CN116850147B - PPC nano-particles, preparation method thereof and application thereof in medicines for treating myocardial infarction - Google Patents
PPC nano-particles, preparation method thereof and application thereof in medicines for treating myocardial infarction Download PDFInfo
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- CN116850147B CN116850147B CN202310652127.0A CN202310652127A CN116850147B CN 116850147 B CN116850147 B CN 116850147B CN 202310652127 A CN202310652127 A CN 202310652127A CN 116850147 B CN116850147 B CN 116850147B
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- ppc
- polydopamine
- prussian blue
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 168
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- 229940079593 drug Drugs 0.000 title abstract description 6
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- 239000013225 prussian blue Substances 0.000 claims abstract description 50
- 229920001690 polydopamine Polymers 0.000 claims abstract description 48
- 229910000420 cerium oxide Inorganic materials 0.000 claims abstract description 37
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- DCYOBGZUOMKFPA-UHFFFAOYSA-N iron(2+);iron(3+);octadecacyanide Chemical compound [Fe+2].[Fe+2].[Fe+2].[Fe+3].[Fe+3].[Fe+3].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] DCYOBGZUOMKFPA-UHFFFAOYSA-N 0.000 claims abstract 9
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The application discloses a PPC nanoparticle, a preparation method thereof and application thereof in medicines for treating myocardial infarction, wherein the PPC nanoparticle has a size of 200-300nm and comprises a polydopamine nanoparticle and a load loaded on the surface of the polydopamine nanoparticle, the load comprises Prussian blue nanoparticles and cerium oxide nanoparticles, and the Prussian blue nanoparticles and the cerium oxide nanoparticles are randomly distributed. The PPC nanoparticle provided by the application can locate infarcted myocardial mitochondria, can be used for converting O 2 ·‑ into nontoxic O 2 and H 2 O through the catalytic action of SOD and CAT enzyme, can be used for converting OH into O 2 through the special form of reversible conversion from 3-valent cerium to 4-valent cerium in cerium oxide, has no toxic byproducts, and can be applied to medicaments for treating myocardial infarction.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a PPC nanoparticle, a preparation method thereof and application thereof in medicines for treating myocardial infarction.
Background
Myocardial infarction has become one of the leading causes of morbidity and mortality worldwide. The treatment effect of the existing treatment methods such as medicaments and vascular reconstruction treatment is limited, and the death rate of more than 10% after 5 years. Therefore, the search for a more effective measure for improving myocardial blood supply is a major breakthrough problem in the current coronary heart disease therapeutic research.
Persistent hypoxia is considered to be the leading cause of heart failure following myocardial infarction. Oxygen plays a key role in maintaining normal function of cardiomyocytes and promoting myocardial repair. In recent years, oxygen delivery to infarcted myocardium has been focused on in an effort to reduce myocardial damage and improve cardiac dysfunction.
The oxygen generating system (Ding J,Yao Y,Li J,et al.A Reactive Oxygen Species Scavenging and O2 Generating Injectable Hydrogel for Myocardial Infarction Treatment In vivo.Small,2020,16(48):e2005038). of the hydrogel synthesized by hyperbranched polymer containing double bond end groups, methacrylic acid modified hyaluronic acid, catalase and photoinitiator is synthesized by the butyl et al, and the hydrogel has the capabilities of scavenging active oxygen and generating oxygen and relieving excessive inflammation and hypoxia after myocardial infarction. However, almost all synthetic nanoenzymes have peroxidase-like activity and may catalyze the production of highly cytotoxic OH by H 2O2, exacerbating tissue damage. The existing nano-enzyme technology is difficult to solve the problem of OH generation.
Disclosure of Invention
The invention provides PPC nano particles, a preparation method thereof and application thereof in medicaments for treating myocardial infarction, and aims to solve the technical problem that the prior art can cause damage to body tissues when relieving hypoxia phenomenon after myocardial infarction.
According to one aspect of the invention, there is provided a PPC nanoparticle having a size of 200-300nm, comprising a polydopamine nanoparticle, and a support supported on the surface of the polydopamine nanoparticle, wherein the support comprises prussian blue nanoparticle and cerium oxide nanoparticle, and the prussian blue nanoparticle and cerium oxide nanoparticle are randomly distributed on the surface of the polydopamine nanoparticle.
Further, the mass ratio of each part in the PPC nano particle is as follows: 80% -90% of polydopamine nano particles; prussian blue nano particles 5-15%; 1-5% of cerium oxide nano particles.
Further, the PPC nano-particles are subjected to surface modification by diamino polyethylene glycol.
According to another aspect of the present invention, there is also provided a method for preparing PPC nanoparticles, comprising the steps of:
(1) Mixing and reacting the polydopamine solution and the Prussian blue solution, wherein the mass ratio of polydopamine to Prussian blue is 1: (5-10), removing impurities to obtain a solution containing polydopamine-Prussian blue nano particles;
(2) Reacting the obtained solution containing the polydopamine-Prussian blue nano particles with Ce (NO 3)3·6H2 O under an acidic condition, wherein the mass ratio of the polydopamine-Prussian blue nano particles to the Ce (NO 3)3·6H2 O) is 1 (15-20), and removing impurities to obtain a solution containing the polydopamine-Prussian blue-cerium oxide nano particles;
(3) Reacting the solution of the obtained polydopamine-Prussian blue-cerium oxide nano particles with NH 2-PEG-NH2 in an organic solvent under alkaline conditions, wherein the mass ratio of the polydopamine-Prussian blue-cerium oxide nano particles to NH 2-PEG-NH2 is 1: (1.1-1.3), removing impurities to obtain PPC nano particles.
Further, the preparation method of the polydopamine solution in the step (1) comprises the following steps: dissolving dopamine hydrochloride in a solvent, and carrying out polymerization reaction under alkaline conditions to obtain a polydopamine solution.
Further, the preparation method of the Prussian blue solution in the step (1) includes: ferric trichloride and potassium ferricyanide are mixed according to the mass ratio of 1: mixing and reacting (1-1.3) in water to obtain Prussian blue solution.
Further, the pH value of the acidic condition in the step (2) is 0.1-3.
Further, the reaction temperature in the step (2) is 25-95 ℃ and the reaction time is 10-60min.
Further, the pH value of the alkaline condition in the step (3) is 7-12.
According to another aspect of the invention, there is also provided an application of the PPC nanoparticle or the PPC nanoparticle prepared by the method in a medicament for treating myocardial infarction.
Further, the PPC nano-particles are dissolved in normal saline to prepare intravenous injection for treating myocardial infarction, and the concentration of the PPC nano-particles intravenous injection is 1-40 ug/mL.
The invention has the following beneficial effects:
Changes in the hypoxic microenvironment after infarction, including reactive oxygen species bursts (e.g., O 2 ·-、H2O2, OH), reduced pH, accumulation of hypoxia products, etc., can cause secondary damage to cells. Melanin effectively eliminates O 2 ·- while producing OH - (formula 1), and has a protective effect in cerebral ischemia diseases. However, natural melanin has a limited yield and limited antioxidant capacity. PB is taken as a strong oxidant, and has the activities of superoxide dismutase and catalase, so that O 2 ·- can be effectively converted into oxygen, and the oxygen-generating capacity and the active oxygen removal capacity are achieved. However, PB also produces toxic by-product OH during the catalysis of O 2 ·- to O 2, which may be related to Fenton's reaction during its catalysis. Excess Prussian blue results in reduced cytotoxicity and oxygen production efficiency. Meanwhile, part of researches show that the oxygen generating capacity of PB is closely related to the change of tissue microenvironment, and PB can generate OH - and OH (formula 2) in an acidic environment, and the OH can cause apoptosis. The cerium oxide nanoparticles can eliminate OH and H 2O2 through oxidation-reduction reaction due to the special existing compound form (reversible conversion of 3 to 4 of cerium), and generate O 2 and H 2 O (formula 3) without toxic and side effects. However, excessive cerium oxide may be somewhat cytotoxic, limiting its further conversion.
Based on the concept of changing the harm into the treasures, the applicant synthesizes PPC nano particles, the PPC is based on the superoxide dismutase enzyme capability of polydopamine to remove O 2 ·- (formula 1), meanwhile, the PB strong catalase capability is combined (formula 2), and the cerium oxide is utilized to quickly utilize and remove OH generated by PB to generate oxygen (formula 3), in addition, OH - released in the chemical reaction process can neutralize the myocardial acid environment under hypoxia, so that good conditions are provided for cell survival.
In addition to the objects, features and advantages described above, the present invention has other objects, features and advantages.
(1)2[O2 ·-]+2H2O→O2+H2O2+2[OH-]
2[OH-]+2[H+]→2H2O
(2)
H2O2→[·OH]+[OH-]
[OH-]+[H+]→H2O
(3)2Ce3++2[·OH]+2[H+]→2Ce4++2H2O
2Ce4++H2O2→2Ce3++2[H+]+O2
The present invention will be described in further detail with reference to the drawings.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention. In the drawings:
FIG. 1 is a reaction scheme of PPC nanoparticles of a preferred embodiment of the present invention;
fig. 2 is a transmission electron microscope image of PPC nanoparticles of a preferred embodiment of the present invention.
FIG. 3 is a graph of an O 2 ·- scavenging capacity test of PPC nanoparticles of a preferred embodiment of the present invention;
FIG. 4 is a biosafety test chart of PPC nanoparticles of a preferred embodiment of the present invention;
FIG. 5 is a graph of a hemolysis assay test of PPC nanoparticles of a preferred embodiment of the present invention;
FIG. 6 is a plot of PPC nanoparticle in vivo for a PPC nanoparticle of a preferred embodiment of the present invention;
FIG. 7 is a graph of a PPC nanoparticle therapeutic efficacy evaluation test according to a preferred embodiment of the present invention;
fig. 8 is a graph showing the therapeutic effect of PPC nanoparticles according to a preferred embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantageous technical effects of the present invention clearer, the present invention will be further described in detail with reference to examples. It should be understood that the examples described in this specification are for the purpose of illustrating the invention only and are not intended to limit the invention.
For simplicity, only a few numerical ranges are explicitly disclosed herein. However, any lower limit may be combined with any upper limit to form a range not explicitly recited; and any lower limit may be combined with any other lower limit to form a range not explicitly recited, and any upper limit may be combined with any other upper limit to form a range not explicitly recited. Furthermore, each point or individual value between the endpoints of the range is included within the range, although not explicitly recited. Thus, each point or individual value may be combined as a lower or upper limit on itself with any other point or individual value or with other lower or upper limit to form a range that is not explicitly recited.
In the description herein, unless otherwise indicated, "above" and "below" are intended to include the present number, "one or more" means two or more, and "one or more" means two or more.
The first aspect of the invention provides a PPC nanoparticle, the PPC nanoparticle has a size of 200-300nm and comprises a polydopamine nanoparticle and a load carried on the surface of the polydopamine nanoparticle, the load comprises Prussian blue nanoparticles and cerium oxide nanoparticles, and the Prussian blue nanoparticles and the cerium oxide nanoparticles are randomly distributed on the surface of the polydopamine nanoparticle.
In the PPC nanoparticle provided by the invention, prussian blue nanoparticle and cerium oxide nanoparticle are loaded on the surface of polydopamine nanoparticle to form spherical or spheroid-like composite nanoparticle, the particle size is 200-300nm, for example, the particle size is 200nm, 210nm, 220nm, 230nm, 240nm, 250nm, 260nm, 270nm, 280nm, 290nm or 300nm, or the like, or the particle size is any combination range of the above values.
In the PPC nano-particles provided by the invention, the PPC is based on the superoxide dismutase capability of polydopamine to remove O 2 ·-, and simultaneously is combined with the strong catalase capability of PB, and cerium oxide is utilized to rapidly utilize and remove OH generated by PB to generate oxygen, and Prussian blue nano-particles and cerium oxide nano-particles are loaded on the surfaces of polydopamine nano-particles, so that the method is beneficial to rapidly removing hydroxyl free radicals and reducing cytotoxicity. In addition, OH - released during the chemical reaction can neutralize the myocardial acid environment under hypoxia, providing a good condition for cell survival.
In an embodiment of the present invention, the mass ratio of each part in the PPC nanoparticle is: 80% -90% of polydopamine nano particles; prussian blue nano particles 5-15%; 1-5% of cerium oxide nano particles.
In an embodiment of the invention, the polydopamine nanoparticles have a particle size of about 200-300nm; prussian blue nanoparticles have a particle size of about 10-20nm; the cerium oxide nanoparticles are about 1-5nm.
In the embodiments of the present invention, in order to make PPC nanoparticles have higher hydrophilicity required for biological applications, polyethylene glycol having excellent biocompatibility is introduced to modify the surface thereof.
In some embodiments, the PPC nanoparticles are subjected to X-ray photoelectron spectroscopy analysis, wherein carbon comprises 69.11%, nitrogen comprises 11.72%, oxygen comprises 17.59%, iron comprises 1.5%, and cerium comprises 0.08%.
In some embodiments, high resolution spectra of Ce element in PPC nanoparticles found that the 3 main peaks of cerium, from cerium 3 and cerium 4, respectively, revealed mixed valence states in the cerium oxide compound where the 3 and 4 valences coexist.
In an embodiment of the second aspect of the present application, there is provided a method for preparing PPC nanoparticles, comprising the steps of:
(1) Mixing and reacting the polydopamine solution and the Prussian blue solution, wherein the mass ratio of polydopamine to Prussian blue is 1: (5-10), removing impurities to obtain a solution containing polydopamine-Prussian blue nano particles;
(2) Reacting the obtained solution containing the polydopamine-Prussian blue nano particles with Ce (NO 3)3·6H2 O under an acidic condition, wherein the mass ratio of the polydopamine-Prussian blue nano particles to the Ce (NO 3)3·6H2 O) is 1 (15-20), and removing impurities to obtain a solution containing the polydopamine-Prussian blue-cerium oxide nano particles;
(3) Reacting the solution of the obtained polydopamine-Prussian blue-cerium oxide nano particles with NH 2-PEG-NH2 in an organic solvent under alkaline conditions, wherein the mass ratio of the polydopamine-Prussian blue-cerium oxide nano particles to NH 2-PEG-NH2 is 1: (1.1-1.3), removing impurities to obtain PPC nano particles.
In the step (1), the mass ratio of polydopamine to Prussian blue is 1: (5-10), for example, the mass ratio of polydopamine to Prussian blue is 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, and the mass ratio of polydopamine to Prussian blue may also be any combination range of the above values.
In the step (2), the mass ratio of the polydopamine-Prussian blue nanoparticle to the Ce (NO 3)3·6H2 O) is 1 (15-20), for example, the mass ratio of the polydopamine-Prussian blue nanoparticle to the Ce (NO 3)3·6H2 O is 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20, and the mass ratio of the polydopamine-Prussian blue nanoparticle to the Ce (NO 3)3·6H2 O can be any combination range of the above values).
In the step (3), the mass ratio of the polydopamine-Prussian blue-cerium oxide nano particles to the NH 2-PEG-NH2 is 1: (1.1-1.3), for example, the mass ratio of polydopamine-Prussian blue-cerium oxide nanoparticles to NH 2-PEG-NH2 is 1:1.1, 1:1.15: the mass ratio of polydopamine-Prussian blue-ceria nanoparticles to NH 2-PEG-NH2 may also be in the range of any combination of the above values, 1:1.2, 1:1.25, or 1:3.
In some embodiments, the method for preparing the polydopamine solution of step (1) comprises: dissolving dopamine hydrochloride in a solvent, and carrying out polymerization reaction under alkaline conditions to obtain a polydopamine solution, wherein the particle size of polydopamine is about 200-300nm.
In some embodiments, the mass ratio of ferric trichloride to potassium ferricyanide is 1: mixing and reacting (1-1.3) in water to obtain Prussian blue solution, wherein the particle size of Prussian blue is about 10-20nm.
In some embodiments, the mass ratio of ferric trichloride to potassium ferricyanide is 1:1, 1:1.1, 1:1.2, or 1:1.3, and the mass ratio of ferric trichloride to potassium ferricyanide can also be any combination of the above values.
In some embodiments, the acidic condition in step (2) has a pH of 0.1 to 3, and the preparation under acidic conditions is more advantageous to increase the proportion of cerium oxide 3 in the product, thereby increasing the active oxygen scavenging capacity.
In some embodiments, the reaction temperature in step (2) is 25 to 95℃and the reaction time is 10 to 60 minutes. If the reaction time exceeds 2 minutes, the subsequent reaction will change part of the nanostructure, resulting in non-uniformity of the material.
In some embodiments, the alkaline conditions of step (3) have a pH of 7 to 12, at which the reaction increases the reaction rate.
In an embodiment of the third aspect of the present application, there is also provided an application of the PPC nanoparticle or the PPC nanoparticle prepared by the method described above in a medicament for treating myocardial infarction.
The PPC nano-particles can position infarcted myocardial mitochondria, not only can the cascade connection of O 2 ·- be converted into nontoxic O 2 and H 2 O through the catalysis of SOD and CAT enzyme, but also the special form of reversible conversion from 3-valence cerium to 4-valence cerium in cerium oxide can be used for converting OH into O 2, and toxic byproducts are avoided. Meanwhile, the SOD-like enzyme capability of PDA can remove O 2 ·- and release OH-, and PB can release OH-in an acidic environment and neutralize acidic products accumulated in an anoxic condition, so that the intracellular pH is improved. Thus, PPC oxygen delivery systems produce oxygen while improving the anoxic microenvironment (including oxidative stress, pH, anoxic toxic byproducts).
In some embodiments, the PPC nanoparticles are dissolved in physiological saline to prepare intravenous injection for treating myocardial infarction, and the concentration of the PPC intravenous injection is 1-40 ug/mL.
For example, the concentration of PPC nanoparticles in the PPC intravenous fluid is 1ug/mL, 5ug/mL, 10ug/mL, 15ug/mL, 20ug/mL, 25ug/mL, 30ug/mL, 35ug/mL, or 40ug/mL, and the concentration of PPC intravenous fluid may also be any combination of the above values.
Examples
The present disclosure is more particularly described in the following examples that are intended as illustrations only, since various modifications and changes within the scope of the present disclosure will be apparent to those skilled in the art. Unless otherwise indicated, all parts, percentages, and ratios reported in the examples below are by weight, and all reagents used in the examples are commercially available or were obtained synthetically according to conventional methods and can be used directly without further treatment, as well as the instruments used in the examples.
1. Synthesis of polydopamine (Polydopamine, P):
(1) Accurately weighing 0.75g of dopamine hydrochloride, dissolving in 10mL of ultrapure water, slowly adding 50mL of absolute ethyl alcohol, 110mL of ultrapure water and 3mL of ammonia water, heating to 30 ℃ and stirring for 24 hours, so that dopamine is polymerized into polydopamine under alkaline conditions (pH > 7.5).
(2) Centrifuging and washing 8-10 times (11000 rpm/10 min) and removing unreacted impurities, and freeze-drying to obtain the P nano particles.
2. Synthesis of polydopamine-Prussian blue nanoparticles (Prussian blue, PP):
(1) Dissolving P40 mg in 50mL of ultrapure water, and recording 1;
(2) Accurately weighing FeCl3.6H2O (50 mg) and potassium ferricyanide K3Fe [ CN ]6 (57.69 mg) dissolved in 10mL of ultrapure water, stirring uniformly, taking 1mL of ultrapure water, adding the ultrapure water to constant volume to 50mL, and obtaining iron hexacyanoferrate Fe3[ Fe (CN) 6 ]3, namely Prussian blue, and recording 2;
3K3[Fe(CN)6]+FeCl3→Fe3[Fe(CN)6]3+9KCl
(3) 2 was slowly added to 1 over 30min using a microinjection pump and reacted for 6h at various temperature gradients (25 ℃, 35 ℃, 45 ℃, 55 ℃, 65 ℃, 75 ℃, 85 ℃, 95 ℃) (25 ℃ optimal).
(4) And (3) centrifugally washing in water for 5-8 times (11000 rpm/10 min) to remove unreacted impurities and freeze-drying to obtain PP solution.
3. Synthesis of polydopamine-Prussian blue-ceria nanoparticles (Polydopamine Prussian blue Cerium oxide, PPC):
(1) Precisely weighing 0.174g of Ce (NO 3) 3.6H2O and PP NPs (30 mg), adding ultrapure water to a constant volume of 50mL, and stirring for 15min at 25 ℃;
(2) Adding 1mL of 0.12M hydrochloric acid, heating to different temperatures (25 ℃, 35 ℃, 45 ℃, 55 ℃, 65 ℃, 75 ℃, 85 ℃ and 95 ℃) under acidic conditions (pH 2-3), taking out immediately after reacting for 10min and waiting for room temperature, centrifugally washing for 5-8 times (11000 rpm/10 min) to remove unreacted impurities, and freeze-drying to obtain polydopamine Prussian blue nano particles which are not modified by the diamino polyethylene glycol (Diaminopolyethylene glycol, NH2-PEG-NH 2);
(3) In order to increase the water solubility, the polydopamine Prussian blue nano-particles which are not modified by NH2-PEG-NH2 and NH2-PEG-NH2 are dissolved in a Tris8.5 organic solvent according to the ratio of 4:5, and react for 24 hours at 25 ℃ under alkaline conditions (pH 7-8.5) to obtain the polydopamine Prussian blue nano-particles which are modified by NH2-PEG-NH2, namely PPC nano-particles.
(4) And (3) centrifugally washing in water for 3-5 times (11000 rpm/10 min) to remove unreacted impurities, and freeze-drying to obtain the polydopamine Prussian blue nano particles modified by NH2-PEG-NH2, namely the PPC nano particles. The reaction process is shown in FIG. 1.
4. Synthesis of fluorescence-labeled PPC (PPC-FITC):
(1) PPC and Fluorescein Isothiocyanate (FITC) are respectively mixed according to the proportion of 10:1:5:1 and 1:1 (PPC is dissolved in 8mL of water, FITC is dissolved in 2mL of dimethyl sulfoxide), and the mixture is reacted for 6 hours under different temperature gradients (25 ℃, 35 ℃, 45 ℃, 55 ℃, 65 ℃, 75 ℃, 85 ℃, 95 ℃) (25 ℃ is optimal) and in the absence of light;
(2) Placing the PPC-FITC solution obtained in the step (1) under different reaction conditions into a dialysis bag with a molecular cutoff of 3.5KD, dialyzing for 24 hours in a dark place, removing unreacted impurities and calculating the concentration of the product;
(3) The fluorescence absorption of PPC and PPC-FITC generated under different reaction conditions is measured by a fluorescence spectrophotometer, and the optimal scheme for synthesizing PPC-FITC is screened (5:1 is optimal, namely 10mg of PPC is dissolved in 8mL of water, and 2mg of FITC is dissolved in 2mL of dimethyl sulfoxide solution).
5. Test part
As shown in fig. 2, it can be clearly observed that P (fig. b), PP (fig. c) and PPC (fig. d) are all round nanoparticles by a transmission electron microscope. x-ray photoelectron spectroscopy showed that PPC nanoparticles were about 200-250nm in diameter (panel e). The elemental mapping shows a uniform distribution of carbon, nitrogen, oxygen, iron and cerium in the PPC nanoparticles (fig. 2 f). Analysis of the PPC nanoparticles by X-ray photoelectron spectroscopy is shown in figure g, and detection peaks of carbon, nitrogen, oxygen, iron and cerium can be observed in the PPC nanoparticles, wherein the carbon accounts for 69.11%, the nitrogen accounts for 11.72%, the oxygen accounts for 17.59%, the iron accounts for 1.5% and the cerium accounts for 0.08%. In the PPC nano-particles, the PDA accounts for 80% -90%, the PB accounts for 5-15%, and CexOy accounts for 1-10%. To investigate the valence properties of cerium in PPC, a high resolution spectrum of Ce element in PPC nanoparticles was further obtained (figure h). The spectrum of FIG. f shows 3main peaks of cerium, from cerium 3 and cerium 4, respectively, with a Ce3+/Ce4+ ratio of 0.53, revealing mixed valence states of 3 and 4 coexisting in the cerium oxide compound (FIG. 2 e). In order to make PPC nano particles have higher hydrophilicity required by biological application, polyethylene glycol with excellent biocompatibility is introduced to modify the surfaces of the PPC nano particles. Infrared spectroscopic measurement of PPC nanoparticles as shown in fig. i, a detection peak of PEG can be detected on the PPC nanoparticles attached to PEG (fig. i, dashed box), indicating successful PEG modification of PPC nanoparticles.
As shown in FIG. 3, in vitro experiments have observed that P, PP and PPC have good O 2 ·- scavenging ability (FIG. 3 a). P and PP showed good neutralization of acids in vitro, PPC nanoparticles combined and utilized this advantage (fig. 3 b). However, the PP group produced more. OH in acid environment than P group (FIG. 3 c), whereas PPC could rapidly scavenge. OH (FIG. 3 d). Further measurements of oxygen production in vitro indicated that PPC bound and developed the best effect of PP on oxygen production (FIGS. 3 e-f). Therefore, through in vitro experiments, we initially find that PPC can convert excessive oxygen-deficient metabolic toxic byproducts into oxygen to change waste into valuable. In fig. 3, the PPC nanoparticle of fig. 3 (a) has the ability to scavenge superoxide anions. (b) acid neutralizing ability of PPC nanoparticles. (c) PP generates OH in an acid environment. (c) determination of OH removal ability. The oxygen generating capacity (e) and the representative bubble image (f) of the PPC nano particles are measured in vitro by an oxygen dissolving instrument.
To further investigate the biosafety of PPC nanoparticles. First we observed the effect of PPC on cardiomyocyte viability under normoxic and 1% hypoxic conditions. Cardiomyocyte viability was assessed using CCK8 by treating cardiomyocytes with 0,1,5, 10, 20, 40ug/ml PPC nanoparticles for 24 hours and 48 hours, respectively. The results showed that PPC NPs did not cause any toxicity to CMs cells involved in MI repair even at high concentrations up to 40ug/mL in vitro (fig. 4 a-b). Under anaerobic conditions, when the concentration of PPC nanoparticles was 5ug/ml, a significant promotion of myocardial cell viability by PPC was observed (FIGS. 4 c-d). In fig. 4, H9C2 cell viability of PPC nanoparticle treatments 24H (a) and 48H (b) under normoxic or PPC np treatments 24H (C) and 48H (d) under hypoxic. All data are expressed as mean ± standard deviation (n=3), ns P >0.05, P <0.01; * P <0.001. Even at very high concentrations, PPC does not cause hemolysis, as shown in fig. 5.
Next we further constructed a mouse myocardial infarction model by tail vein injection of PPC nanosolution (150 ugPPC in 125ul saline/patient) to determine the effect of PPC on myocardial infarction treatment. As shown in fig. 6a, ROS burst in MI can disrupt endothelial cell attachment and vascular basement membrane, PPC NPs are specifically enriched in ischemic myocardium after intravenous injection. We labeled PPC NPs with Fluorescein Isothiocyanate (FITC), a strong fluorescent group (fig. 6 b), and used ex vivo fluorescence imaging to track organ level distribution of PPC NPs. The results of tail vein injection of PPC NPs show that PPC nano-particles are mainly distributed in the liver in the sham group or MI group due to rich capillary networks, and the PPC is mainly metabolized by the liver. Interestingly, myocardial mice accumulate primarily in the left ventricular infarct after PPC injection (fig. 6 c-f). Distribution of cerium element was further examined in each organ 1 day after injection of myocardium and healthy mice using inductively coupled plasma mass Spectrometry (Inductively Coupled PLASMA MASS Spectrometry, ICP-MS). The results showed that, 1 day after injection, the cerium element was most distributed in the heart, followed by the liver, approximately 48.68% of the heart, whereas healthy mice were mainly distributed in the liver (fig. 6 g). This may be associated with changes in the physiological adaptation of the damaged tissue caused by acute ischemia, particularly under conditions of altered microenvironment and increased vascular permeability of hypoxic tissue. In addition PPC remained in infarcted myocardium for a longer period of time (FIGS. 6 h-j). As shown in FIGS. 6h-j, PPC NP remained for more than 7 days. On day 3, the PPC fluorescence intensity was reduced by about 56.79%, on day 7 by about 87.9% (FIG. 6 h-i), while on day 3, the Ce element was reduced by 51.9% and on day 7 by 67.27% according to ICP-MS (FIG. 6 j), which fully demonstrated that PPC NPs were effectively bioavailable and retained in ischemic myocardium. The distribution of PPC NPs in MI tissues was observed by transmission electron microscopy (fig. 6 k), which indicated that PPC was widely distributed in MI tissues, consistent with fluorescence imaging results. Interestingly, PPC NPs were also distributed in cardiac myocyte mitochondria (fig. 6 k).
Although PPC NPs have not been modified to a specific mitochondrial targeting group, PPC NPs can still target mitochondria in cardiac myocytes due to the extremely high myocardial energy demands and the extremely rich mitochondrial density distribution in the myocardium. The subcellular location of nanoenzymes is a key factor in determining their enzymatic activity and active oxygen scavenging efficiency. Mitochondria are the major organelles that produce O 2 ·- and are also the major sources of oxidative damage to induced cells. Thus, mitochondrial targeting of PPC NPs suggests that PPC NPs may protect ischemic myocardium by scavenging O 2 ·-.
In fig. 6, (a) schematic representation of PPC nanoparticles leaking through the damaged myocardial circulation to the ischemic area. (b) FITC-labeled PPC nanoparticles. (c) Myocardial tissue images showed that PPC-FITC NPs leaked into ischemic areas on day 1 post myocardial infarction, (d) fluorescence intensity quantitative analysis of myocardial infarction +PPC-FITC group (blue) versus healthy +PPC-FITC group (yellow). (e) Representative ex vivo fluorescent imaging of the heart, liver, spleen and kidneys of mice following tail vein injection of PPC-FITC nanoparticles into healthy and MI mice. (f) The fluorescence intensity and (g) cerium content of PPC-FITC nanoparticles in different organs were quantitatively analyzed. (h) Myocardial tissue images of PPC-FITC nanoparticles leaking into ischemic areas 1,3, and 7 days after myocardial infarction. (i-j) quantitative analysis of fluorescence intensity and cerium content of ischemic regions relative to healthy myocardium at days 1,3 and 7 after myocardial infarction. (k) Transmission electron microscopy images showed PPC-FITC nanoparticles loaded on the myocardial mitochondria (yellow arrow). (n=3), ns P >0.05, P <0.01, P <0.001.
Alterations in the hypoxic microenvironment (hypoxia, reactive oxygen species, pH) after myocardial infarction are key to affecting cardiac function. Mitochondria are organelles of cellular energy metabolism. The mitochondrial respiratory chain is damaged during hypoxia, resulting in insufficient productivity, the mitochondrial electron transport chain complex is transferred to oxygen, O 2 ·- is first produced, H 2O2 and OH are then further produced under conversion by antioxidant enzymes, and finally ROS burst is caused. Thus, first we evaluate PPC nanoparticle ROS scavenging ability by a dihydroethidium (Dihydroethidium, DHE) O 2 ·- probe. As shown in fig. 7a and 7b, the myocardial tissue of the myocardial infarction group at day 1 after myocardial infarction detected a significant DHE fluorescence signal compared to the healthy group, suggesting that there was a significant accumulation of active oxygen in the myocardial infarction region, and the fluorescence signal of the P/PP/PPC NPs treatment group was significantly reduced, with the PPC NPs group decreasing the greatest in magnitude.
Further defines the treatment effect of PPC on the tissue hypoxic acid environment, and adopts a pH sensitive fluorescent probe pHrodo to detect the pH change of myocardial tissue after myocardial infarction. As shown in FIG. 7b, a large amount of pHrodo red fluorescence signal was detected in the infarcted area, suggesting that a large amount of acidic substances were accumulated after myocardial infarction. The fluorescence intensity of the pHrodo of the P/PP/PPC NPs treatment group is obviously reduced, which indicates that the P/PP/PPC has a certain capacity of improving the anoxic acid environment, and meanwhile, the fluorescence intensity of the pHrodo of the PPC treatment group is found to be the lowest, which indicates that the effect of the PPC on improving the anoxic acid environment of the tissue is better than that of the P/PP (figure 7 b).
Hif-1 alpha acts as an oxygen receptor and is closely related to the degree of cellular hypoxia. For this purpose, we used the expression of Hif-1. Alpha. To assess whether PPC was able to produce oxygen in myocardial tissue following myocardial infarction. Immunofluorescence results show that the ischemia region Hif-1 alpha is obviously up-regulated after myocardial infarction of the mice, and the expression level of Hif-1 alpha is obviously reduced by PPC treatment (figure 7 c), which indicates that PPC generates oxygen in hypoxic cardiac muscle and promotes degradation of Hif-1 alpha.
As previously described, we found that PB can generate OH in acid environment, whereas cerium oxide can generate oxygen by OH conversion (FIG. 2 h), so we examined infarcted myocardial OH content. The OH measurement result shows that the OH content of the PP NPs group is higher than that of the P NPs group, and the PPC NPs can clear approximately 55.08% of OH and have the lowest content, so that our hypothesis is further confirmed, and the PPC can effectively clear OH while generating oxygen, thereby changing waste into valuable.
FIG. 7PPC nanoparticle effect on anoxic microenvironment was improved. Representative fluorescent images of myocardial tissue ROS activity (DHE) (a), pH (pHrodo) (b) and hypoxia content (Hif-1α) (c) on day 1 post myocardial infarction.
Next we intravenously injected PPC NPs into the tail of mice on postoperative days 0, 3, 6, and assessed cardiac functional recovery on postoperative day 28. As shown in fig. 8a, we evaluate gold standard echocardiography through cardiac function to evaluate cardiac function recovery following PPC treatment. As shown in fig. 6b-g, both the left ventricular ejection fraction (Left Ventricular Ejection Fraction, LVEF) (fig. 8 b) and the left ventricular short axis foreshortening rate (Left Ventricular Fraction Shortening, LVFS) (fig. 8 c) were improved in the PPC treated group compared to the myocardial infarction group, while the left ventricular end diastole Volume (Left Ventricular End-diastonic Volume, LVEDV) (fig. 8 d) and the end systole Volume (Left Ventricular End Systolic Volume, LVESV) (fig. 8 e) were reduced, and the left ventricular inner diameter (Left Ventricular Internal Dimension diastole, LVIDd) (fig. 8 f) and the systolic inner diameter (Left Ventricular Internal Dimension systole, LVIDs) (fig. 8 g) were shortened, suggesting a restoration of left ventricular function. LVEF returned to 76.79% of normal mouse cardiac function after PPC treatment, whereas P treatment returned to about 56.4% and only 45.89% after PP treatment (fig. 8 b). Notably, PP shows cardiac function impairment after treatment, possibly due to the generation of hydroxyl radicals during the process of scavenging active oxygen by PB, which results in a poor cardiac function improvement effect compared to PDA, while PPC combines both PDA and PB capabilities, and reverses PB defects that generate hydroxyl radicals, showing optimal therapeutic effects. Because the PPC continuously generates oxygen and eliminates active oxygen in the infarcted area, the infarcted cardiac muscle can be effectively repaired, and the cardiac function is protected. Among them, the effect of PPC nanoparticle treatment of fig. 8 on infarcted heart structure and heart function recovery after 28 days. (a) representative echocardiographic images of different treatments 28 d. Quantitative analysis of LVEF (b), LVFS (c), EDV (d), ESV (e), LVIDd (f), LVIDs (g) (n=6). (h) schematic representation of border and infarct zone. (i) Hematoxylin-eosin staining of representative images of the whole heart, infarct area and border area for 28 days of different treatments. Scale bar 100 μm.
Pathological remodeling is a major cause of post-mortem cardiac dysfunction and heart failure. On day 28, different groups of mouse heart samples were collected, and the tissue morphology was observed by hematoxylin and eosin staining (HE), and as a result, myocardial tissue disorder was seen after infarction, myocardial cells in the infarcted area were replaced by fibrous tissue, the myocardial arrangement was more orderly after PPC treatment, and interstitial fibrous deposition was less (fig. 8 h-i). The above results prove that the PPC treatment can effectively improve the post-infarction heart function and improve myocardial remodeling.
The above results further demonstrate that PPC has the ability to reduce oxidative stress, neutralize the anoxic acid environment and produce oxygen at the histological level.
Myocardial infarction is of great concern worldwide with its high morbidity and mortality. Hypoxia is the most important feature of myocardial infarction, and the balance between myocardial oxygen consumption and hypoxia determines heart function recovery. Although cardioprotection by drugs that partially reduce myocardial oxygen consumption has been established, such as beta blockers, calcium antagonists, etc., therapeutic efficacy is limited because myocardial damage is irreversible. Thus, continuous supply of oxygen is a therapeutic means to accelerate recovery of cardiac function after infarction.
The PPC nano-particles position infarcted myocardial mitochondria, not only can the cascade connection of O 2 ·- be converted into nontoxic O 2 and H 2 O through the catalysis of SOD and CAT enzyme, but also the special form of reversible conversion from 3-valence cerium to 4-valence cerium in cerium oxide can be used for converting OH into O 2, and toxic byproducts are avoided. Meanwhile, the SOD-like enzyme capability of PDA can remove O 2 ·- and simultaneously release OH -, meanwhile, PB can also release OH - in an acidic environment, and the accumulated acidic products in the anoxic condition are neutralized, so that the intracellular pH is improved. Thus, PPC oxygen delivery systems produce oxygen while improving the anoxic microenvironment (including oxidative stress, pH, anoxic toxic byproducts). The advantages of the components of the PPC nano particles are complementary, and the extremely low dose of the PPC nano particles can realize high-efficiency oxygen production and improve the anoxic micro environment, thereby providing a foundation for further clinical conversion of the PPC nano particles.
In conclusion, PPC oxygen delivery systems exhibit superior therapeutic effects in myocardial infarction models due to their surprising oxygen generating capacity and hypoxic microenvironment regulation. The PPC oxygen transfer system as a therapeutic nanomaterial has great clinical conversion potential in the treatment of myocardial infarction diseases and also has potential treatment value in other ischemic diseases.
While the invention has been described with reference to a preferred embodiment, various modifications may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention, and in particular, the technical features set forth in the various embodiments may be combined in any manner so long as there is no structural conflict. The present invention is not limited to the specific embodiments disclosed herein, but encompasses all technical solutions falling within the scope of the claims.
Claims (8)
1. The PPC nanoparticle is characterized by comprising polydopamine nanoparticles and a load substance loaded on the surfaces of the polydopamine nanoparticles, wherein the load substance comprises Prussian blue nanoparticles and cerium oxide nanoparticles, and the Prussian blue nanoparticles and the cerium oxide nanoparticles are randomly distributed on the surfaces of the polydopamine nanoparticles; the mass ratio of each part in the PPC nano particle is as follows: 80% -90% of polydopamine nano particles; prussian blue nano particles 5-15%; 1-5% of cerium oxide nano particles; the PPC nano-particles are subjected to surface modification by diamino polyethylene glycol.
2. A method of preparing PPC nanoparticle according to claim 1, comprising the steps of:
(1) Mixing and reacting the polydopamine solution and the Prussian blue solution, wherein the mass ratio of polydopamine to Prussian blue is 1: (5-10), removing impurities to obtain a solution containing polydopamine-Prussian blue nano particles;
(2) Reacting the obtained solution containing the polydopamine-Prussian blue nano particles with Ce (NO 3)3·6H2 O under an acidic condition, wherein the mass ratio of the polydopamine-Prussian blue nano particles to the Ce (NO 3)3·6H2 O) is 1 (15-20), and removing impurities to obtain a solution containing the polydopamine-Prussian blue-cerium oxide nano particles;
(3) Reacting the solution of the obtained polydopamine-Prussian blue-cerium oxide nano particles with NH 2-PEG-NH2 in an organic solvent under alkaline conditions, wherein the mass ratio of the polydopamine-Prussian blue-cerium oxide nano particles to NH 2-PEG-NH2 is 1: (1.1-1.3), removing impurities to obtain PPC nano particles.
3. The method for preparing PPC nanoparticle according to claim 2, wherein said method for preparing polydopamine solution in step (1) comprises: dissolving dopamine hydrochloride in a solvent, and carrying out polymerization reaction under alkaline conditions to obtain a polydopamine solution.
4. The method for preparing PPC nanoparticle according to claim 2, wherein the method for preparing the prussian blue solution in step (1) comprises: ferric trichloride and potassium ferricyanide are mixed according to the mass ratio of 1: mixing and reacting (1-1.3) in water to obtain Prussian blue solution.
5. The method for preparing PPC nanoparticle according to claim 2, wherein the pH of said acidic condition in step (2) is 0.1 to 3; the reaction temperature in the step (2) is 25-95 ℃ and the reaction time is 10-60min.
6. The method for preparing PPC nanoparticle according to claim 2, wherein the pH of the alkaline condition of step (3) is 7 to 12.
7. Use of the PPC nanoparticle of claim 1 or the PPC nanoparticle prepared by the preparation method of any one of claims 2 to 6 in the preparation of a medicament for treating myocardial infarction.
8. The use according to claim 7, wherein the PPC nanoparticle is dissolved in physiological saline to prepare an intravenous solution for treating myocardial infarction, and the concentration of the PPC nanoparticle intravenous solution is 1-40 ug/mL.
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