A drug delivery system with the ability of targeted drug delivery within coronary atherosclerotic plaques and its preparation method

Abstract

The present invention discloses a drug-loading system with the ability of targeted drug delivery within coronary atherosclerotic plaques and a preparation method thereof. Using PBCA NPs synthesized from BCA monomers under the suspension aggregation and protocol as a drug carrier, when used in conjunction with intravascular ultrasound (IVUS), targeted drug delivery can be achieved, namely, the IVUS-PBCA NPs targeted drug delivery system. The PBCA NPs drug carrier prepared by the present invention has an average particle size of 216 nm, a stable negative potential of -22.2 mV on the surface, is safe and non-toxic, can match the high-frequency probe of IVUS, and has an ultrasound enhancement effect, thereby improving the resolution of IVUS. Moreover, under the action of the IVUS ultrasonic radiation force, it can penetrate through the gaps of the diseased vascular endothelium to reach the inside of the lesion, and then naturally hydrolyze, releasing the internal drug to achieve targeted drug delivery.

Description

Technical Field

[0001] The present invention belongs to the field of drug carriers, and particularly relates to a drug-loaded system with the ability of targeted drug delivery within coronary atherosclerotic plaques and a preparation method thereof. Background Art

[0002] In recent years, the incidence of coronary heart disease (CHD) has been rising continuously, and the mortality rate ranks first, which has seriously endangered human health. However, current research shows that only statin drugs have the effect of stabilizing atherosclerotic plaques, and interventional therapy has a local therapeutic effect. There is still no targeted drug delivery technology for the treatment of coronary heart disease.

[0003] Intravascular ultrasound (IVUS) is a commonly used technique in clinical practice in recent years. By means of intervention, a tiny ultrasound probe is sent to the lesion of coronary heart disease for ultrasound imaging, which is mainly used for further fine examination of local lesions. IVUS uses a high-frequency ultrasound probe, and the resolution is insufficient during clinical use. Currently, there are microbubble contrast agents on the market that can be used in combination with ordinary ultrasound for enhanced imaging to improve the ultrasound resolution. However, because they are lipid vesicles at the micron level (too large in volume and not hard enough), they cannot be matched with high-frequency IVUS for use. Theoretically, nanoscale polymers (smaller in volume and harder) can be matched with the high-frequency probe of IVUS to play an enhancing effect and thus improve its resolution.

[0004] Under normal circumstances, due to the "axial flow effect" in the body, nanoparticles cannot adhere well to the blood vessel wall, while the ultrasonic radiation force can cause the nanoparticles to deviate from the center of the axial flow and shift towards the blood vessel wall to achieve targeted adhesion. When the nanoparticles form good resonance with ultrasound, an ultrasonic enhancement effect can be achieved, and at the same time, good ultrasonic radiation force can be obtained.

[0005] The cell gap of normal tissue vascular endothelial cells is 6 - 7 nm, while the vascular endothelial gap in the diseased state (such as coronary heart disease) allows particles with a diameter less than 700 nm to pass through. Therefore, smaller nanoparticles can enter the interior of coronary atherosclerotic plaques through the vascular endothelial gap under the action of ultrasonic radiation force.

[0006] Poly(butyl cyanoacrylate) nanoparticles (PBCANPs) are self-aggregated from the safe, non-toxic, and easily biodegradable n-butyl cyanoacrylate (BCA) monomers in an acidic medium. The polymerization process does not require any energy input and has relatively high stability. By adjusting the parameters in the PBCA NPs preparation scheme, nanoscale polymer carriers with different physicochemical properties can be prepared.

[0007] In summary, if nanoparticles loaded with drugs and matching IVUS can be prepared, it can not only improve the resolution of IVUS, but also achieve targeted drug delivery within coronary atherosclerotic plaques, thus achieving the effect of targeted treatment of coronary heart disease. However, up to now, there is no related technology. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a drug carrier system aiming at the insufficient resolution of the above-mentioned IVUS and the lack of a targeted drug delivery treatment approach for coronary heart disease. This system can improve the resolution of IVUS and has the ability of targeted drug delivery within coronary atherosclerotic plaques.

[0009] The technical solution adopted by the present invention to solve the above-mentioned problems is as follows: The drug carrier system provided by the present invention uses BCA as a monomer and is prepared into PBCA NPs through a suspension polymerization scheme, and is used in combination with IVUS, that is, the IVUS-PBCA NPs targeted drug delivery system.

[0010] The preparation method of the above-mentioned drug carrier system mainly includes the following steps: On the one hand, the present invention provides a preparation method of a drug-loaded system with the ability of targeted drug delivery within coronary atherosclerotic plaques, and the specific steps are as follows:

[0011] Step 1, prepare drug aqueous solution I

[0012] Take 2 OD of RNA drug and 0.5 g of BCA and dissolve them in 20 ml of 0.01 M HCL to prepare drug aqueous solution I;

[0013] Step 2, prepare drug aqueous solution II

[0014] Dissolve 1% (mass fraction) of Poloxamer 188 in 20 ml of 0.01 M HCL to prepare drug aqueous solution II;

[0015] Step 3, prepare PBCA NPs by suspension polymerization

[0016] Add drug aqueous solution I to drug aqueous solution II, shear with a high-speed disperser at 8000 - 15000 rpm for 90 s, and stir on a heatable magnetic stirrer at 600 - 800 rpm for 4 h; neutralize with 0.1 M NaOH solution to stop the polymerization (pH is 6.7 - 7.0), then stir for 1 h, centrifuge at 15000 rpm for 60 min, resuspend and wash with ultrapure water 3 times, and centrifuge at 15000 rpm for 10 min each time to remove the supernatant; after the last wash, obtain NPs, resuspend the NPs in 1% (mass fraction) of trehalose dihydrate and then freeze-dry with a freeze-dryer to finally obtain drug-loaded PBCA NPs.

[0017] Furthermore, in step three, use a precision pH test paper to detect the pH after the polymerization stops. If the solution is overly alkaline and turns pink, use HCL to adjust it back to a pH of 6.7 - 7.0.

[0018] Furthermore, 100 mg of PBCA NPs can be prepared at one time.

[0019] Furthermore, the prepared PBCA NPs have an average particle size of 216 nm, a stable negative surface potential of -22.2 mV, and are safe and non-toxic.

[0020] Furthermore, in step one, the RNA drug is any drug with a molecular size below the nanometer level.

[0021] Furthermore, in step one, the RNA drugs include miR-126-3p antagomir and miR-126-3p.

[0022] On the other hand, the present invention also provides a drug delivery system with the ability of targeted drug delivery within coronary atherosclerotic plaques.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] 1. For the drug carrier system provided by the present invention, during use, PBCA NPs can be used in combination with IVUS. By resonating with the ultrasonic frequency, it has an enhancing effect, thereby improving the resolution of IVUS.

[0025] 2. For the drug carrier system provided by the present invention, during use, PBCA NPs can obtain the ultrasonic radiation force of IVUS, thereby passing through the vascular endothelial gap and entering the atherosclerotic plaque. The polymer hydrolyzes naturally, and the drug encapsulated inside is released, achieving targeted drug delivery. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a schematic diagram of the morphology of the PBCA NPs drug carrier under a transmission electron microscope (scale bar 1 um) in the present invention;

[0027] Figure 2 It is a schematic diagram of the morphology of the PBCA NPs drug carrier under a transmission electron microscope (scale bar 500 nm) in the present invention;

[0028] Figure 3 It is a schematic diagram of the morphology of the PBCA NPs drug carrier under a transmission electron microscope (scale bar 200 nm) in the present invention;

[0029] Figure 4Schematic diagram of the morphology of PBCA NPs drug carriers in the present invention under transmission electron microscopy (scale bar: 100 nm);

[0030] Figure 5 Schematic diagram of the morphology of PBCA NPs drug carriers in the present invention under transmission electron microscopy (scale bar: 50 nm);

[0031] Figure 6 Schematic diagram of the morphology of PBCA NPs drug carriers in the present invention under transmission electron microscopy (scale bar: 50 nm);

[0032] Figure 7 Schematic diagram of the particle size distribution of PBCA NPs drug carriers in the present invention;

[0033] Figure 8 Schematic diagram of the surface potential distribution of PBCA NPs drug carriers in the present invention;

[0034] Figure 9 Schematic diagram of the toxicity detection of PBCA NPs drug carriers in the present invention;

[0035] Figure 10 IVUS ordinary imaging diagram;

[0036] Figure 11 IVUS imaging diagram enhanced by PBCA NPs drug carriers in the present invention;

[0037] Figure 12 IVUS imaging diagram obtained after 1 minute of enhancement by PBCA NPs drug carriers in the present invention;

[0038] Figure 13 Effect diagram of the IVUS-PBCA NPs targeted drug delivery system in the present invention;

[0039] Figure 14 Schematic diagram of the morphology of PBCA NPs loaded with miR-126-3p antagomir in Example 1 under transmission electron microscopy (scale bar: 1 μm);

[0040] Figure 15 Schematic diagram of the morphology of PBCA NPs loaded with miR-126-3p antagomir in Example 1 under transmission electron microscopy (scale bar: 500 nm);

[0041] Figure 16 Schematic diagram of the morphology of PBCA NPs loaded with miR-126-3p antagomir in Example 1 under transmission electron microscopy (scale bar: 200 nm);

[0042] Figure 17Schematic diagram of the morphology of miR-126-3p antagomir-loaded PBCA NPs under transmission electron microscopy in Example 1 (scale bar: 100 nm);

[0043] Figure 18 Schematic diagram of the morphology of miR-126-3p antagomir-loaded PBCA NPs under transmission electron microscopy in Example 1 (scale bar: 50 nm);

[0044] Figure 19 Schematic diagram of the morphology of miR-126-3p antagomir-loaded PBCA NPs under transmission electron microscopy in Example 1 (scale bar: 50 nm);

[0045] Figure 20 Schematic diagram of the particle size distribution of miR-126-3p antagomir-loaded PBCA NPs in Example 1;

[0046] Figure 21 Schematic diagram of the surface potential distribution of miR-126-3p antagomir-loaded PBCA NPs in Example 1. Detailed implementation manners

[0047] To better understand the present invention, the content of the present invention will be further clarified below in conjunction with examples. Obviously, the described examples are only a part of the examples of the present invention, rather than all the examples. All other examples obtained by those of ordinary skill in the art based on the examples of the present invention without making creative efforts belong to the scope of protection of the present invention.

[0048] The PBCA NPs and drug-loaded PBCA NPs involved in the following examples can be prepared by the following methods or other methods.

[0049] 1. Preparation of aqueous drug solution I

[0050] Take 0.5 g of BCA (butyl 2-cyanoacrylate, B895525 Macklin, Shanghai, China) and dissolve it in 20 ml of 0.01 M HCl to prepare aqueous drug solution I.

[0051] 2. Preparation of aqueous drug solution II Dissolve 1% by mass of Poloxamer 188 [poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), P131347 Aladdin, Shanghai, China)] in 20 ml of 0.01 M HCl to prepare aqueous drug solution II.

[0052] 3. Preparation of PBCA NPs by suspension polymerization method

[0053] Add the aqueous drug solution I into the aqueous drug solution II, shear it at 8000 - 15000 rpm for 90 s using a portable high-speed disperser (Model S10, Ningbo Xinzhi), and stir it at 600 - 800 rpm for 4 h on a heatable magnetic stirrer (Model MS-H280-pro, Dailong). Neutralize it with 0.1 M NaOH solution to stop the polymerization (pH 6.7 - 7.0) (detect the pH with a precision pH test paper. If the solution is too alkaline, it will turn pink and need to be adjusted back to pH 6.7 - 7.0 with HCl), and then stir for another 1 h. Centrifuge at 15000 rpm for 60 min, resuspend and wash with ultrapure water 3 times, and centrifuge at 15000 rpm for 10 min each time to remove the supernatant. After the last wash, NPs are obtained. Resuspend the nanoparticles (NPs) in 1% (mass fraction) trehalose dihydrate (Solarbio, G8570, Beijing, China), and then lyophilize them with a freeze dryer to finally obtain the PBCA NPs drug carrier.

[0054] Figure 1-6 This is the morphology of the PBCA NPs drug carrier in the present invention under a transmission electron microscope. It can be seen from Figure 1-6 that PBCA NPs are hollow nanoparticles with a round shape.

[0055] Figure 7 This is the particle size distribution of the PBCA NPs drug carrier in the present invention. It can be seen from Figure 7 that the average particle size of PBCA NPs is about 216 nm, and the particle size distribution is concentrated.

[0056] Figure 8 This is the surface potential distribution of the PBCA NPs drug carrier in the present invention. It can be seen from Figure 8 that PBCA NPs have a stable negative surface potential of -22.2 mV.

[0057] Figure 9 This is the toxicity detection of the PBCA NPs drug carrier in the present invention. Add different concentrations of PBCA NPs (0, 0.1, 0.5, 1, 2, 4, 10 mg / ml respectively) into the well plate. After culturing for 48 hours, the cell survival rate exceeds 100%. It can be seen from Figure 9 that PBCA NPs are safe and non-toxic.

[0058] 4. Implementation of the IVUS-PBCA NPs targeted drug delivery system

[0059] Perform IVUS operation in the porcine aortic blood vessel. Inject 2 ml of PBCA NPs near the imaging catheter through a guiding catheter, keep the imaging catheter in a fixed position, and continue for 1 - 2 minutes.

[0060] Figure 10 This is an ordinary IVUS imaging diagram. Using a porcine aorta as the experimental blood vessel, fresh blood was injected, and IVUS operation was performed. It can be seen from Figure 10 that under ordinary IVUS operation, the imaging is relatively blurred and the blood vessel edge is not clearly shown.

[0061] Figure 11 This is the imaging diagram of IVUS enhanced by PBCA NPs drug carrier in the present invention. Using a porcine aorta as the experimental blood vessel, fresh blood was injected, and PBCA NPs were added before performing the IVUS operation. It can be seen from Figure 11 that under the enhancement of the PBCA NPs drug carrier, the clarity of the image is significantly improved compared with ordinary imaging. Thus, it can be known that the PBCA NPs drug carrier and IVUS can match and resonate, so as to achieve the enhancement effect.

[0062] Figure 12 This is the imaging diagram obtained after 1 minute of continuous enhancement by PBCA NPs drug carrier in the present invention. Using a porcine aorta as the experimental blood vessel, fresh blood was injected, and the PBCA NPs drug carrier was added before performing the IVUS operation, and then the IVUS operation was continued for 1 minute. It can be seen from Figure 12 that after continuous IVUS operation, the enhancement effect in the center of the blood vessel is weakened, but the enhancement effect at the blood vessel edge is further enhanced, and the blood vessel edge is shown more clearly than when PBCA NPs were just added. Thus, it can be seen that the PBCA NPs drug carrier can obtain the ultrasonic radiation force of IVUS, concentrate towards the blood vessel edge, and can penetrate through the endothelial gaps of the blood vessel and enter the blood vessel. When drugs are loaded inside the PBCA NPs, the loaded drugs can be released after the natural hydrolysis of the PBCA NPs, so as to achieve the effect of targeted drug delivery.

[0063] Figure 13 This is the effect diagram of the IVUS-PBCA NPs targeted drug delivery system in the present invention. Drugs are loaded inside the PBCA NPs drug carrier and used in combination with IVUS. The drug-loaded PBCA NPs can obtain ultrasonic radiation force, thus concentrating at the blood vessel edge, penetrating through the endothelial gaps of the blood vessel at the lesion site, entering the lesion site, and then the PBCA NPs are naturally hydrolyzed and the internal drugs are released to achieve targeted drug delivery.

[0064] Example 1

[0065] IVUS-PBCA NPs targeted drug delivery loaded with miR-126-3p antagomir is carried out as follows:

[0066] 1. Prepare drug aqueous solution I

[0067] Take 2 OD (29 * 2 μg) of miR-126-3p antagomir and 0.5 g of BCA (2-cyano-2-butyl acrylate, B895525 Macklin, Shanghai, China) and dissolve them in 20 ml of 0.01 M HCl to prepare aqueous drug solution I.

[0068] 2. Prepare aqueous drug solution II

[0069] Dissolve 1% (mass fraction) of Poloxamer 188 [poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), P131347 Aladdin, Shanghai, China] in 20 ml of 0.01 M HCl to prepare aqueous drug solution II.

[0070] 3. Prepare miR-126-3p antagomir-loaded PBCA NPs by suspension polymerization

[0071] Add aqueous drug solution I to aqueous drug solution II, shear it at 8000 - 15000 rpm for 90 s using a portable high-speed disperser (Model S10, Ningbo Xinzhi), and stir it at 600 - 800 rpm for 4 h on a heatable magnetic stirrer (MS-H280-pro Dalong). Neutralize it with 0.1 M NaOH solution to stop the polymerization (pH 6.7 - 7.0) (detect the pH with a precision pH test paper. If the solution is too alkaline, it will turn pink and needs to be adjusted back to pH 6.7 - 7.0 with HCl), and then stir for 1 h. Centrifuge at 15000 rpm for 60 min, resuspend and wash with ultrapure water 3 times, and centrifuge at 15000 rpm for 10 min each time to remove the supernatant. After the last wash, resuspend the NPs in 1% (mass fraction) of trehalose dihydrate (G8570 Solarbio, Beijing, China) and then freeze-dry with a freeze dryer to finally obtain miR-126-3p antagomir-loaded PBCA NPs.

[0072] Figure 14-19 For the morphology of miR-126-3p antagomir-loaded PBCA NPs in Example 1 under transmission electron microscopy, it can be seen from Figure 14-19 that miR-126-3p antagomir-loaded PBCA NPs are spherical nanoparticles with miR-126-3p antagomir inside.

[0073] Figure 20 For the particle size distribution of miR-126-3p antagomir-loaded PBCA NPs in Example 1, it can be seen from Figure 20It is known that the average particle size of miR-126-3p antagomir-loaded PBCA NPs is about 428 nm, and the particle size distribution is concentrated.

[0074] Figure 21 Figure Figure 21 shows the surface potential distribution of miR-126-3p antagomir-loaded PBCA NPs in Example 1. Figure 21 It can be seen that miR-126-3p antagomir-loaded PBCA NPs carry a stable negative potential of -22.7 mV on the surface.

[0075] 4. IVUS-mediated targeted drug delivery of miR-126-3p antagomir-loaded PBCA NPs

[0076] Perform IVUS operation in the coronary artery. Locate the lesion through IVUS. Inject 2 ml of miR-126-3p antagomir-loaded PBCA NPs near the imaging catheter through the guiding catheter, keep the imaging catheter in a fixed position for 1 - 2 minutes. When injecting miR-126-3p antagomir-loaded PBCA NPs, the IVUS image is enhanced, the resolution for identifying the lesion site is improved. During continuous IVUS operation, providing ultrasonic radiation force, miR-126-3p antagomir-loaded PBCA NPs concentrate towards the vascular margin, penetrate through the vascular endothelial gaps at the lesion site, enter the lesion site, that is, enter the coronary atherosclerotic plaque. Then, PBCA NPs are naturally hydrolyzed, and the internal drug miR-126-3p antagomir is released, achieving targeted drug delivery. Subsequently, miR-126-3p in the plaque is down-regulated, affecting its downstream related factors and proteins, inhibiting angiogenesis, enhancing plaque stability, and achieving the effect of treating coronary atherosclerotic plaques.

[0077] Example 2

[0078] IVUS-mediated targeted gene regulation of miR-126-3p-loaded PBCA NPs is carried out as follows:

[0079] 1. Preparation of drug aqueous solution I

[0080] Take 2 OD (29 * 2 μg) of miR-126-3p and 0.5 g of BCA (2-cyano-2-butyl acrylate, B895525 Macklin, Shanghai, China) and dissolve them in 20 ml of 0.01 M HCl to prepare drug aqueous solution I.

[0081] 2. Preparation of drug aqueous solution II

[0082] Dissolve 1% (mass fraction) of Poloxamer 188 [poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), P131347, Aladdin, Shanghai, China] in 20 ml of 0.01 M HCl to prepare aqueous drug solution II.

[0083] 3. Preparation of miR-126-3p-loaded PBCA NPs by suspension polymerization

[0084] Add aqueous drug solution I to aqueous drug solution II, shear with a hand-held high-speed disperser (Model S10, Ningbo Xinzhi) at 8000 - 15000 rpm for 90 s, and stir on a heatable magnetic stirrer (MS-H280-pro, Dailong) at 600 - 800 rpm for 4 h. Neutralize with 0.1 M NaOH solution to stop the polymerization (pH 6.7 - 7.0) (detect the pH with precision pH test paper. If the solution is too alkaline, it will turn pink and needs to be adjusted back to pH 6.7 - 7.0 with HCl), and then stir for 1 h. Centrifuge at 15000 rpm for 60 min, resuspend and wash with ultrapure water 3 times, and centrifuge at 15000 rpm for 10 min each time to remove the supernatant. After the last wash, resuspend the NPs in 1% (mass fraction) of trehalose dihydrate (G8570, Solarbio, Beijing, China), and then freeze-dry with a freeze dryer to finally obtain miR-126-3p-loaded PBCA NPs.

[0085] 4. Targeted gene regulation of IVUS-miR-126-3p-loaded PBCA NPs

[0086] Perform IVUS operation in the coronary artery. Locate the lesion through IVUS, and inject 2 ml of miR-126-3p-loaded PBCA NPs near the imaging catheter through the guiding catheter, keep the imaging catheter in a fixed position for 1 - 2 minutes. Inject miR-126-3p-loaded PBCA NPs, the IVUS image is enhanced, and the resolution for identifying the lesion site is improved. Continuously perform the IVUS operation to provide ultrasonic radiation force. The miR-126-3p-loaded PBCA NPs concentrate towards the vascular margin, penetrate through the vascular endothelial gaps at the lesion site, and enter the lesion site, that is, enter the coronary atherosclerotic plaque. Then the PBCA NPs are naturally hydrolyzed, and the internal drug miR-126-3p is released to achieve targeted drug delivery. Subsequently, miR-126-3p in the plaque is upregulated, affecting its downstream related factors and proteins, promoting angiogenesis, and achieving the effect of targeted gene regulation.

[0087] Example 3

[0088] Preparation of an enhanced ultrasound contrast agent for improving the resolution of IVUS, and the implementation steps are as follows:

[0089] 1. Preparation of drug aqueous solution I

[0090] Take 0.5 g of BCA (butyl 2-cyanoacrylate, B895525 Macklin, Shanghai, China) and dissolve it in 20 ml of 0.01 M HCL to prepare drug aqueous solution I.

[0091] 2. Preparation of drug aqueous solution II

[0092] Dissolve 1% (by mass) of Poloxamer 188 [poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), P131347 Aladdin, Shanghai, China] in 20 ml of 0.01 M HCL to prepare drug aqueous solution II.

[0093] 3. Preparation of PBCA NPs by suspension polymerization

[0094] Add drug aqueous solution I to drug aqueous solution II, shear it at 8000 - 15000 rpm for 90 s using a portable high-speed disperser (Model S10, Ningbo Xinzhi), and stir it at 600 - 800 rpm for 4 h on a heatable magnetic stirrer (MS-H280-pro Dalong). Neutralize it with 0.1 M NaOH solution to stop the polymerization (pH 6.7 - 7.0) (detect the pH with a precision pH test paper. If the solution is overly alkaline, it will turn pink and needs to be adjusted back to pH 6.7 - 7.0 with HCL), and then stir for 1 h. Centrifuge at 15000 rpm for 60 min, resuspend and wash with ultrapure water 3 times, each time centrifuging at 15000 rpm for 10 min to remove the supernatant. After the last wash, resuspend the NPs in 1% (by mass) of trehalose dihydrate (G8570 Solarbio, Beijing, China) and then freeze-dry with a freeze dryer to finally obtain PBCA NPs.

[0095] 4. IVUS-PBCA NPs ultrasound enhancement

[0096] Perform an IVUS operation in the coronary artery. Locate the lesion through IVUS, inject 2 ml of PBCA NPs through the guiding catheter near the imaging catheter, keep the imaging catheter in a fixed position for 1 - 2 minutes. The IVUS image is enhanced, the resolution for identifying the lesion site is improved, which is beneficial for distinguishing the stability of plaques and guiding clinical treatment.

[0097] In Example 1, the targeted drug delivery of IVUS-PBCA NPs can achieve similar effects by loading other drugs, not limited to miR-126-3p antagomir; the administration site can be other sites, not limited to the coronary artery.

[0098] In Example 2, the gene regulation of IVUS-PBCA NPs can achieve similar effects by loading other drugs, not limited to the gene regulation of miR-126-3p; the regulation site can be other sites, not limited to the coronary artery.

[0099] In Example 3, IVUS is enhanced by PBCA NPs, and similar nanoparticles can also achieve similar effects, not limited to the polymers of bca, but also other types of nanoparticles.

[0100] Finally, it should be noted that the above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, for those skilled in the art, without departing from the creative concept of the present invention, they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A preparation method of a drug-loaded system with the ability of targeted drug delivery within coronary atherosclerotic plaques, characterized in that, The specific steps are as follows: Step 1: Prepare drug aqueous solution Ⅰ Take 2 OD of RNA drug miR-126-3p antagomir and 0.5 g of BCA and dissolve them in 20 ml of 0.01 M HCl to prepare drug aqueous solution Ⅰ; Step 2: Prepare drug aqueous solution Ⅱ Dissolve 1% (mass fraction) of Poloxamer 188 in 20 ml of 0.01 M HCl to prepare drug aqueous solution Ⅱ; Step 3: Prepare PBCA NPs by suspension polymerization Add drug aqueous solution Ⅰ to drug aqueous solution Ⅱ, shear with a high-speed disperser at 8000 - 15000 rpm for 90 s, and stir on a heatable magnetic stirrer at 600 - 800 rpm for 4 h; neutralize with 0.1 M NaOH solution to stop the polymerization, with the pH being 6.7 - 7.0, then stir for another 1 h, centrifuge at 15000 rpm for 60 min, resuspend and wash with ultrapure water 3 times, and centrifuge at 15000 rpm for 10 min each time to remove the supernatant; after the last wash, obtain NPs, resuspend the NPs in 1% (mass fraction) of trehalose dihydrate and then freeze-dry with a freeze dryer. Finally, prepare drug-loaded PBCA NPs, which are used in combination with IVUS, penetrate through the vascular endothelial space, and enter the atherosclerotic plaque to achieve targeted drug delivery.

2. The preparation method of a drug delivery system with the ability of targeted drug delivery within coronary atherosclerotic plaques according to claim 1, characterized in that, In Step 3, use a precision pH test paper to detect the pH after stopping the polymerization. If the solution is too alkaline, it will turn pink, and HCl needs to be used to adjust it back to pH 6.7 - 7.

0.

3. The preparation method of a drug-loading system with the ability of targeted drug delivery within coronary atherosclerotic plaques according to claim 1, wherein: 100 mg of PBCA NPs can be prepared at one time.

4. The preparation method of a drug-loading system with the ability of targeted drug delivery within coronary atherosclerotic plaques according to claim 1, wherein: The prepared PBCA NPs have an average particle size of 216 nm, a stable negative surface potential of -22.2 mV, and are safe and non-toxic.

5. A drug delivery system with the ability of targeted drug delivery within coronary atherosclerotic plaques prepared by the method according to any one of claims 1 - 4.

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