COMPOSITION FOR ULTRASOUND CONTRAST AGENT, ULTRASOUND CONTRAST AGENT AND PREPARATION METHOD THEREOF

Abstract

Disclosed are a composition for ultrasound contrast agent, an ultrasound contrast agent, and a preparation method thereof. The composition for ultrasound contrast agent includes a lipid, a stabilizer and an acoustic-induced deformation material; relative to 100 parts by weight of the lipid, the content of the stabilizer is 20 to 100 parts by weight, and the content of the acoustic-induced deformation material is 1 to 15 parts by weight; and the acoustic-induced deformation material is deformed under a specific acoustic wave, and the characteristic response frequency of the acoustic-induced deformation material is 0.01 MHz to 50 MHz. The microbubble ultrasound contrast agent has better stability, thereby it circulates in vivo for a longer time, and has lower mechanical index, so that the inertial cavitation occurs under a low-energy ultrasonic wave.

Claims

1. A composition for ultrasound contrast agent, wherein: the composition for ultrasound contrast agent comprises a lipid, a stabilizer and an acoustic-induced deformation material; relative to 100 parts by weight of the lipid, a content of the stabilizer is 20 to 100 parts by weight, and a content of the acoustic-induced deformation material is 1 to 15 parts by weight; and the acoustic-induced deformation material is deformed under an acoustic wave of a characteristic response frequency for the acoustic-induced deformation material, and the characteristic response frequency is 0.01 MHz to 50 MHz.

2. The composition for ultrasound contrast agent according to claim 1, wherein relative to 100 parts by weight of the lipid, the content of the stabilizer is 30 to 60 parts by weight, and the content of the acoustic-induced deformation material is 3 to 12 parts by weight.

3. The composition for ultrasound contrast agent according to claim 1, wherein relative to 100 parts by weight of the lipid, the content of the stabilizer is 42 to 50 parts by weight, and the content of the acoustic-induced deformation material is 4 to 10 parts by weight.

4. The composition for ultrasound contrast agent according to claim 1, wherein the composition for ultrasound contrast agent further comprises a drug, and relative to 100 parts by weight of the lipid, the content of the drug is 2 to 20 parts by weight.

5. The composition for ultrasound contrast agent according to claim 1, wherein the characteristic response frequency of the acoustic-induced deformation material is 1 MHz to 30 MHz.

6. The composition for ultrasound contrast agent according to claim 5, wherein the characteristic response frequency of the acoustic-induced deformation material is 2 MHz to 20 MHz.

7. The composition for ultrasound contrast agent according to claim 1, wherein the acoustic-induced deformation material is any one or more selected from the group consisting of: poly N-isopropylacrylamide, poly vinyl caprolactam, hematoporphyrin, photofrin, mesoporphyrin, sodium porphyrin, gallium porphyrin, hydrophilic chlorin derivative, protoporphyrin, copper protoporphyrin, tetraphenylporphyrin tetrasulfonate, phoeophorbide a, photosensory proteins, adriamycin, chlorin, bengal red, erythrosin B, curcumin, methylene blue, tenoxicam, piroxicam, artemether, and water-soluble chlorin derivative.

8. The composition for ultrasound contrast agent according to claim 1, wherein the lipid is a carboxylated phospholipid.

9. The composition for ultrasound contrast agent according to claim 8, wherein the lipid is any one or more selected from the group consisting of: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), distearoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylcholine, 1,2-bis(diphenylphosphine)ethane (DPPE), and distearoylphosphatidylethanolamine-polyethylene glycol.

10. The composition for ultrasound contrast agent according to claim 9, wherein the lipid consists of a first lipid and a second lipid in a weight ratio of 1:0.05 to 1:0.5, wherein the first lipid is dipalmitoylphosphatidylcholine (DPPC) and/or DSPC, and the second lipid is DSPE and/or DPPE.

11. The composition for ultrasound contrast agent according to claim 1, wherein the stabilize is any one or more selected from the group consisting of: polyoxypropylene polyoxyethylene block polyether, polyethylene glycol 4000, polyethylene glycol 2000, polyethylene glycol 1400, polyethylene glycol 40s, and polysorbate-80.

12. The composition for ultrasound contrast agent according to claim 11, wherein the stabilizer is Pluronic, or the stabilizer is a combination of Pluronic with at least one of the PEG4000, PEG2000, PEG1400 and PEG40s in a weight ratio of 1:0.5 to 1:0.8.

13. An ultrasound contrast agent, wherein the ultrasound contrast agent comprises or is prepared from the composition for ultrasound contrast agent according to claim 1.

14. A method for preparing an ultrasound contrast agent, comprising: (1) mixing the composition for ultrasound contrast agent according to claim 1 with a solvent to obtain solution A; (2) rotary evaporating the solution A in a first water bath until a thin film is formed; and, (3) adding a hydration solution into the material obtained by step (2) and rotary evaporating the resulting hydration solution in a second water bath until the thin film is dissolved to obtain solution B; and optionally, (4) pumping a gas into the solution B, conducting ultrasonic cavitation to form gas-filled microbubbles.

15. The method according to claim 14, wherein the rotary evaporation temperature of the first water bath is 45° C. to 70° C., and the rotary evaporation pressure of the first water bath is 0.05 MPa to 0.5 Mpa.

16. The method according to claim 14, wherein the rotary evaporation temperature of the second water bath is 45° C. to 70° C.

17. The method according to claim 14, wherein the conditions of the ultrasonic cavitation comprise: a power of 6 kW to 12 kW, and a time of 2 min to 15 min.

18. The method according to claim 14, wherein the conditions of the ultrasonic cavitation comprise: a power of 8 kW to 12 kW, and a time of 4 min to 10 min.

19. The method according to claim 14, wherein the hydration solution is a mixture of glycerol and water or a mixture of glycerol and acid-base buffer solution.

20. The method according to claim 19, wherein the volume content of the glycerol in the hydration solution is 10% to 30%.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0048] FIG. 1 is an image of the contrast agent II1 obtained in Example 1 under an optical microscope.

[0049] FIG. 2 is real-time ultrasonic images of the contrast agent II1 obtained in Example 1 before ultrasound-induced blast in rabbit kidney (a) and after ultrasound-induced blast in rabbit kidney (b).

DETAILED DESCRIPTION OF EMBODIMENTS

[0050] The present disclosure will be described in detail below by the Examples. The described Examples of the present disclosure are only a part of the examples of the present disclosure, but not all of the examples. Based on the examples of the present disclosure, all other examples obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present disclosure.

[0051] Unless otherwise specified, the materials used in the following Examples are all commercially available analytical grades.

Preparation Example

[0052] The preparation example is used to prepare the hydration solution used in step (3), i.e., PBS-glycerol hydration solution. The preparation example is only a specific embodiment and not a limitation of the present disclosure. The specific process includes:

[0053] Weighing 0.097 g of KCl, 4.005 g of NaCl, 1.145 g of Na.sub.2HPO.sub.4. H.sub.2O and 0.096 g of KH.sub.2PO.sub.4 to a beaker of 1 L, adding deionized water and making up to 500 ml to prepare phosphate buffered saline (PBS solution) for use. Weighting 85 ml of the PBS solution, adding 15 ml of glycerol, mixing well to obtain a PBS-glycerol hydration solution.

Example 1

[0054] (I) Preparing a composition for ultrasound contrast agent, denoted as I1, including:

[0055] Lipid: 100 mg of dipalmitoylphosphatidylcholine (DPPC), 30 mg of distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) (including 8 mg of lipid DSPE and 22 mg of stabilizer PEG2000);

[0056] Stabilizer: 30 mg of polyoxypropylene polyoxyethylene block polyether (Pluronic);

[0057] Acoustic-induced deformation material: 5 mg of poly N-isopropylacrylamide (PNIPAm);

[0058] Drug: 10 mg of paclitaxel.

[0059] (II) Preparing an ultrasound contrast agent, denoted as II1.

[0060] (1) Putting the composition for ultrasound contrast agent I1 into a round flask of 250 ml, and then adding 20 ml of chloroform, and fully mixing to make the solution clear and transparent;

[0061] (2) Removing the chloroform by a condition of the rotary evaporation temperature is 55° C. in water bath and the negative pressure is 0.05 MPa for 25 min to form a uniform thin film on the bottle of the flask;

[0062] (3) Adding 40 ml of the hydration solution obtained in the preparation example into the flask after step (2), continue rotary evaporating of 55° C. in water bath for 15 min to make the thin film dissolved completely, and then taking 5 ml of the resulting solution into a container of 15 ml;

[0063] (4) Putting the container into an ultrasonic pulverizer of 10 kW for 4 minutes while pumping perfluoropropane into the container to obtain an ultrasound contrast agent II1.

[0064] The obtained ultrasound contrast agent II1 is observed by an optical microscope and the result is shown in FIG. 1. It may be seen from the FIG. 1 that the contrast agent is covered in dense microbubbles with particle sizes of about 1 μm, and the particle size distribution of the microbubbles is narrow, and there are no obvious impurities in the solution, which can meet the imaging requirement for the ultrasound contrast agent.

[0065] Taking a Japanese long-eared white rabbit as the experimental object, a peripheral vein channel is established through the marginal ear vein in the left ear of the rabbit, and a tri-branch tube is connected at the end of the catheter, and one of the channels is used for injecting the drug-loaded ultrasound contrast agent prepared by the present disclosure, and one channel for injecting normal saline solution. The Japanese white rabbit is anesthetized with 3% (40 mg/kg) sodium pentobarbital. After the rabbit is fully anesthetized, the right waist is depilated to facilitate renal angiography. The drug-loaded ultrasound contrast agent II1 (0.1 ml/kg) prepared by Example 1 is bolus injected through the rabbit marginal ear vein, and contrast-enhanced ultrasound and focused ultrasound, these two kinds of sequences are applied periodically on the same ultrasonic imaging probe. Recording the renal angiography of the rabbit under the contrast-enhanced ultrasound mode (center frequency: 8 MHz), and then breaking the microbubbles in artery specifically under the focused ultrasound mode (center frequency: 4 MHz (the frequency is the characteristic response frequency for PNIPAm), mechanical index: 0.8), switching the contrast-enhanced ultrasound mode immediately and recording the renal angiography of the rabbit after breaking the microbubbles specifically. The real-time ultrasonic images before and after the ultrasound-induced blast are shown in (a) and (b) of FIG. 2, respectively. The ultrasonic signal in the breaking point and the downstream of blood vessels of the breaking point are changed obviously in the images of before and after breaking the microbubbles specifically. The breaking point and the downstream of blood vessels of the breaking point are fully perfused before breaking the microbubbles, and the blood vessels boundary is clearly developed. Almost no echo signal may be seen in the breaking point and the downstream of blood vessels of the breaking point after breaking the microbubbles.

Example 2

[0066] (I) Preparing a composition for ultrasound contrast agent, denoted as I2, including:

[0067] Lipid: 100 mg of DPPC, 10 mg of distearoylphosphatidylethanolamine (DSPE);

[0068] Stabilizer: 20 mg of polyethylene glycol 1400 (PEG1400), 30 mg of Pluronic;

[0069] Acoustic-induced deformation material: 10 mg of PNIPAm;

[0070] Drug: 10 mg of paclitaxel.

[0071] (II) Preparing an ultrasound contrast agent, denoted as II2.

[0072] (1) Putting the composition for ultrasound contrast agent I2 into a round flask of 250 ml, and then adding 20 ml of chloroform, and fully mixing to make the solution clear and transparent;

[0073] (2) Removing the chloroform by a condition of the rotary evaporation temperature is 55° C. in water bath and the negative pressure is 0.1 MPa for 30 min to form a uniform thin film on the bottle of the flask;

[0074] (3) Adding 40 ml of the hydration solution obtained in the preparation example into the flask after step (2), continue rotary evaporating of 55° C. in water bath for 15 min to make the thin film dissolved completely, and then taking 5 ml of the resulting solution into a container of 15 ml;

[0075] (4) Putting the container into an ultrasonic pulverizer of 10 kW for 6 minutes while pumping perfluoropropane into the container to obtain an ultrasound contrast agent II2.

Example 3

[0076] (I) Preparing a composition for ultrasound contrast agent, denoted as I3, including:

[0077] Lipid: 100 mg of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 10 mg of DSPE;

[0078] Stabilizer: 20 mg of polyethylene glycol 4000 (PEG4000), 30 mg of Pluronic;

[0079] Acoustic-induced deformation material: 5 mg of poly vinyl caprolactam;

[0080] Drug: 10 mg of paclitaxel.

[0081] (II) Preparing an ultrasound contrast agent, denoted as II3.

[0082] (1) Putting the composition for ultrasound contrast agent I3 into a round flask of 250 ml, and then adding 20 ml of chloroform, and fully mixing to make the solution clear and transparent;

[0083] (2) Removing the chloroform by a condition of the rotary evaporation temperature id 55° C. in water bath and the negative pressure is 0.01 MPa for 20 min to form a uniform thin film on the bottle of the flask;

[0084] (3) Adding 40 ml of the hydration solution obtained in the preparation example into the flask after step (2), continue rotary evaporating of 55° C. in water bath for 15 min to make the thin film dissolved completely, and then taking 5 ml of the resulting solution into a container of 15 ml;

[0085] (4) Putting the container into an ultrasonic pulverizer of 10 kW for 8 minutes while pumping perfluoropropane into the container to obtain an ultrasound contrast agent II3.

Example 4

[0086] (I) Preparing a composition for ultrasound contrast agent, denoted as I4, including:

[0087] Lipid: 100 mg of DPPC, 10 mg of 1,2-bis(diphenylphosphine)ethane (DPPE);

[0088] Stabilizer: 20 mg of polyethylene glycol 40s (PEG40s), 30 mg of Pluronic;

[0089] Acoustic-induced deformation material: 10 mg of poly vinyl caprolactam;

[0090] Drug: 10 mg of paclitaxel.

[0091] (II) Preparing an ultrasound contrast agent, denoted as II4.

[0092] (1) Putting the composition for ultrasound contrast agent I4 into a round flask of 250 ml, and then adding 20 ml of chloroform, and fully mixing to make the solution clear and transparent;

[0093] (2) Removing the chloroform by a condition of the rotary evaporation temperature is 55° C. in water bath and the negative pressure is 0.15 MPa for 30 min to form a uniform thin film on the bottle of the flask;

[0094] (3) Adding 40 ml of the hydration solution obtained in the preparation example into the flask after step (2), continue rotary evaporating of 55° C. in water bath for 15 min to make the thin film dissolved completely, and then taking 5 ml of the resulting solution into a container of 15 ml;

[0095] (4) Putting the container into an ultrasonic pulverizer of 10 kW for 4 minutes while pumping perfluoropropane into the container to obtain an ultrasound contrast agent II4.

Example 5

[0096] (I) Preparing a composition for ultrasound contrast agent, denoted as I5, including:

[0097] Lipid: 100 mg of DSPC, 30 mg of DSPE-PEG2000 (including 8 mg of lipid DSPE and 22 mg of stabilizer PEG2000);

[0098] Stabilizer: 30 mg of Pluronic;

[0099] Acoustic-induced deformation material: 5 mg of artemether (LEA);

[0100] Drug: 10 mg of paclitaxel.

[0101] (II) Preparing an ultrasound contrast agent, denoted as II5.

[0102] (1) Putting the composition for ultrasound contrast agent I5 into a round flask of 250 ml, and then adding 20 ml of chloroform, and fully mixing to make the solution clear and transparent;

[0103] (2) Removing the chloroform by a condition of the rotary evaporation temperature is 55° C. in water bath and the negative pressure is 0.2 MPa for 30 min to form a uniform thin film on the bottle of the flask;

[0104] (3) Adding 40 ml of the hydration solution obtained in the preparation example into the flask after step (2), continue rotary evaporating of 55° C. in water bath for 15 min to make the thin film dissolved completely, and then taking 5 ml of the resulting solution into a container of 15 ml;

[0105] (4) Putting the container into an ultrasonic pulverizer of 10 kW for 4 minutes while pumping perfluoropropane into the container to obtain an ultrasound contrast agent II5.

Example 6-25

[0106] Example 6-25 are carried out referring to the method of Example 1, the difference is that 5 mg of the acoustic-induced deformation material PNIPAm of Example 1 is replaced with other acoustic-induced deformation material in the same weight, as shown below:

[0107] In Example 6, hematoporphyrin is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I6 and an ultrasound contrast agent II6;

[0108] In Example 7, mesoporphyrin is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I7 and an ultrasound contrast agent II7;

[0109] In Example 8, sodium porphyrin is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I8 and an ultrasound contrast agent II8;

[0110] In Example 9, protoporphyrin is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I9 and an ultrasound contrast agent II9;

[0111] In Example 10, copper protoporphyrin is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I10 and an ultrasound contrast agent II10;

[0112] In Example 11, tetraphenylporphyrin tetrasulfonate is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I11 and an ultrasound contrast agent II11;

[0113] In Example 12, phoeophorbide a is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I12 and an ultrasound contrast agent II12;

[0114] In Example 13, Photofrin II is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I13 and an ultrasound contrast agent II13;

[0115] In Example 14, ATX-70 is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I14 and an ultrasound contrast agent II14;

[0116] In Example 15, ATX-S10 is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I15 and an ultrasound contrast agent II15;

[0117] In Example 16, photosensory proteins is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I16 and an ultrasound contrast agent II16;

[0118] In Example 17, adriamycin is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I17 and an ultrasound contrast agent II17;

[0119] In Example 18, chlorin e6 is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I18 and an ultrasound contrast agent II18;

[0120] In Example 19, bengal red is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I19 and an ultrasound contrast agent II19;

[0121] In Example 20, erythrosin B is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I20 and an ultrasound contrast agent II20;

[0122] In Example 21, curcumin is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I21 and an ultrasound contrast agent II21;

[0123] In Example 22, methylene blue is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I22 and an ultrasound contrast agent II22;

[0124] In Example 23, tenoxicam is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I23 and an ultrasound contrast agent II23;

[0125] In Example 24, piroxicam is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I24 and an ultrasound contrast agent II24;

[0126] In Example 25, water-soluble chlorin derivative PAD-S31 (13,17-bis(1-carboxypropion)carbamoylethyl-3-ethenyl-8-ethoxyiminoethylidene-7-hydroxy-2,7,12,18-tetramethyl-porphyrin sodium) (manufacturer: Photochemical Co., Ltd., Okayama, Japan) is used to replace PNIPAm to obtain a composition for ultrasound contrast agent I25 and an ultrasound contrast agent II25.

Example 26

[0127] Referring to the method of Example 2, the difference is that the dosage of the stabilizer in the composition for ultrasound contrast agent is changed, Specifically, the stabilizer includes 18 mg of PEG1400 and 18 mg of Pluronic.

[0128] Finally, a composition for ultrasound contrast agent I26 and an ultrasound contrast agent II26 are obtained.

Example 27

[0129] Referring to the method of Example 2, the difference is that the dosage of the stabilizer in the composition for ultrasound contrast agent is changed, Specifically, the stabilizer includes 40 mg of PEG1400 and 60 mg of Pluronic.

[0130] Finally, a composition for ultrasound contrast agent I27 and an ultrasound contrast agent II27 are obtained.

Example 28

[0131] Referring to the method of Example 2, the difference is that the dosage of the acoustic-induced deformation material in the composition for ultrasound contrast agent is changed, Specifically, the dosage of PNIPAm is changed to 14 mg.

[0132] Finally, a composition for ultrasound contrast agent I28 and an ultrasound contrast agent II28 are obtained.

Example 29

[0133] Referring to the method of Example 2, the difference is that the dosage of the acoustic-induced deformation material in the composition for ultrasound contrast agent is changed, Specifically, the dosage of PNIPAm is changed to 2.5 mg.

[0134] Finally, a composition for ultrasound contrast agent I29 and an ultrasound contrast agent II29 are obtained.

Comparative Example 1

[0135] Referring to the method of Example 1, the difference is that no acoustic-induced deformation material PNIPAm is added to obtain a composition for ultrasound contrast agent IDI and an ultrasound contrast agent IID1.

Comparative Example 2

[0136] An ultrasound contrast agent of SonoVue (manufacturer: Bracco Imaging B.V.) is purchased and denoted as an ultrasound contrast agent IID2.

Comparative Example 3

[0137] Referring to the method of Example 1, the difference is that the dosage of PNIPAm is changed to 20 mg to obtain a composition for ultrasound contrast agent ID3 and an ultrasound contrast agent IID3.

Test Example

[0138] The ultrasound contrast agent II1˜II26 and IID1˜IID3 obtained above are tested as follows:

[0139] (1) Stability Test

[0140] The stability of the ultrasound contrast agent in vivo is reflected by the half-life of the ultrasound contrast agent, and the longer the half-life, the higher the stability. Particularly, the test method includes (taking a rabbit as the object):

[0141] Selecting a length of vascular area in the ultrasonic image randomly after the ultrasound contrast agent is injected under the record of real-time ultrasound imaging, and recording the change of the average grey value in the area. Recording the point-in-time as t1 when the average grey value reaches a maximum A, and recording the point-in-time as t2 when the average grey value drops to 50% of the A, so the half-life of this kind of microbubbles is |t1−t2|. Note: Ensuring the concentration and dosage of the ultrasound contrast agent are same for each injection.

[0142] The measured half-life results of the ultrasound contrast agents from the Examples and Comparative Examples are recorded in Table 1, respectively.

[0143] (2) Mechanical Index Test

[0144] In vitro enriched blasting experiment is performed. Particularly, the test method includes:

[0145] Injecting the ultrasound contrast agent of the Examples and Comparative Examples with the same concentration (10.sup.6 pcs/mL) into the cellulose hose (inner diameter is 1 mm) with ndfeb magnet placed on one side respectively, and performing an in-vitro blasting experiment of the ultrasound contrast agent under the condition of physiological flow rate (100 mL/h). The ultrasonic imaging/blasting probe uses a linear array probe with 196 array elements and a bandwidth of 8 MHz. Setting the frequency of each examples as the characteristic response frequency (the frequency of IID1 and IID2 are set to the same as II1) for the acoustic-induced deformation material correspondingly, and controlling the mechanical index (control range is MI=0.3-1.9, stepping is 0.1) of the ultrasonic wave emitted by the ultrasonic probe through controlling the excitation pulse voltage of the ultrasonic probe. Observing the blast of the microbubbles under different mechanical index and recording the mechanical indexes respectively when the blasting rates of the ultrasound contrast agent according to each Examples and Comparative Example are greater than 90% (blasting rate=|before blasting−after blasting|/before blasting*100%), and the results are recorded in Table 1.

TABLE-US-00001 TABLE 1 Blasting Half-life mechanical Acoustic-induced deformation material (min) index II1 PNIPAm 15.7 ± 0.5 0.8 II2 PNIPAm 13.4 ± 1.4 0.6 II3 poly vinyl caprolactam 13.3 ± 1.1 0.7 II4 poly vinyl caprolactam 12.5 ± 1.6 0.6 II5 artemether (LEA) 14.9 ± 0.9 0.9 II6 hematoporphyrin 12.1 ± 0.6 1.2 II7 mesoporphyrin 11.8 ± 0.9 1.3 II8 sodium porphyrin 11.9 ± 1.1 1.2 II9 protoporphyrin 12.3 ± 0.7 1.2 II10 copper protoporphyrin 11.3 ± 1.2 1.3 II11 tetraphenylporphyrin tetrasulfonate 12.6 ± 1.7 1.1 II12 phoeophorbide a 10.8 ± 0.7 1.2 II13 Photofrin II 11.6 ± 1.3 1.3 II14 ATX-70 11.9 ± 1.5 1.2 II15 ATX-S10 11.7 ± 1.1 1.2 II16 photosensory proteins 12.8 ± 2.4 1.1 II17 adriamycin 14.9 ± 1.6 1.2 II18 chlorin e6 13.4 ± 3.1 1.0 II19 bengal red 12.7 ± 2.1 1.3 II20 erythrosin B 12.9 ± 1.7 1.2 II21 curcumin 13.6 ± 1.4 1.2 II22 methylene blue 13.1 ± 2.4 1.3 II23 tenoxicam 11.5 ± 1.1 0.9 II24 piroxicam 13.7 ± 1.1 1.0 II25 PAD-S31 11.6 ± 1.8 1.1 II26 PNIPAm  6.9 ± 2.3 0.4 II27 PNIPAm  7.4 ± 1.5 0.5 II28 PNIPAm  9.3 ± 2.1 0.5 II29 PNIPAm 16.1 ± 0.7 0.9 IID1 null 14.3 ± 0.1 >1.9 IID2 null  6.2 ± 2.6 0.8 IID3 PNIPAm  3.2 ± 0.3 0.4

[0146] It can be seen from the test results above, compared with the comparative example, the composition for ultrasound contrast agent and the ultrasound contrast agent according to the present disclosure have both higher stability and lower mechanical index, so it is possible for the ultrasound contrast agent according to the present disclosure to act as a contrast agent and a drug delivery agent simultaneously. The preferred embodiments of the present disclosure have been described above in detail; however, the present disclosure is not limited thereto. Within the scope of the technical concept of the present disclosure, a variety of simple modifications may be made to the technical solutions of the present disclosure, including combining various technical features in any other suitable manner. These simple modifications and combinations should also be regarded as the content disclosed in the present disclosure, and they all belong to the protection scope of the present disclosure.