CN113730614A - Lutetium marked nano carrier and preparation method thereof - Google Patents

Lutetium marked nano carrier and preparation method thereof Download PDF

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CN113730614A
CN113730614A CN202111057427.1A CN202111057427A CN113730614A CN 113730614 A CN113730614 A CN 113730614A CN 202111057427 A CN202111057427 A CN 202111057427A CN 113730614 A CN113730614 A CN 113730614A
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solution
lutetium
dota
gip
spn
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CN113730614B (en
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施秀敏
王峰
朱然
李庆
杨凯
王广林
吴正参
张川
梁茂林
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Nanjing First Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The invention relates to the technical field of radioactive nuclides, in particular to a lutetium-labeled nano carrier and a preparation method thereof. The preparation method of the lutetium marked nano carrier comprises the following steps: mixing glucose-dependent insulinotropic polypeptide and Mal-PEG12-DSPE and tri (2-carboxyethyl) phosphine are mixed and reacted, and a product is dissolved in tetrahydrofuran to obtain solution A; adding dimethyl sulfoxide solution of DOTA-NHS and NH2‑PEG45-mixing dimethyl sulfoxide solutions of DSPE to obtain a solution B; dissolving PCPDTBT in fourHydrogen furan to obtain a solution C; mixing the solution A, the solution B and the solution C, and carrying out ultrasonic self-assembly in water to obtain DOTA-SPN-GIP; the obtained DOTA-SPN-GIP solution,177LuCl3Mixing HCl solution and sodium acetate solution, reacting, adding PBS or normal saline, and ultrafiltering. The method is simple and easy to implement, and has good stability both in vivo and in vitro.

Description

Lutetium marked nano carrier and preparation method thereof
Technical Field
The invention relates to the technical field of radioactive nuclides, in particular to a lutetium-labeled nano carrier and a preparation method thereof.
Background
Lutetium is a metal element, the chemical symbol is Lu, the simple substance corresponding to lutetium is silver metal, and the lutetium is the hardest and most compact metal in rare earth elements; melting point 1663 deg.C, boiling point 3395 deg.C, and density 9.8404. Lutetium is relatively stable in air; lutetium oxide is a colorless crystal and dissolves in acid to form a corresponding colorless salt. Lutetium is mainly used for research work, has few other purposes, is dissolved in dilute acid and can slowly act with water. The salts are colorless, and the oxides are white. Naturally occurring isotopologues are:175lu and half-life of 2.1X 1010Beta-emitting body of year176Lu. The lutetium fluoride LuF is used as a raw material of the material with very little reserve and high price in the natural world3·2H2O is prepared by calcium reduction and is used in atomic energy industry.
Because of the promising basic clinical methods of radionuclide therapy and radionuclide diagnostics, the world is dealing with reactor nuclides177The demand for Lu is increasing. As having a shorter half-life T1/26.71 days of low energy beta emitters,177lu constitutes an excellent vehicle for the specific deposition of large amounts of energy in small volumes. These physical properties are largely in oncologyIn the form of radioimmuno-radionuclide therapy and peptide receptor radionuclide therapy, in particular for the therapy and diagnosis of tumors.
A semiconductor polymer nano material taking a glucose-dependent insulinotropic polypeptide (GIP) receptor as a target has been used as an active targeting nano carrier to transport alpha particles to tumor cells with high GIPR expression. The DOTA (1,4,7, 10-tetraazacyclododecane-tetraacetic acid) with stable chelation function can be used as a bridge for connecting the nano-carrier and the radionuclide.
Thus, how to provide a simple nuclide lutetium based on the characteristics of DOTA177The preparation method of the labeling nano-carrier of Lu is a problem which needs to be solved urgently by the technical personnel in the field.
Disclosure of Invention
The invention aims to provide a lutetium-labeled nano carrier and a preparation method thereof, and the lutetium-labeled nano carrier is a linker prepared from an actively-targeted semiconductor polymer SPN-GIP and hydroxysuccinimide-tetraazacyclododecane tetraacetic acid (DOTA-NHS) and subjected to the preparation177Lu labeling and assay, and describes177Lu labeling and purification method.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of a lutetium-labeled nano carrier, which comprises the following steps:
(1) mixing glucose-dependent insulinotropic polypeptide and Mal-PEG12Mixing DSPE and tri (2-carboxyethyl) phosphine, reacting, purifying and freeze-drying a reaction product, and dissolving the reaction product in tetrahydrofuran to obtain a solution A;
(2) adding dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45-mixing dimethyl sulfoxide solutions of DSPE to obtain a solution B;
(3) dissolving PCPDTBT in tetrahydrofuran to obtain a solution C;
(4) mixing the solution A, the solution B and the solution C, carrying out ultrasonic self-assembly in water, introducing nitrogen, passing through a column, carrying out ultrafiltration to obtain DOTA-SPN-GIP, and adding water to obtain a DOTA-SPN-GIP solution;
(5) d obtained in the step (4)OTA-SPN-GIP solution,177LuCl3Mixing HCl solution and sodium acetate solution, reacting, adding PBS or normal saline into the reaction product, and performing ultrafiltration to obtain the lutetium-labeled nano-carrier.
Preferably, in step (1), the glucose-dependent insulinotropic polypeptide, Mal-PEG12The mass ratio of the DSPE to the tris (2-carboxyethyl) phosphine is 8-12: 1-3: 13-15;
before reaction, glucose-dependent insulinotropic polypeptide, Mal-PEG12Respectively adjusting the pH value of DSPE and tris (2-carboxyethyl) phosphine to 7.2-7.6, and then mixing for reaction;
the reaction is performed by shaking for 10-14 h at room temperature;
glucose-dependent insulinotropic polypeptide, Mal-PEG12The volume ratio of the total mass of the DSPE and the tri (2-carboxyethyl) phosphine to the tetrahydrofuran is 1.6-3.6 g: 130-170L.
Preferably, DOTA-NHS is reacted with NH in dimethyl sulfoxide in step (2)2-PEG45The concentration of the DSPE in the dimethyl sulfoxide is 8-12 g/L;
the mixing is performed by oscillating for 1.5-2.5 h at room temperature;
dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45The volume ratio of dimethyl sulfoxide solution of DSPE is 3-5: 24-28.
Preferably, the mass volume ratio of the PCPDTBT to the tetrahydrofuran in the step (3) is 1-2 g: 1-2L.
Preferably, the water adding amount in the step (4) is 3-5 times of the total volume of the solution A, the solution B and the solution C; the ultrasonic frequency is more than or equal to 20 KHz; the self-assembly time is 12-18 min.
Preferably, in the step (4), the volume ratio of the solution A to the solution B to the solution C is 130-170: 25-35: 40-60; introducing nitrogen, passing through PD10 gel column, collecting intermediate product of specific section, and ultrafiltering;
when the dosage of the glucose-dependent insulinotropic polypeptide is 1mg, the intermediate product is 4-5 mL flowing out of a PD10 gel column;
when the dosage of the glucose-dependent insulinotropic polypeptide is 2Nmg, the intermediate product is NmL of (3N +1) - (3+2) th flowing out of a PD10 gel column;
the volume ratio of DOTA-SPN-GIP to water is 3-7: 10.
Preferably, in the step (5), the177LuCl3The emission amount of the HCl solution is 148-185 MBq;
177LuCl3the volume ratio of the HCl solution, the DOTA-SPN-GIP solution and the sodium acetate solution is 3-5: 4-6: 0.5-1.5; the concentration of the sodium acetate solution is 0.15-0.35M;
the reaction is performed by shaking at room temperature for 25-35 min.
Preferably, in the step (5), the volume ratio of the reaction product to the added PBS or physiological saline is 1: 3-5.
Preferably, the purification in the step (1) is ultrafiltration, and the parameters are set to 4000-6000 rpm and 25-35 min, and the ultrafiltration is carried out for 5-8 times;
in the steps (4) and (5), the ultrafiltration parameters are set to 3000-4000 revolutions per minute, 4-6 minutes and ultrafiltration is carried out for 1-3 times.
The invention also provides a lutetium marked nano-carrier prepared by the preparation method of the lutetium marked nano-carrier.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention prepares the active targeting semiconductor polymer SPN-GIP and the connector of hydroxysuccinimide-tetraazacyclododecane tetraacetic acid (DOTA-NHS) and carries out the preparation177Lu labeling and assay, optimize177Lu labeling and purification method.
2. The invention modifies the semiconductor polymer on the surface of DOTA-NHS, which is easy to mark the nuclide lutetium 177, the method is convenient to synthesize, and the marking can be stably and efficiently carried out under the condition of normal temperature. The marking method is simple and easy to implement, and the mark is synthesized177Lu-SPN-GIP has good in vivo and in vitro stability. After marking177Lu-SPN-GIP ratio free177LuCl3Has more excellent cell activity inhibiting effect at the cell level.177Lu-SPN-GIP on tumor cellsThe inhibition of (a) is not only dose-dependent but also time-dependent in radioactivity, and after 24 hours of incubation, the inhibition is more significant as the observed period is longer.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a schematic representation of a free form177LuCl3TLC result with water as developing agent;
FIG. 2 is177TLC results with water as the developing agent Lu-SPN-GIP;
FIG. 3 is a drawing showing177Analyzing the in-vivo and in-vitro stability of Lu-SPN-GIP;
FIG. 4 shows CFPAC-1 cells at various doses177Survival rate after different time in Lu-SPN-GIP;
FIG. 5 shows CFPAC-1 cells in177Lu-SPN-GIP and177LuCl3cell viability after 96 hours;
FIG. 6 shows CFPAC-1 cells in177Uptake in Lu-SPN-GIP;
FIG. 7 shows the uptake of SPN-GIP by CFPAC-1 cells at different time points.
Detailed Description
The invention provides a preparation method of a lutetium-labeled nano carrier, which comprises the following steps:
(1) mixing glucose-dependent insulinotropic polypeptide and Mal-PEG12Mixing DSPE and tri (2-carboxyethyl) phosphine, reacting, purifying and freeze-drying a reaction product, and dissolving the reaction product in tetrahydrofuran to obtain a solution A;
(2) adding dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45-mixing dimethyl sulfoxide solutions of DSPE to obtain a solution B;
(3) dissolving PCPDTBT in tetrahydrofuran to obtain a solution C;
(4) mixing the solution A, the solution B and the solution C, carrying out ultrasonic self-assembly in water, introducing nitrogen, passing through a column, carrying out ultrafiltration to obtain DOTA-SPN-GIP, and adding water to obtain a DOTA-SPN-GIP solution;
(5) the DOTA-SPN-GIP solution obtained in the step (4),177LuCl3Mixing HCl solution and sodium acetate solution, reacting, adding PBS or normal saline into the reaction product, and ultrafiltering to obtain lutetium-labeled nano-carrier (177Lu-SPN-GIP)。
In the present invention, in the step (1), the glucose-dependent insulinotropic polypeptide, Mal-PEG12The mass ratio of the DSPE to the tris (2-carboxyethyl) phosphine is 8-12: 1-3: 13-15; preferably 9-11: 2: 14; further preferably 10: 2: 14;
in the present invention, the step (1) is to subject the glucose-dependent insulinotropic polypeptide, Mal-PEG, to the reaction12Respectively adjusting the pH value of DSPE and tris (2-carboxyethyl) phosphine to 7.2-7.6, and then mixing for reaction; preferably adjusting the pH value to 7.3-7.5; more preferably, the pH is adjusted to 7.4;
in the invention, the reaction in the step (1) is performed by shaking at room temperature for 10-14 h; preferably 11-13 h; more preferably 12 h;
in the present invention, the glucose-dependent insulinotropic polypeptide, Mal-PEG, in the step (1)12The volume ratio of the total mass of the DSPE and the tri (2-carboxyethyl) phosphine to the tetrahydrofuran is 1.6-3.6 g: 130-170L; preferably 2.0-3.2 g: 140-160L; further preferably 2.4-2.8 g: 145-155L; more preferably 2.6 g: 150L.
In the present invention, DOTA-NHS in said step (2) is reacted with NH in dimethyl sulfoxide2-PEG45The concentration of the DSPE in the dimethyl sulfoxide is 8-12 g/L; preferably 9-11 g/L; further preferably 10 g/L;
the mixing is performed by oscillating for 1.5-2.5 h at room temperature; preferably 1.7-2.3 h; further preferably 1.9-2.1 h; more preferably 2 h;
dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45The volume ratio of dimethyl sulfoxide solution of DSPE is 3-5: 24-28; preferably 425-27; further preferably 4: 26.
In the invention, the mass-to-volume ratio of PCPDTBT to tetrahydrofuran in the step (3) is 1-2 g: 1-2L; preferably 1 g: 1L.
In the invention, the water adding amount in the step (4) is 3-5 times of the total volume of the solution A, the solution B and the solution C; preferably 4 times;
the ultrasonic frequency is more than or equal to 20 KHz; the self-assembly time is 12-18 min; preferably 13-17 min; further preferably 14-16 min; more preferably 15 min.
In the invention, in the step (4), the volume ratio of the solution A, the solution B and the solution C is 130-170: 25-35: 40-60; preferably 140-160: 27-33: 44-56; further preferably 145-155: 29-31: 48-52; more preferably 150: 30: 50;
introducing nitrogen, passing through PD10 gel column, collecting intermediate product of specific section, and ultrafiltering;
when the dosage of the glucose-dependent insulinotropic polypeptide is 1mg, the intermediate product is 4-5 mL flowing out of a PD10 gel column;
when the dosage of the glucose-dependent insulinotropic polypeptide is 2Nmg, the intermediate product is NmL of (3N +1) - (3+2) th flowing out of a PD10 gel column;
the volume ratio of DOTA-SPN-GIP to water is 3-7: 10; preferably 4-6: 10; further preferably 5: 10.
In the present invention, in the step (5), the177LuCl3The emission amount of the HCl solution is 148-185 MBq; preferably 158 to 175 MBq; more preferably 162 to 171 MBq; more preferably 165 MBq;
177LuCl3the volume ratio of the HCl solution, the DOTA-SPN-GIP solution and the sodium acetate solution is 3-5: 4-6: 0.5-1.5; preferably 4: 5: 0.7-1.3; further preferably 4: 5: 0.9-1.1; more preferably 4: 5: 1;
the concentration of the sodium acetate solution is 0.15-0.35M; preferably 0.20-0.30M; more preferably 0.25M;
the reaction is performed by shaking at room temperature for 25-35 min; preferably 27-33 min; further preferably 29-31 min; more preferably 30 min.
In the invention, in the step (5), the volume ratio of the reaction product to the added PBS or normal saline is 1: 3-5; preferably 1: 4.
In the invention, the purification in the step (1) is ultrafiltration, and the parameters are set to 4000-6000 r/min and 25-35 min, and the ultrafiltration is carried out for 5-8 times; preferably, the parameters are set to be 4500-5500 r/min, 27-33 min and 6-7 times of ultrafiltration; further preferably 4800-5200 r/min, 29-31 min, ultrafiltering 7 times; more preferably 5000 r/min, 30min, ultrafiltering for 7 times;
setting ultrafiltration parameters in the steps (4) and (5) to be 3000-4000 r/min, 4-6 min and carrying out ultrafiltration for 1-3 times; preferably setting parameters of 3300-3700 r/min, 5min, and carrying out ultrafiltration for 2 times; further preferably 3400-3600 r/min, 5min, ultra-filtering for 2 times; more preferably 3500 rpm/min, 5min, and 2 times of ultrafiltration.
The invention also provides a lutetium marked nano-carrier prepared by the preparation method of the lutetium marked nano-carrier.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Instruments and reagents for experimentation
Figure BDA0003255128430000071
Self-prepared reagent
(1)0.05MHCl 30% HCl 264. mu.L was diluted to a volume of 50mL with ultrapure water.
(2)0.25M sodium acetate (NaOAc) 1.025g of anhydrous sodium acetate powder was weighed into 50mL of ultrapure water and dissolved by sonication.
Example 1
A preparation method of a lutetium marked nano carrier comprises the following steps:
(1) before reaction, glucose-dependent insulinotropic polypeptide, Mal-PEG12DSPE and tris (2-carboxyethyl) phosphine, respectivelyAdjusting pH to 7.2, mixing the three solutions, shaking at room temperature for 10h, ultrafiltering the reaction product (with parameters of 4000 rpm, 25min, and 5 times of ultrafiltration), lyophilizing, and dissolving in tetrahydrofuran to obtain solution A;
wherein the glucose-dependent insulinotropic polypeptide and Mal-PEG are12-the mass ratio of DSPE to tris (2-carboxyethyl) phosphine is 8: 1: 13; glucose-dependent insulinotropic polypeptide, Mal-PEG12The volume ratio of the sum of DSPE and tris (2-carboxyethyl) phosphine to tetrahydrofuran is 1.6 g: 130L;
(2) adding dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45Mixing dimethyl sulfoxide solutions of DSPE, and shaking for 1.5h at room temperature to obtain a solution B;
wherein DOTA-NHS is reacted with NH in dimethyl sulfoxide2-PEG45The concentration of DSPE in dimethyl sulfoxide is 8 g/L; dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45-volume ratio of dimethyl sulfoxide solution of DSPE 3: 24;
(3) dissolving PCPDTBT in tetrahydrofuran to obtain a solution C;
wherein the mass-volume ratio of PCPDTBT to tetrahydrofuran is 1 g: 2L
(4) Mixing the solution A, the solution B and the solution C, carrying out ultrasonic (ultrasonic frequency is more than or equal to 20KHz) self-assembly for 12min in water, introducing nitrogen, passing through a PD10 gel column, connecting an intermediate product of a specific section, then carrying out ultrafiltration (ultrafiltration parameters are set to be 3000 r/min, 4min, and ultrafiltration is carried out for 1 time) to obtain DOTA-SPN-GIP, and adding water to obtain a DOTA-SPN-GIP solution;
wherein the water adding amount is 3-5 times of the total volume of the solution A, the solution B and the solution C; the volume ratio of the solution A to the solution B to the solution C is 130: 25: 40;
when the dosage of the glucose-dependent insulinotropic polypeptide is 1mg, the intermediate product is 4-5 mL flowing out of a PD10 gel column;
when the dosage of the glucose-dependent insulinotropic polypeptide is 2Nmg, the intermediate product is NmL of (3N +1) - (3+2) th flowing out of a PD10 gel column; the volume ratio of DOTA-SPN-GIP to water is 3: 10;
(5) subjecting the product obtained in step (4)DOTA-SPN-GIP solution, 148MBq177LuCl3Mixing HCl solution and 0.15M sodium acetate solution, oscillating at room temperature for 25min, adding PBS or normal saline into the reaction product, and ultrafiltering (setting ultrafiltration parameters are 3000 r/min, 4min, and ultrafiltering for 1 time) to obtain lutetium-labeled nano-carrier;
wherein the content of the first and second substances,177LuCl3the volume ratio of the HCl solution, the DOTA-SPN-GIP solution and the sodium acetate solution is 3: 4: 0.5; the volume ratio of the reaction product to the added PBS or physiological saline was 1: 3.
Example 2
A preparation method of a lutetium marked nano carrier comprises the following steps:
(1) before reaction, glucose-dependent insulinotropic polypeptide, Mal-PEG12Respectively adjusting the pH value of DSPE and tris (2-carboxyethyl) phosphine to 7.6, mixing the three, oscillating at room temperature for 14h, ultrafiltering the reaction product (with the parameter set to 6000 r/min, 35min, and ultrafiltering for 8 times), freeze-drying, and dissolving in tetrahydrofuran to obtain solution A;
wherein the glucose-dependent insulinotropic polypeptide and Mal-PEG are12-the mass ratio of DSPE to tris (2-carboxyethyl) phosphine is 12: 3: 15; glucose-dependent insulinotropic polypeptide, Mal-PEG12The volume ratio of the sum of DSPE and tris (2-carboxyethyl) phosphine to tetrahydrofuran is 3.6 g: 170L;
(2) adding dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45Mixing dimethyl sulfoxide solutions of DSPE, and shaking for 2.5 hours at room temperature to obtain a solution B;
wherein DOTA-NHS is reacted with NH in dimethyl sulfoxide2-PEG45The concentration of DSPE in dimethyl sulfoxide is 12 g/L; dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45-volume ratio of dimethyl sulfoxide solution of DSPE 5: 28;
(3) dissolving PCPDTBT in tetrahydrofuran to obtain a solution C;
wherein the mass-volume ratio of PCPDTBT to tetrahydrofuran is 2 g: 1L
(4) Mixing the solution A, the solution B and the solution C, carrying out ultrasonic (ultrasonic frequency is more than or equal to 20KHz) self-assembly for 18min in water, introducing nitrogen, passing through a PD10 gel column, connecting an intermediate product of a specific section, then carrying out ultrafiltration (ultrafiltration parameters are set to be 4000 revolutions per minute, 6min, and ultrafiltration is carried out for 1-3 times) to obtain DOTA-SPN-GIP, and adding water to obtain a DOTA-SPN-GIP solution;
wherein the water adding amount is 5 times of the total volume of the solution A, the solution B and the solution C; the volume ratio of the solution A to the solution B to the solution C is 170: 35: 60;
when the dosage of the glucose-dependent insulinotropic polypeptide is 1mg, the intermediate product is 5mL flowing out of a PD10 gel column;
when the dosage of the glucose-dependent insulinotropic polypeptide is 2Nmg, the intermediate product is NmL of (3N +1) - (3+2) th flowing out of a PD10 gel column; the volume ratio of DOTA-SPN-GIP to water is 7: 10;
(5) the DOTA-SPN-GIP solution obtained in the step (4) and 185MBq177LuCl3Mixing HCl solution and 0.35M sodium acetate solution, oscillating at room temperature for 35min, adding PBS or normal saline into the reaction product, and ultrafiltering (setting ultrafiltration parameters are 4000 r/min, 6min, and ultrafiltering for 3 times) to obtain lutetium-labeled nano-carrier;
wherein the content of the first and second substances,177LuCl3the volume ratio of the HCl solution, the DOTA-SPN-GIP solution and the sodium acetate solution is 5: 6: 1.5; the volume ratio of the reaction product to the added PBS or physiological saline was 1: 5.
Example 3
A preparation method of a lutetium marked nano carrier comprises the following steps:
(1) before reaction, glucose-dependent insulinotropic polypeptide, Mal-PEG12Respectively adjusting the pH value of DSPE and tris (2-carboxyethyl) phosphine to 7.4, mixing the three, oscillating at room temperature for 10-14 h, ultrafiltering the reaction product (the parameters are set to 5000 r/min, 30min, and ultrafiltering for 7 times), freeze-drying, and dissolving in tetrahydrofuran to obtain a solution A;
wherein the glucose-dependent insulinotropic polypeptide and Mal-PEG are12-the mass ratio of DSPE and tris (2-carboxyethyl) phosphine is 10: 2: 14; glucose-dependent insulinotropic polypeptide, Mal-PEG12Of the total mass of DSPE and tris (2-carboxyethyl) phosphine with tetrahydrofuranThe volume ratio is 2.6 g: 150L;
(2) adding dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45Mixing dimethyl sulfoxide solutions of DSPE, and shaking for 2 hours at room temperature to obtain a solution B;
wherein DOTA-NHS is reacted with NH in dimethyl sulfoxide2-PEG45The concentration of DSPE in dimethyl sulfoxide is 10 g/L; dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45-volume ratio of dimethyl sulfoxide solution of DSPE 4: 26;
(3) dissolving PCPDTBT in tetrahydrofuran to obtain a solution C;
wherein the mass-volume ratio of PCPDTBT to tetrahydrofuran is 1 g: 1L
(4) Mixing the solution A, the solution B and the solution C, carrying out ultrasonic (ultrasonic frequency is more than or equal to 20KHz) self-assembly for 15min in water, introducing nitrogen, passing through a PD10 gel column, connecting an intermediate product of a specific section, then carrying out ultrafiltration (ultrafiltration parameters are all set to 3500 rpm, 5min, and 2 times of ultrafiltration) to obtain DOTA-SPN-GIP, and adding water to obtain a DOTA-SPN-GIP solution;
wherein the water adding amount is 4 times of the total volume of the solution A, the solution B and the solution C; the volume ratio of the solution A to the solution B to the solution C is 150: 30: 50;
when the dosage of the glucose-dependent insulinotropic polypeptide is 1mg, the intermediate product is 4-5 mL flowing out of a PD10 gel column;
when the dosage of the glucose-dependent insulinotropic polypeptide is 2Nmg, the intermediate product is NmL of (3N +1) - (3+2) th flowing out of a PD10 gel column; the volume ratio of DOTA-SPN-GIP to water is 5: 10;
(5) the DOTA-SPN-GIP solution obtained in the step (4) and 165MBq177LuCl3Mixing HCl solution and 0.25M sodium acetate solution, oscillating at room temperature for 30min, adding PBS or normal saline into the reaction product, and ultrafiltering (setting of ultrafiltration parameters are 3500 rpm/min, 5min, and ultrafiltering for 2 times) to obtain lutetium-labeled nano-carrier;
wherein the content of the first and second substances,177LuCl3the volume ratio of the HCl solution, the DOTA-SPN-GIP solution and the sodium acetate solution is 4: 5: 1; reaction product with added PBS or physiological salineThe volume ratio of (A) to (B) is 1: 4.
Example 4177Lu-SPN-GIP radioactive purity analysis (with the lutetium-labeled nanocarrier obtained in example 3 as an experimental object, the same applies below)
(1) Centrifugally purifying the lutetium-labeled nano-carrier in a 100K ultrafiltration tube by using PBS as an eluent;
(2) collecting the upper solution of the ultrafiltration tube as a marked product;
(3) cutting the silica gel plate into paper strips with the length of 1 multiplied by 10cm, and marking the paper strips at the position of 1cm by drawing horizontal lines with a pencil;
(4) and (3) spotting the collected labeled product in a median transverse line at a position of 1cm by using a capillary pipette, taking ultrapure water as a developing agent (1mL), taking out the product when the product is developed to a position of 8cm, and naturally drying the product.
(5) And (3) lightly wrapping the dried silica gel paper strips with paper (preventing TCL from being polluted), and loading, measuring and analyzing.
(6) After purification of the tag177Lu-SPN-GIP was placed in normal saline NS and 10% FBS, respectively, and the radiochemical purity was measured at different time points (0.5h, 4h, 24h, 48 h).
As a result: (1)177labeling rate and radiochemical purity of Lu-SPN-GIP
177LuCl3The pH value of the labeled semiconductor polymer is adjusted to be 4-5 through an HCl-NaOAc buffer system, the reaction is carried out for half an hour at normal temperature, the labeling rate is 86.36 +/-6.12%, and although the labeling rate is reduced compared with that of a heating labeling method, the damage of semiconductor polymer nanoparticles is avoided. Through comparison of several developing agents, pure water is the most suitable developing agent and can completely free177Lu divided, labelled177Lu-SPN-GIP was all left at the origin. The specific results are shown in FIGS. 1 and 2 (radiochemical purity analysis; FIG. 1: dissociation)177LuCl3TLC result with water as developing agent; FIG. 2:177Lu-SPN-GIP developed TLC results with water as a developing agent).
(2)177Lu-SPN-GIP marker stability assay
After purification of the tag177Lu-SPN-GIP was placed in PBS and 10% FBS, respectively, and the radiochemical purity was measured after 0.5h, 4h, 24h, 48h, respectively. After 24 hours177Lu-SPN-GIP has an in vitro radiochemical purity of 95.52 +/-1.67% and an in vivo radiochemical purity of 89.46 +/-2.24% (P0.0198); the in vitro chemosynthesis purity is 89.78 +/-0.75% after 48h, and the in vivo chemosynthesis purity is 84.22 +/-2.60% (P is 0.0235). Indicating the mark177Lu-SPN-GIP has good in vitro and in vivo stability within 48h, and specific results thereof are shown in (FIG. 3)177Lu-SPN-GIP in vitro and in vivo stability analysis).
Example 5177Experiment of Effect of Lu-SPN-GIP on growth inhibition of CFPAC-1 cells
(1) Collecting CFPAC-1 cells in logarithmic growth phase, and regulating to 5 × 10 by trypsinization4one/mL, spread in 96-well plates at 100. mu.L per well, cell concentration 5X 103Per well, 5% CO at 37 ℃2The incubator stays overnight;
(2) changing the culture solution for each group, and adding 100 μ L of culture solution with prescribed dosage, wherein the concentration of each dosage is 0, 0.37, 3.7, 7.4, 11.1, 14.8, 18.5 MBq/mL; after 24 hours, replacing the normal culture medium to continue culturing;
(3) adding 10 mu LCCK8 solution (10%) at 0 hr, 24 hr, 48 hr, 72 hr and 96 hr after replacing normal culture medium, and culturing in incubator for 1 hr;
(4) after 1 hour, the absorbance at 450nm of each well was measured using a microplate reader. And calculating the relative survival rate of the cells according to the measured OD value. Cell viability ═ 100% (added material-blank)/(control-blank).
As a result: by adding177When the culture medium is replaced with the normal medium after the Lu-SPN-GIP is incubated for 24 hours, it can be observed that the cells show no growth inhibition effect within 24 hours, but the cumulative growth inhibition effect is gradually shown along with the time, and the culture is dose-dependent. Simultaneous and free group177LuCl3In contrast to the above-mentioned results,177Lu-SPN-GIP showed more excellent growth inhibitory effect, and the specific results are shown in FIG. 4(CFPAC-1 cells at different doses177Survival after different time in Lu-SPN-GIP) and FIG. 5(CFPAC-1 cells in177Lu-SPN-GIP and177LuCl3cell viability after medium 96 hours).
Example 6
1. CFPAC-1 cell pairs177Binding experiments with Lu-SPN-GIP
(1) Digesting the cells with 0.25% pancreatin when the cells grow to more than 90%, and adjusting the cell concentration to
1×105Per mL, 12-well plates were plated and 1mL of medium was added to each well. At 37 ℃ 5% CO2The incubator was overnight.
(2) The next day after the cells are completely attached to the wall, the cells are replaced177Lu-SPN-GIP and177 LuCl 33 multiple wells per group of the medium (37 kBq/mL).
(3) The culture medium added with the radioactive labeled drug is respectively acted on CFPAC-1 cells for 1 hour, 2 hours, 4 hours, 8 hours and 24 hours, then a pipette is used for sucking supernatant into an EP tube (corresponding to the number), and the cell bottom of the well is completely digested by pancreatin after being washed twice by PBS, and the whole cell is collected in the corresponding tube after being washed by PBS. The total radioactivity count T was measured.
(4) The EP tube was centrifuged for 10 minutes at 1500 rpm, the supernatant was discarded, and the cell pellet was washed twice with PBS, removed from the supernatant, and counted by cell pellet count B.
(5) The cell binding rate at different time points was B/T.times.100%.
2. The uptake of DOTA-SPN-GIP by CFPAC-1 cells was observed by confocal microscopy
(1) CFPAC-1 cells in logarithmic growth phase were taken and digested with 0.25% pancreatin, and cell concentration was adjusted and plated. Cofocal dish with diameter of 10mm, 105One/well, standing at 37 deg.C and 5% CO2The incubator is 24 hours.
(2) After 24 hours, the cells are attached to the wall and then are respectively added with DOTA-SPN-GIP of 25 mu g/mL and a control group (not added), and are cultured for 1h, 2h, 4h and 8h together, and two separate experiments are carried out at each time point.
(3) At various time points the effect was completed and fixed with 4% paraformaldehyde for 30 minutes.
(4) Then washed three times with PBS for 5 minutes each.
(5) Incubated with Hoechst33342(1:2000) in the dark at room temperature for 5 minutes, washed three times with PBS and stored in a moist dark box.
(6) And (3) respectively selecting 635nm and Hoechst33342 channels to excite and observe the cell uptake condition.
As a result: in this section, CFPAC-1 cells were studied primarily in177The uptake in Lu-SPN-GIP was reflected by the radioactivity counting of cell-bound radionuclides, and was confirmed visually by confocal microscopy, as shown in FIG. 6(CFPAC-1 cells in cell type)177Lu-SPN-GIP uptake) and FIG. 7 (uptake of SPN-GIP by CFPAC-1 cells at different time points):
the semiconductor polymer is modified on the surface of DOTA (1,4,7, 10-tetraazacyclododecane-tetraacetic acid), so that the marking of a nuclide lutetium 177 is facilitated, the method is convenient to synthesize, and the marking can be stably carried out at high efficiency under the normal temperature condition. The marking method is simple and easy to implement, and the mark is synthesized177Lu-SPN-GIP has good in vivo and in vitro stability. After marking177Lu-SPN-GIP ratio free177LuCl3Has more excellent cell activity inhibiting effect at the cell level.177The tumor cell inhibition effect of Lu-SPN-GIP is not only in radioactivity dose dependence, but also in time dependence, and after 24 hours of incubation, the inhibition effect is more obvious along with the longer observation period.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. A preparation method of a lutetium marked nano carrier is characterized by comprising the following steps:
(1) mixing glucose-dependent insulinotropic polypeptide and Mal-PEG12Mixing DSPE and tri (2-carboxyethyl) phosphine, reacting, purifying and freeze-drying a reaction product, and dissolving the reaction product in tetrahydrofuran to obtain a solution A;
(2) adding dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45-mixing dimethyl sulfoxide solutions of DSPE to obtain a solution B;
(3) dissolving PCPDTBT in tetrahydrofuran to obtain a solution C;
(4) mixing the solution A, the solution B and the solution C, carrying out ultrasonic self-assembly in water, introducing nitrogen, passing through a column, carrying out ultrafiltration to obtain DOTA-SPN-GIP, and adding water to obtain a DOTA-SPN-GIP solution;
(5) the DOTA-SPN-GIP solution obtained in the step (4),177LuCl3Mixing HCl solution and sodium acetate solution, reacting, adding PBS or normal saline into the reaction product, and performing ultrafiltration to obtain the lutetium-labeled nano-carrier.
2. The method for preparing a lutetium-labeled nanocarrier according to claim 1, wherein in step (1), the glucose-dependent insulinotropic polypeptide and Mal-PEG are used12The mass ratio of the DSPE to the tris (2-carboxyethyl) phosphine is 8-12: 1-3: 13-15;
before reaction, glucose-dependent insulinotropic polypeptide, Mal-PEG12Respectively adjusting the pH value of DSPE and tris (2-carboxyethyl) phosphine to 7.2-7.6, and then mixing for reaction;
the reaction is performed by shaking for 10-14 h at room temperature;
glucose-dependent insulinotropic polypeptide, Mal-PEG12The volume ratio of the total mass of the DSPE and the tri (2-carboxyethyl) phosphine to the tetrahydrofuran is 1.6-3.6 g: 130-170L.
3. The method for preparing a lutetium-labeled nanocarrier according to claim 1, wherein DOTA-NHS is reacted with NH in dimethyl sulfoxide in step (2)2-PEG45The concentration of the DSPE in the dimethyl sulfoxide is 8-12 g/L;
the mixing is performed by oscillating for 1.5-2.5 h at room temperature;
dimethyl sulfoxide solution of DOTA-NHS and NH2-PEG45The volume ratio of dimethyl sulfoxide solution of DSPE is 3-5: 24-28.
4. The preparation method of the lutetium-labeled nanocarrier according to claim 1, wherein the mass-to-volume ratio of PCPDTBT to tetrahydrofuran in step (3) is 1-2 g: 1-2L.
5. The preparation method of the lutetium labeled nano carrier as recited in claim 1, wherein the amount of water added in the step (4) is 3 to 5 times of the total volume of the solution A, the solution B and the solution C; the ultrasonic frequency is more than or equal to 20 KHz; the self-assembly time is 12-18 min.
6. The preparation method of the lutetium labeled nano carrier as recited in claim 1 or 5, wherein in the step (4), the volume ratio of the solution A, the solution B and the solution C is 130-170: 25-35: 40-60; introducing nitrogen, passing through PD10 gel column, collecting intermediate product of specific section, and ultrafiltering;
when the dosage of the glucose-dependent insulinotropic polypeptide is 1mg, the intermediate product is 4-5 mL flowing out of a PD10 gel column;
when the dosage of the glucose-dependent insulinotropic polypeptide is 2Nmg, the intermediate product is NmL of (3N +1) - (3+2) th flowing out of a PD10 gel column;
the volume ratio of DOTA-SPN-GIP to water is 3-7: 10.
7. The method of claim 1, wherein in step (5), the lutetium-labeled nanocarrier is prepared177LuCl3The emission amount of the HCl solution is 148-185 MBq;
177LuCl3the volume ratio of the HCl solution, the DOTA-SPN-GIP solution and the sodium acetate solution is 3-5: 4-6: 0.5-1.5; the concentration of the sodium acetate solution is 0.15-0.35M;
the reaction is performed by shaking at room temperature for 25-35 min.
8. The preparation method of a lutetium-labeled nanocarrier according to claim 1 or 7, wherein in step (5), the volume ratio of the reaction product to the added PBS or physiological saline is 1: 3-5.
9. The preparation method of the lutetium-labeled nano-carrier as claimed in claim 1, wherein the purification in step (1) is ultrafiltration, and the parameters are set to 4000-6000 rpm, 25-35 min, and 5-8 times of ultrafiltration;
in the steps (4) and (5), the ultrafiltration parameters are set to 3000-4000 revolutions per minute, 4-6 minutes and ultrafiltration is carried out for 1-3 times.
10. A lutetium labeled nanocarrier prepared according to any of claims 1-9.
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