CN111617034A

CN111617034A - Local delivery nano preparation for inhibiting radio frequency ablation heart tissue inflammation and preparation method and application thereof

Info

Publication number: CN111617034A
Application number: CN202010528365.7A
Authority: CN
Inventors: 刘晔; 胥玲玲; 刘小青; 杨新春; 李舟
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-06-11
Filing date: 2020-06-11
Publication date: 2020-09-04
Anticipated expiration: 2040-06-11
Also published as: CN111617034B

Abstract

The invention belongs to the field of nano-drug preparations, and particularly relates to a nano-preparation capable of being locally delivered and used for inhibiting radio frequency ablation cardiac tissue inflammation, and a preparation method and application thereof. The nano-preparation comprises a nano-carrier and fat-soluble glucocorticoid encapsulated in the nano-carrier, wherein the fat-soluble glucocorticoid is included in the nano-preparation in a therapeutically effective amount, so that the nano-preparation can inhibit radio frequency ablation cardiac tissue inflammation. The PLGA-BUD-CS nanoparticles provided by the preferred embodiment of the invention can stably exist in water to form uniform suspension, local delivery of the inner wall of a heart cavity can be realized through a radio frequency ablation catheter, the fat solubility of budesonide ensures that enough medicaments can enter local tissues to play an anti-inflammatory role, and the PLGA ensures that the residence time of the medicaments in the tissues is longer.

Description

Local delivery nano preparation for inhibiting radio frequency ablation heart tissue inflammation and preparation method and application thereof

Technical Field

The invention relates to the field of medicines, in particular to a nano preparation capable of being locally delivered and used for inhibiting radio frequency ablation cardiac tissue inflammation, and a preparation method and application thereof.

Background

Atrial fibrillation can significantly increase the risk of ischemic stroke and arterial embolism, where ablation for symptomatic paroxysmal atrial fibrillation has entered category I indications. The radiofrequency ablation has more exact effect on arrhythmia of paroxysmal supraventricular tachycardia, ventricular or atrial premature beat and the like. During radiofrequency ablation, effective release of radiofrequency energy and the size of a damaged area are crucial to the success of the surgery. Catheter stability, contact pressure, energy output, temperature and ablation time are important factors in determining lesion extent and transmural conditions.

Infiltration of inflammatory cells and inflammatory factor release response are closely related to the occurrence of atrial fibrillation. The radiofrequency energy causes thermal damage to the myocardium, and after the damage occurs, the myocardial cells develop edema and inflammatory responses. When edema occurs, local cardiac muscle becomes relatively thick, and the electrical resistance of the portion of the ablation catheter in contact with the cardiac tissue changes, thereby affecting the effect of the injury caused by ablation. Acute inflammation occurs after myocardial cell injury, affecting the stability of myocardial electrical activity, which is associated with the occurrence of post-operative arrhythmias and early recurrence of atrial fibrillation. The control of cell edema and inflammatory reaction generated after ablation is beneficial to improving the damage efficiency of radiofrequency ablation energy and improving the early success rate of ablation.

The most direct and effective method for controlling inflammation and edema is the use of anti-inflammatory drugs, and a great deal of research has been conducted to reduce the post-radiofrequency ablation inflammatory response via peripheral veins or oral glucocorticoids. The use of anti-inflammatory agents may reduce the recurrence of early atrial fibrillation, which may include longer survival without atrial fibrillation, improved electrical and structural remodeling, lower acute inflammatory response and less edema, and also delay scarring for tissue repair by inhibiting fibroblast proliferation. The use of the anti-inflammatory drug can find dormant pulmonary vein connection which is not ablated, reduce gaps among ablation points and improve the ablation success rate.

The anti-inflammatory drugs used in the research are directly administrated intravenously or orally, the required dosage is large, and meanwhile, the systemic application has large adverse reactions, such as gastrointestinal reaction, infection induction or aggravation, blood sugar rise, aggravation of the ulcer-causing effect of the non-steroidal drugs and the like.

Glucocorticoids have a strong anti-inflammatory effect and are often used in the treatment of inflammatory responses caused by various causes, such as immunity, injury, etc. Glucocorticoids can be classified as water-soluble and lipid-soluble. The fat-soluble glucocorticoid can better enter local tissues to exert the effect, but can only be administrated by adopting the modes of external application, atomization inhalation and the like because the glucocorticoid cannot be dissolved in water. Water-soluble glucocorticoids are usually administered systemically and have a higher incidence of systemic side effects.

Disclosure of Invention

In view of the deficiencies of the prior art, it is an object of the present invention to provide a locally deliverable nanopreparative for inhibition of radiofrequency ablation of inflammation of cardiac tissue; it is another object of the present invention to provide a method for preparing a locally deliverable nano-formulation for inhibiting inflammation in radiofrequency ablated cardiac tissue; still another object of the present invention is to provide a use of a fat-soluble anti-inflammatory drug for preparing a nano formulation for inhibiting radiofrequency ablation of cardiac tissue, which can be locally delivered.

In order to achieve the above objects, in one aspect, the present invention provides a locally deliverable nano-formulation for inhibiting radio frequency ablation cardiac tissue inflammation, the nano-formulation comprising a nano-carrier and a fat-soluble glucocorticoid encapsulated in the nano-carrier, preferably, the fat-soluble glucocorticoid is included in the nano-formulation in a therapeutically effective amount, so that the nano-formulation can inhibit radio frequency ablation cardiac tissue inflammation.

The local delivery of the invention means that the effective components of the medicine only enter local tissues along with the saline infusion of the radio frequency catheter, the effect is generated locally, the part entering the blood circulation can be quickly removed, and the generated hormone has small systemic reaction.

The therapeutically effective amount of the composition is the amount of the medicament which is used by the fat-soluble glucocorticoid to inhibit the radiofrequency ablation heart tissue inflammation.

The heart tissue refers to a heart part which can be damaged by radiofrequency ablation heat energy, and more specifically, the heart tissue refers to heart cavity myocardial tissue which is damaged by the radiofrequency ablation heat energy. The heart tissue inflammation refers to the heart cavity myocardial tissue inflammation swelling, bleeding or edema damaged by radiofrequency ablation heat.

The fat-soluble glucocorticoid provided by the invention is dissolved in a non-polar solvent, and the higher the fat solubility of the glucocorticoid is, the easier the glucocorticoid can penetrate through cell membranes on cardiac myocardium of a heart cavity to reach cytoplasm, so that a better anti-inflammatory effect is obtained.

Further, the fat-soluble glucocorticoid is selected from one or more of hydrocortisone, prednisone, dexamethasone, budesonide, methylprednisolone, betamethasone and beclomethasone dipropionate; according to a particular embodiment provided by the present invention, the fat-soluble glucocorticoid is budesonide.

Budesonide, as a fat-soluble glucocorticoid, has a strong local anti-inflammatory effect, has a high liver first-pass metabolic effect (about 90 percent) in the metabolic process of an organism, has few systemic reactions, is very suitable for local administration, and currently, local delivery of aqueous suspension or aqueous sol of budesonide is not adopted to inhibit tissue inflammation in the heart radiofrequency ablation. According to the invention, the stability of the budesonide in the aqueous solution can be improved by adopting the nano carrier for entrapment, and the local delivery of the budesonide on the heart wall is realized.

The nano preparation is prepared by processing fat-soluble glucocorticoid by adopting a nano carrier, and is a medicine particle with the particle size of 1-1000 nm; further, the particle size of the nano preparation is 10-1000 nm; furthermore, the particle size of the nano preparation is 10-300nm, the particle size of the PLGA-BUD-CS nano particle improved in the specific embodiment of the invention is about 100nm, and stability tests prove that the obtained nano particle can stably exist in water and can realize the local delivery of the cardiac wall of the budesonide.

Further, the nano-formulation can be stably present in an aqueous carrier; preferably, the aqueous carrier is normal saline.

It is understood that the nanoformulation of the present invention may also include an aqueous carrier, including but not limited to, physiological saline.

Further, the nano preparation is aqueous sol or suspension; preferably, the drug content in the aqueous sol or suspension is 1-2mg/100 mL.

Wherein, it is understood that the nano-preparation of the present invention can exist stably in an aqueous carrier, which means that the nano-preparation can be suspended stably in water without agglomeration or with little agglomeration. According to the experiment of the specific embodiment of the invention, the finally obtained nano preparation can obtain satisfactory suspension effect without using a stabilizer or other auxiliary agents, but the nano preparation can not be used together with pharmaceutical auxiliary materials on the basis of the consideration, and the appropriate pharmaceutical auxiliary materials can be added according to the performance requirements in order to enhance the performance of a certain aspect of the nano preparation.

Further, the nano-preparation is selected from one or more of liposome preparation, nano-particle preparation and nano-micelle preparation; the present invention provides specific embodiments of nanoparticle formulations or liposomal formulations; preferably, the nano-formulation is a nano-particle formulation.

Further, the nano-carrier comprises one or more of polysaccharide, protein, polypeptide, phospholipid and block copolymer, preferably the nano-carrier is a block copolymer, and more preferably the nano-carrier is polylactic-co-glycolic acid.

In a specific embodiment provided by the present invention, the mass ratio of polylactic acid to glycolic acid in the polylactic-glycolic acid copolymer is 50: 50. the molecular weight of the polylactic-co-glycolic acid is 40000 Da.

Polylactic-co-glycolic acid (PLGA) is a synthetic degradable biological material, has good biological safety and is approved to be used as a pharmaceutical adjuvant. The drug-loaded PLGA nanoparticles obtained by using PLGA to encapsulate budesonide are hundred-nanometer particles with uniform particle size and can be stable in aqueous solution for a long time. The catheter is injected into local myocardial tissues during myocardial ablation to play an anti-inflammatory role, so that the dosage entering the tissues is increased, the retention time of the medicine is prolonged, the high first-pass effect is kept, the dosage entering the circulation of a human body is reduced, and the adverse reaction of the medicine is relieved.

In a specific embodiment of the invention, the nanoformulation can be delivered to the local myocardium by an ablation catheter.

In another aspect, the present invention provides a method for preparing a locally deliverable nano-formulation for inhibiting inflammation in radiofrequency ablated cardiac tissue, the nano-formulation being as described above, comprising the steps of:

s1: dissolving budesonide and polylactic-co-glycolic acid (PLGA) in chloroform to obtain a mixed solution;

s2: adding a polyvinyl alcohol aqueous solution into the mixed solution obtained in the step S1, stirring, and carrying out ultrasonic crushing to obtain a uniform emulsion;

s3: evaporating the uniform emulsion obtained in the step S2 under reduced pressure to remove trichloromethane to obtain a suspension;

s4: centrifuging the suspension obtained in the step S3 to remove free budesonide to obtain a budesonide-polylactic-co-glycolic acid copolymer nanoparticle solution;

s5: and dispersing the budesonide-polylactic acid-glycolic acid copolymer nanoparticle solution obtained in the step S4 in MES buffer solution, adding ethyl dimethyl aminopropyl carbodiimide hydrochloride (EDC) and hydroxysuccinimide (NHS) for activation, adding a chitosan oligosaccharide solution, and centrifuging to obtain the budesonide-polylactic acid-glycolic acid copolymer nanoparticles (PLGA-BUD-CS).

In still another aspect, the present invention provides a use of a fat-soluble anti-inflammatory drug in the preparation of a nano-formulation for local delivery for inhibiting radiofrequency ablation cardiac tissue inflammation, which is used for inhibiting the inflammation of the endocardial wall tissue caused by thermal injury in the radiofrequency ablation of a mammal, wherein the fat-soluble glucocorticoid is encapsulated in a nano-carrier to form the nano-formulation, and the nano-formulation is as described above; preferably, the nano-formulation is a nanoparticle formulation, a liposome formulation or a nano-micelle formulation; more preferably, the nano-formulation is a nano-particle formulation.

Preferably, the mammal of the present invention is a human.

In the present invention, a fat-soluble glucocorticoid is included in the nano-formulation in a therapeutically effective amount such that the fat-soluble glucocorticoid is capable of inhibiting tissue inflammation caused by ablation damage at a local delivery site.

Further, the fat-soluble glucocorticoid is selected from one or more of hydrocortisone, prednisone, dexamethasone, budesonide, methylprednisolone, betamethasone and beclomethasone dipropionate, and preferably, the fat-soluble glucocorticoid is budesonide.

Further wherein the nanoformulation is delivered to local myocardium by an ablation catheter; preferably, the nano-formulation is delivered to the local myocardium through the ablation catheter while perfusing cold saline, more preferably, the nano-formulation is delivered to the local myocardium through the ablation catheter while perfusing cold saline during and after the ablation procedure.

During the process of radio frequency ablation, the used radio frequency ablation catheter needs to be locally perfused with cold saline. The nanometer preparation containing fat-soluble glucocorticoid is added into the saline water to enter the local myocardial tissue of the heart cavity wall at the ablation part, so that the tissue edema generated in the ablation process is reduced, the local hemorrhage is reduced, the ablation effectiveness can be improved, and the occurrence of postoperative arrhythmia is reduced.

The technical scheme of the invention has the following advantages: the PLGA-BUD-CS nanoparticles provided by the preferred embodiment of the invention can stably exist in water, can form uniform suspension, can realize local delivery of cardiac chamber myocardium through a radio frequency ablation catheter, and can achieve the effect of inhibiting inflammation, edema and hemorrhage of cardiac myocardium tissue of radio frequency ablation heart when a small amount of drugs are used. PLGA makes the medicine stay in tissue for a longer time, has slow release effect, and the chitosan oligosaccharide has broad-spectrum antibacterial effect and regulates normal immune function. The fat solubility of budesonide ensures that enough medicine enters local tissues, quickly and continuously plays a local anti-inflammatory effect, and simultaneously avoids the risk of large side effect caused by oral administration and other systemic administration.

Drawings

FIG. 1 is a flow chart of the preparation of budesonide-PLGA nanoparticles;

FIG. 2 is a scanning electron micrograph of nanoparticles prepared;

FIG. 3 is a stability characterization of nanoparticles in PBS buffer;

FIG. 4 is a partial schematic view of budesonide nanoparticles used for cardiac ablation;

FIG. 5 is a diagrammatic illustration of a myocardial ablation procedure;

FIG. 6 is a swine M-mode echocardiogram after volume ablation;

FIG. 7 is a graph of left ventricular ejection fraction;

FIG. 8 is a three-day postoperative slice of myocardial tissue at an ablation site;

FIG. 9 is a graph depicting postoperative, IL-6, IL-8, IL-10, TNF- α, and CRP inflammatory factor characterization vs;

in the figure, 1, a trichloromethane solution 2 of budesonide and PLGA, an ultrasonic probe 3, a 2% PVA solution 4, an ice bath device 5, an emulsion 6 after ultrasonic treatment, nanoparticles 7 after rotary evaporation and centrifugation, a nanoparticle drug-coated schematic diagram 8, an ablation catheter 9, a drug-containing physiological saline 10, a cardiac muscle 11 and an uptake nanoparticle.

Detailed Description

The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials in the following examples are all commercially available products and are commercially available, unless otherwise specified. The present invention is described in further detail below with reference to examples:

example 1: preparation method of PLGA-BUD-CS nanoparticles

Fig. 1 provides a preparation flow chart of PLGA-BUD nanoparticles, specifically, the preparation method of PLGA-BUD-CS nanoparticles comprises: 1.5mg of Budesonide (BUD) and 10mg of PLGA were dissolved in 0.5mL of chloroform, added to 8mL of a 2% aqueous polyvinyl alcohol solution and stirred for 30 minutes, followed by ultrasonication with 150w of ultrasound for 5 minutes to form a homogeneous emulsion. Chloroform was removed by rotary evaporation at 40 ℃ to give a suspension. 17800g, centrifuging for 30min to remove free drug in the supernatant, and obtaining BUD-PLGA nanoparticle solution. The prepared nanoparticles were weighed and dispersed in MES buffer (0.1mmol/L, pH5.5) to a final concentration of 0.5mg/mL, and ethyldimethylaminopropylcarbodiimide hydrochloride (EDC) (0.2mg/mL) and hydroxysuccinimide (NHS) (0.4mg/mL) were added to activate the reaction for 3 hours. Dissolving chitosan oligosaccharide in acetic acid solution with pH of 4 to the concentration of 0.2mg/mL, adding the prepared chitosan oligosaccharide (CS) solution into the nanoparticle solution to the final concentration of 0.1mg/mL, stirring and reacting for 12h at room temperature, centrifuging to obtain PLGA-BUD-CS, and taking a picture of the prepared PLGA-BUD-CS by a scanning electron microscope, wherein the picture of the electron microscope is shown in figure 2, and the picture in figure 2 shows that the monodisperse complete nanoparticles with the particle size of about 100nm are prepared.

And (3) carrying out a stability test on the obtained PLGA-BUD-CS nanoparticles to verify the stability of the nanoparticles, and setting PLGA for comparison in the test. The method for stability test is as follows: nanoparticle stability was analyzed using a Turbiscan stability analyzer. Adding 2mL of physiological saline solution containing 0.1mg/mL of PLGA and 2mL of physiological saline solution containing 0.1mg/mL of PLGA-BUD-CS nanoparticles into a matched measuring cell, measuring the change of transmission light and backscattering intensity for three days, and processing by software to obtain the TSI stability index.

The stability data of the PLGA-BUD-CS nanoparticles and the cardiac chamber are plotted by taking time as a horizontal coordinate and a turbidity stability index TSI as a vertical coordinate, and the result is shown in figure 3, and as can be seen from figure 3, the PLGA-BUD-CS nanoparticles are slightly poor in stability relative to a PLGA control group, but have better stability, which indicates that the PLGA-BUD-CS nanoparticles can stably exist in a physiological saline solution and can be injected into the cardiac chamber through an ablation catheter.

Example 2: budesonide liposome construction

DPPC, PEG-DSPE and total cholesterol in a mass ratio of 1.85: 0.15: 1 into a 50mL round bottom flask, 10mL absolute ethanol was added, heated to 50 ℃ in a water bath until completely dissolved, and ethanol was removed by rotary evaporation to give a dry liposome membrane, which was then dried for 30min under a stream of nitrogen. Heating 100mg/mL budesonide phosphate aqueous solution to 50 ℃, adding the heated budesonide phosphate aqueous solution into a liposome membrane at 50 ℃ for 5-10 minutes of rotary hydration to obtain liposomes with uneven particle sizes, injecting into a polycarbonate liposome extruder with a pore size of 200nm five times, and repeatedly injecting into a polycarbonate liposome extruder with a pore size of 100nm five times to obtain liposome particles with uniform particle sizes. The solution was dialyzed in a dialysis bag of MWCO 30000Da at 4-8 deg.C for 48 hours to remove free drug. Finally obtaining the budesonide liposome solution.

Example 3: construction of budesonide albumin nanoparticles

Chloroform and ethanol mixed solvent (11:1, v/v) is used as solvent, and is added into 1% w/v Bovine Serum Albumin (BSA) solution (BUD: BSA 1:1) with different molar ratios, and the BSA solution is pre-saturated by 1% chloroform. Then, the system is subjected to ultrasonic treatment for 5min (at an interval of 1s), and then the system is transferred to a rotary evaporator to remove chloroform at 30 ℃ to prepare the BUD-BSA nano-particles.

Example 4: PLGA-BUD-CS nanoparticles for simulating atrial fibrillation radio frequency ablation drug delivery

Fig. 4 and 5 provide a schematic illustration of a local part and a schematic illustration of an operation of budesonide nanoparticles for cardiac ablation, and the specific test steps are as follows:

45-55kg of Bama miniature pig for Chinese experiment, and a control group: radiofrequency ablation + saline perfusion; experimental groups: radiofrequency ablation + saline infusion + PLGA-BUD-CS (Bud 8mg + NS500 mL). Preoperative diet was prohibited for 24h, the back, the chest was preserved, phenobarbital 25mg/kg was used for general anesthesia, and mechanical ventilation was performed. Two 8F sheaths are placed through the right femoral vein and a 6F sheath is placed through the right internal jugular vein. The 10-pole coronary sinus electrode is placed into the coronary sinus from the right internal jugular vein. The atrial septum is punctured and 100IU/kg heparin is added for anticoagulation. Left and right atrial modeling was performed using the Pentaray mapping electrode row under the direction of the CARTO 3 system. Linear ablation was performed in left and right atrial rows using a 56-hole STSF ablation catheter, with a saline infusion rate of 2mL/min (no discharge), 25mL/min (discharge) power set at 35w, and an Ablation Index (AI) of 400-.

The method comprises the following specific steps of filling saline containing the medicine: PLGA-BUD-CS was added to the saline used for ablation so that the nanoparticles could enter the local myocardium with the perfused saline, as shown in fig. 4.

As shown in FIG. 5, the ablation catheter was connected to a flow pump with 500mL of saline, which was infused through the orifice of the ablation catheter to the local myocardium via the flow pump.

The flow pump can set the flow rate, and the radio frequency energy is distributed through the radio frequency instrument.

The saline infusion starts 2 seconds before the radiofrequency ablation discharge and stops after the discharge is finished.

The flow pump can also be used for directly carrying out saline infusion independently of radio frequency discharge.

Record impedance, temperature, ablation time, AI during the ablation process. After the operation of the heart color ultrasound, rivaroxaban is orally taken for 10mg per day for anticoagulation 4 hours after the operation is finished.

Fig. 6 is an M-mode echocardiogram after the pig is ablated, fig. 7 is a left ventricular ejection fraction chart, the control group is ablated by pure normal saline, and the experimental group is normal saline containing PLGA-BUD-CS. As can be seen from FIG. 6 and FIG. 7, the experimental group and the control group have no significant difference, and have no difference with the heart function of healthy pigs. The nano-particle medicinal preparation has no obvious influence on the cardiac function and good biological safety in cardiac ablation administration.

Fig. 8 is a section of local tissue of ablated myocardium three days after operation, and it can be seen that the control group has obvious diffuse hemorrhagic edema, in contrast, the experimental group has obviously reduced hemorrhagic edema, which indicates that the nanoparticle pharmaceutical preparation can effectively reduce postoperative local hemorrhage and edema.

FIG. 9 shows the postoperative characteristics of IL-6, IL-8, IL-10, TNF-alpha and CRP inflammatory factors, and it can be seen from FIG. 9 that various inflammatory factors are significantly reduced compared with the control group, indicating that the budesonide nanoparticles can effectively inhibit inflammatory reaction.

Claims

1. A locally deliverable nanoformulation for inhibiting inflammation in radio frequency ablated cardiac tissue, comprising a nanocarrier and a fat soluble glucocorticoid entrapped in the nanocarrier, preferably the fat soluble glucocorticoid is comprised in the nanoformulation in a therapeutically effective amount such that the nanoformulation is capable of inhibiting inflammation in radio frequency ablated cardiac tissue.

2. The locally deliverable nanopreparation for inhibiting inflammation in radiofrequency ablated cardiac tissue according to claim 1, wherein the lipid soluble glucocorticoid is selected from one or more of hydrocortisone, prednisone, dexamethasone, budesonide, methylprednisolone, betamethasone and beclomethasone dipropionate; preferably, the fat-soluble glucocorticoid is budesonide.

3. The locally deliverable nano-formulation for inhibiting inflammation in radiofrequency ablated cardiac tissue according to claim 1, wherein the nano-formulation is selected from one or more of a nano-liposome formulation, a nano-particle formulation and a nano-micelle formulation; preferably, the nano-formulation is a nano-particle formulation.

4. The locally deliverable nano-formulation for inhibiting inflammation in radiofrequency ablated cardiac tissue according to any one of claims 1 to 3, wherein the particle size of the nano-formulation is in the range of 10 to 1000 nm; preferably, the particle size of the nano-formulation is 10 to 300 nm.

5. The locally deliverable nanopreparation for inhibiting radio frequency ablation cardiac tissue inflammation as claimed in claim 1, wherein the nanopreparation is capable of being stably present in an aqueous carrier; preferably, the aqueous carrier is normal saline.

6. The locally deliverable nano-formulation for inhibiting inflammation in radiofrequency ablated cardiac tissue according to claim 1 or 5, wherein the nano-formulation is an aqueous sol or suspension; preferably, the drug content in the aqueous sol or suspension is 1-2mg/100 mL.

7. The locally deliverable nano-formulation for inhibiting inflammation in radiofrequency ablated cardiac tissue according to claim 1, 2, 3 or 5, wherein the nano-carrier comprises one or more of a polysaccharide, a protein, a polypeptide, a phospholipid and a block copolymer, preferably the nano-carrier is a block copolymer, more preferably the nano-carrier is a poly (lactic-co-glycolic acid).

8. The locally deliverable nano-formulation for inhibiting inflammation in radiofrequency ablated cardiac tissue according to claim 7, wherein the polylactic-co-glycolic acid has a polylactic-co-glycolic acid mass ratio of polylactic acid to glycolic acid of 50: 50.

9. the locally deliverable nano-formulation for inhibiting inflammation in radiofrequency ablated cardiac tissue according to claim 7 or 8, wherein the molecular weight of the poly (lactic-co-glycolic acid) is 40000 Da.

10. The locally deliverable nanoparticies for inhibiting inflammation in radiofrequency ablated cardiac tissue according to claim 1, 2, 3, 5 or 8, wherein the nanoparticies are deliverable to the local myocardium via an ablation catheter.

11. A method of preparing a locally deliverable nanopreparative for inhibiting inflammation in radiofrequency ablated cardiac tissue, comprising the steps of:

s1: dissolving budesonide and polylactic-co-glycolic acid in chloroform to obtain a mixed solution;

s5: and dispersing the budesonide-polylactic acid-glycolic acid copolymer nanoparticle solution obtained in the step S4 in MES buffer solution, adding ethyl dimethyl aminopropyl carbodiimide hydrochloride and hydroxysuccinimide for activation, adding a chitosan oligosaccharide solution, and centrifuging to obtain the budesonide-polylactic acid-glycolic acid copolymer nanoparticles.

12. Use of a lipid-soluble glucocorticoid for the preparation of a locally deliverable nano-formulation for inhibiting inflammation in radiofrequency ablated cardiac tissue, for inhibiting inflammation in the endocardial wall tissue caused by thermal injury in a mammal undergoing radiofrequency ablation, wherein the lipid-soluble glucocorticoid is formulated as a nano-formulation by entrapment in a nano-carrier, the nano-formulation being as defined in any one of claims 1 to 10.

13. The use according to claim 12, wherein the nano-formulation is a nanoparticle formulation, a liposomal formulation, or a nano-micelle formulation; more preferably, the nano-formulation is a nano-particle formulation.

14. Use according to claim 12, wherein the fat-soluble glucocorticoid is selected from one or more of hydrocortisone, prednisone, dexamethasone, budesonide, methylprednisolone, betamethasone and beclomethasone dipropionate, preferably wherein the fat-soluble glucocorticoid is budesonide.

15. Use according to claim 12, wherein the nanocarrier comprises one or more of a polysaccharide, a protein, a polypeptide, a phospholipid and a block copolymer, preferably wherein the nanocarrier is a block copolymer, more preferably wherein the nanocarrier is a poly (lactic-co-glycolic acid).

16. The use of claim 12, wherein the nanoformulation is delivered to local myocardium by an ablation catheter; preferably, the nano-formulation is delivered to the local myocardium through the ablation catheter while perfusing cold saline, more preferably, the nano-formulation is delivered to the local myocardium through the ablation catheter while perfusing cold saline during and after the ablation procedure.