomaterial (hyaluronic acid) to which a model drug (rhodamine B) is bound through an ester bond, microbubbles with a diameter of 1-3 μm are formed and have a negative charge. It was confirmed that hyaluronic acid (HA-RhB, red) was selectively formed on the surface of the bubble, and the surface charge by DSPE-PEG (2000) and hyaluronic acid having a negative charge showed a negative value (-28 mV).

In addition, in the case of a drug delivery system (control, MB-AFHA) containing a biomaterial to which a model drug (Fluorescein) is bound through an amide bond, microbubbles having a diameter of 1-3 μm are formed and hyaluronic acid (HA-Fluorescine) having a negative charge , green) was confirmed to be selectively formed on the surface of the bubble, and the surface charge by DSPE-PEG (2000) and hyaluronic acid having a negative charge similarly was about -29 mV.

On the other hand, in the case of microbubbles to which a fluorescent dye (nile red) was added without hyaluronic acid, microbubbles with a diameter of 1-5 μm were formed, and it was confirmed that the uniformity of the bubbles was decreased due to the presence of hydrophobic nile red. In addition, although nile red exists only on the surface of the bubble in the ring-shaped bubble, most of it was observed in a spherical shape because nile red can be dissolved in liquid gas. Since DSPE-PEG has a negative charge, the surface charge is negative. However, because of the absence of hyaluronic acid, it exhibited a relatively small -23 mV.

Example 2: Preparation of microbubble drug delivery system using contrast medium

Dissolve 1-10 mg of a biomaterial (hyaluronic acid, HA) to which a drug is bound by an ester bond in 5 mL of sodium chloride (0.9%) aqueous solution. Put the drug-dissolved sodium chloride solution in a syringe and inject it into the container containing SonoVue powder through a rubber stopper, and then mix by vigorously stirring for at least 20 seconds using a vortex mixer (SonoVue powder: Sulfur hexafluoride, Macrogol 4000, Distearoylphosphatidylcholine, Dipalmitoylphosphatidylglycerol Sodium, Palmitic acid).

Example 3: Drug release experiment according to ultrasonic irradiation

Experimental group dispersed in PBS in two dialysis membrane bags (drug delivery system containing a biomaterial (HA-RhB) to which a red model drug (rhodamine B) is bound through an ester bond, MB-ERHA) and a control group (Dispersed biomaterial without microbubbles, HA-RhB) solution was loaded, respectively. The permeable membrane bag carrying each biomaterial was placed in a beaker containing PBS solution, and then ultrasonic wave was irradiated. The experimental group analyzed the concentration of the drug released in the beaker after irradiating for 10, 30, and 60 seconds, and the control group analyzed the concentration of the drug released after irradiating it for 60 seconds.

As a result, the control group without microbubbles released a small amount of drug by ultrasonic irradiation, but the experimental group prepared with microbubbles showed more than 10 times the drug release compared to the control group, and this release rate depends on the ultrasonic irradiation time. was observed (FIG. 8).

Example 4: Drug diffusion experiment according to ultrasonic irradiation

Experimental group dispersed in PBS in a channel composed of hydrophilic agarose gel (drug carrier containing a biomaterial to which red model drug (rhodamine B) is bound through ester bond, MB-ERHA) and control group (green model drug through amide bond) (Fluorescein) was injected with a drug delivery system containing a bound biomaterial, MB-AFHA) solution. Thereafter, ultrasonic waves were irradiated over the channel into which the solution was injected to collapse the microbubbles, and accordingly, it was confirmed whether and the extent and extent of diffusion of each model drug into the hydrophilic agarose gel.

As a result, the hydrolysis reaction of the ester bond in the drug delivery system was accelerated due to the physical stimulation by ultrasonic irradiation and the local high temperature/high pressure generated by the collapse of microbubbles, so that the bound red model drug (rhobmine B) in the experimental group It was confirmed by a confocal analyzer that the drug was rapidly released and the released model drug penetrated and dispersed into the hydrophilic agarose gel.

On the other hand, in the case of the green model drug (Fluorescein) fixed with an amide bond in the control group, the amide bond is hardly decomposed even at high temperature/high pressure by ultrasonic irradiation, so the drug cannot be released and is attached to a biomaterial (hyaluronic acid) and is attached to a macromolecule. was maintained, and it was confirmed that the permeability into the hydrophilic agarose gel was weak (FIG. 10).

Example 5: In-vitro cell experiments

5-1: Cytotoxicity test

The biomaterial (HA-RhB) and the model drug bound to the model drug (rhobmine B) through ester bond were added to U-251 MG cells to obtain final concentrations of 1 nM, 0.01 µM, 0.1 µM, 1 µM, 10 µM, Cells were cultured for 24 hours after each adjustment at 100 μM. Then, the cell culture medium and a solution composed of a tetrazolium salt derivative were added to measure the cell viability, and the in-vitro cytotoxicity of each material was confirmed. As a result, in the case of free rhobmine B, almost no toxicity was observed at a low concentration, but toxicity could be observed at a concentration of 1 μM or more. On the other hand, the biomaterial (HA-RhB) to which the model drug was bound through ester linkage was toxic from a much higher concentration of 100 μM. This shows the excellent biocompatibility of the prepared drug delivery system due to the characteristics of the hyaluronic acid platform with excellent biocompatibility (FIG. 11).

5-2: Analysis of the degree of absorption in cells according to ultrasonic irradiation

Experimental group (drug carrier, MB-ERHA, containing a biomaterial to which a red model drug (rhobmine B) is bound through an ester bond) and a control group (a drug containing a biomaterial to which a green model drug (Fluorescein) is bound through an amide bond Using the carrier, MB-AFHA) solution, the degree of in-vitro cell uptake was analyzed with or without ultrasound irradiation. Experimental group and control group were added together to U-251 MG cells, and the cell culture medium was newly replaced before observation in order to remove substances not absorbed into the cells and observed with a confocal microscope.

As a result, before ultrasonic irradiation, red and green fluorescence colors hardly appeared because both the experimental group and the control group showed slow cell uptake due to the polymer hyaluronic acid microbubble platform. Confocal analyzer confirmed that the bound red model drug (rhobmine B) was rapidly released and absorbed into cells as the hydrolysis reaction of the ester bond was accelerated in the drug delivery system of the experimental group due to the local high temperature/high pressure generated by it.

On the other hand, in the case of the green model drug (Fluorescein) fixed with an amide bond in the control group, the amide bond is hardly decomposed even at high temperature/high pressure due to bubble collapse caused by ultrasonic irradiation, so the drug cannot be released and the biomaterial (hyaluronic acid) is not released. It was adhered and maintained as macromolecules, and it was confirmed by confocal analyzer that cellular uptake still proceeded slowly (FIG. 12).

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the following claims and their equivalents.

Claims (9)

An ultrasound-guided drug delivery system comprising a biomaterial to which a drug is bound through an ester bond, a phospholipid, and a PEGylated phospholipid. The drug delivery system according to claim 1, wherein the biomaterial is a protein or a biocompatible polymer. According to claim 2, wherein the protein is gelatin (gelatin), collagen (collagen), fibrin (fibrin), gluten (gluten), elastin (elastin) or albumin, the biocompatible polymer is alginic acid (alginic acid), pectin ( pectin), chitin, carrageenin, gellan gum, carboxymethyl cellulose, dextran, PCL, PLA, PGA, PVA, PAA or hyaluronic acid ), a drug delivery system. According to claim 1, wherein the phospholipid is dipalmitoylphosphatidylcholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), dioleoyl phosphatidylcholine (DOPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), didecanoyl phosphatidylcholine (DDPC), dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE) , distearoyl phosphatidylethanolamine (DSPE), dioleyl phosphatidylethanolamine (DOPE), diarachidoyl phosphatidylethanolamine (DAPE), dilinoleyl phosphatidylethanolamine (DLPE), dipalmitoylphosphatidylglycerol (DPPG) ), dilauroyl phosphatidylglycerol (DLPG), distearoyl phosphatidylglycerol (DSPG), dioleoyl phosphatidylglycerol (DOPG), phosphatidylcholine (PC) and egg phosphatidylcholine (EPC) Any one or more selected from the group consisting of that is, a drug delivery system. The drug delivery system according to claim 1, wherein the drug delivery system forms microbubbles or nanobubbles having a diameter of 0.2 to 10 μm. The drug delivery system according to claim 1, wherein the drug delivery system is characterized in that the release of the drug is accelerated by the collapse of the bubble and the promotion of hydrolysis of the ester bond by irradiation with ultrasonic waves. The drug delivery system according to claim 1, wherein a targeting agent (targeting material) is additionally introduced on the surface of the biomaterial or phospholipid in the drug delivery system. A composition for drug delivery, comprising the drug delivery system of any one of claims 1 to 7. administering the composition for drug delivery of claim 8 to a subject other than a human; and irradiating ultrasound to the site to which the composition is administered to release a drug, preventing or treating a disease.

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