CN115403697A - Temperature-sensitive fluorescent nano material and preparation method thereof - Google Patents
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Abstract
The invention belongs to the technical field of vascular embolization, and particularly relates to a temperature-sensitive fluorescent nano material and a preparation method thereof. The temperature-sensitive fluorescent nano material provided by the invention comprises: the rhodamine-labeled poly N-isopropyl acrylamide temperature-sensitive nanogel is prepared by at least taking N-isopropyl acrylamide and allyl rhodamine as synthetic monomers, and the allyl rhodamine has a structure shown as a formula (I'). The temperature sensitive fluorescent nano-tubeThe rice material not only has the characteristic of high chemical stability, but also does not influence the original physical and chemical properties of the temperature-sensitive nanogel, such as gelation temperature, particle size distribution, viscosity, embolism strength and the like.
Description
Technical Field
The invention belongs to the technical field of vascular embolization, and particularly relates to a temperature-sensitive fluorescent nano material and a preparation method thereof.
Background
The poly-N-isopropyl acrylamide temperature-sensitive nano gel has lower viscosity in a sol state, is converted into a non-flowable gel state from a good flowing state in a human body temperature environment, has good fluidity and embolization, can overcome the contradiction between the fluidity and the embolization of the traditional embolization agent, has drug-carrying slow-release performance, and is expected to become a new generation of injectable interventional embolization materials. For injectable interventional embolic materials, their systemic metabolic distribution in vivo is the basis for toxicological studies. The concentration of the temperature-sensitive nanogel in blood at different administration time is researched by carrying out fluorescence labeling on the temperature-sensitive nanogel, so that the method is an effective way for researching the metabolic distribution condition of the embolic material.
At present, the method for carrying out fluorescence labeling on the temperature-sensitive nanogel is mainly to combine fluorescent molecules on the temperature-sensitive nanogel by a physical method or a chemical method. Some researchers have tried to chemically graft 4- (4-dimethylaminostyryl) pyridine onto poly (NIPAM-co-CMS) to synthesize poly (NIPAM-co-HC) having both a fluorescence signal unit and a thermal response unit, and the detection temperature of the fluorescence signal of the aqueous solution of the polymer is limited to 25-40 ℃, and the fluorescence signal of the polymer is very weak at a temperature of less than 25 ℃ and reaches saturation at a temperature of more than 40 ℃. However, in the actual fluorescence signal detection experiment, the temperature is usually room temperature, so the above method of chemically grafting the fluorescence signal unit HC onto the N-isopropylacrylamide polymer has great limitations. Some researchers have developed a temperature-sensitive fluorescent nanomaterial: the rhodamine B/PolyNIPAM microsphere is synthesized by firstly synthesizing MPS modified rhodamine B/SiO 2 Taking the particle water dispersion as a seed, adding NIPAM, a cross-linking agent and an initiator to synthesize core-shell structure particles, and then adding a hydrofluoric acid solution to remove SiO 2 And (3) a layer. The method is complicated in operation and has been synthesizedIn the process, various materials need to be introduced, or certain biological toxicity exists, so that the method is not suitable for synthesizing injectable interventional embolization materials.
Disclosure of Invention
In view of the above, the present invention provides a temperature-sensitive fluorescent nano-material, which is suitable for being used as a fluorescent temperature-sensitive nanogel for injectable embolization materials, and simplifies the preparation process steps.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a temperature-sensitive fluorescent nanomaterial, comprising: the rhodamine-labeled poly N-isopropyl acrylamide temperature-sensitive nanogel is prepared by at least taking N-isopropyl acrylamide and allyl rhodamine as synthetic monomers;
the allylrhodamine has a structure shown as a formula (I'):
wherein R is 1 、R 2 、R 3 、R 4 Each independently selected from one of hydrogen, alkyl, cycloalkyl and hydroxyalkyl, R 5 、R 6 、R 7 And R 8 Each independently selected from one of hydrogen, alkyl, cycloalkyl, amino, halo, hydroxyalkyl, heterocycloalkyl, each R 9 ' independently of one another, is a substituted or unsubstituted allyl, each R 10 Each independently selected from at least one of hydrogen, isothiocyanate, alkyl, cycloalkyl and hydroxyalkyl, m is an integer from 1 to 5, n is an integer from 0 to 4, and the sum of m and n is not more than 5.
In the temperature-sensitive fluorescent nano material provided by the invention, allylrhodamine is a fluorescent molecular labeling monomer, and chemical labeling is realized by copolymerizing allylrhodamine with synthetic monomers such as N-isopropylacrylamide and the like, so that rhodamine-labeled poly N-isopropylacrylamide temperature-sensitive nano gel is prepared. Through experimental detection, the temperature-sensitive fluorescent nano material has the characteristic of high chemical stability, and does not influence the original physical and chemical properties of the temperature-sensitive nano gel, such as gelation temperature, particle size distribution, viscosity, embolism strength and the like. In addition, the lowest effective detection limit of the temperature-sensitive fluorescent nano material reaches 0.61mg/L, which is beneficial to exploring the whole body metabolism condition of the temperature-sensitive nano gel vascular embolization agent in the process of treating complete liver cancer.
In a second aspect, the invention further provides a preparation method of the temperature-sensitive fluorescent nanomaterial, and the preparation method comprises the following steps: forming a synthesis system of poly N-isopropyl acrylamide temperature-sensitive nanogel, and carrying out polymerization reaction;
wherein the synthesis system comprises a monomer mixture comprising at least: n-isopropylacrylamide and allylrhodamine.
According to the method provided by the invention, the allyl rhodamine is added into a synthesis system of the poly N-isopropyl acrylamide temperature-sensitive nanogel, so that monomers such as the allyl rhodamine and the N-isopropyl acrylamide are polymerized to synthesize the poly N-isopropyl acrylamide temperature-sensitive nanogel, the fluorescent molecules are successfully and chemically grafted onto the temperature-sensitive nanogel, the preparation process steps are simplified, and the synthesized temperature-sensitive fluorescent nanomaterial is high in chemical stability and does not influence the original physical and chemical properties of the temperature-sensitive nanogel, such as gelation temperature, particle size distribution, viscosity, embolism intensity and the like.
Drawings
FIG. 1 is a photograph of the temperature-sensitive nanogels prepared in example 1 and comparative example 1 at 25 ℃ and 37 ℃, which reflects the macroscopic physical states of the temperature-sensitive nanogels at 25 ℃ and 37 ℃ before and after fluorescent labeling, wherein the left image corresponds to the temperature-sensitive nanogel before fluorescent labeling, and the right image corresponds to the temperature-sensitive nanogel after fluorescent labeling;
FIG. 2 is a linear relationship diagram between the concentration of the temperature-sensitive nanogel prepared in example 1 in the range of 0.61-4.88mg/L and the fluorescence intensity, wherein the abscissa is the concentration and the ordinate is the fluorescence intensity;
FIG. 3 is the NMR spectrum of allylrhodamine, 3-bromo-1-propene and rhodamine B synthesized in example 1.
Detailed Description
In the description of the present invention, the compounds and derivatives thereof are named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, colombia, ohio) naming system, and the groups of the compounds specifically referred to are illustrated and described as follows:
"alkyl" refers to a class of saturated chain hydrocarbon radicals containing only two atoms of carbon and hydrogen, having a straight and/or branched carbon chain, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like. The number of carbon atoms in the alkyl group of the embodiments of the present invention is 1 to 10, and in particular embodiments the number of carbon atoms in the alkyl group is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
"cycloalkyl" refers to a group of saturated hydrocarbon groups containing cyclic structures such as monocyclic, bicyclic, fused, spiro, and bridged rings in the molecule, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, tetrahydronaphthyl, adamantyl, and the like. The number of carbon atoms in the cycloalkyl group of the embodiments of the present invention is 3 to 10, and in particular embodiments, the number of carbon atoms in the cycloalkyl group is 3, 4, 5, 6, 7, 8, 9, or 10.
"hydroxyalkyl" refers to a hydroxy-substituted alkyl group, such as-CH 2 OH the number of carbon atoms in the hydroxyalkyl groups of the embodiments of the present invention is 1 to 5, and in particular embodiments the number of carbon atoms in the hydroxyalkyl group is 1, 2, 3, 4, or 5.
The "amino group" refers to a group formed by substituting the hydrogen of an amino group with an alkyl group, and the number of carbon atoms is 1 to 10.
"halogen" refers to elements of group VIIA of the periodic Table of elements, including chlorine (Cl), bromine (Br), iodine (I), and the like.
"heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom in the molecule, including, but not limited to, azepanyl, azetidinyl, indolinyl, morpholinyl, pyrazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroindazolyl, tetrahydroindolyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinoxalinyl, tetrahydrothiopyranyl, thiazolidinyl, thiomorpholinyl, thioxanthyl, thiaxanyl, and the like. The number of carbon atoms in the heterocycloalkyl group is from 3 to 20, and in some embodiments, the number of carbon atoms in the heterocycloalkyl group is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"alkenyl" refers to a class of alkyl groups containing at least one carbon-carbon double bond, such as ethenyl, propenyl, and the like. The number of carbon atoms of the alkenyl group is 2 to 20, and in some embodiments, the number of carbon atoms of the alkenyl group is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"carboxy" means-COOH and isothiocyanate means-N = C = S.
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
The embodiment of the invention provides a temperature-sensitive fluorescent nano material, which comprises the following components in part by weight: the rhodamine-labeled poly N-isopropyl acrylamide temperature-sensitive nanogel is prepared by at least taking N-isopropyl acrylamide and allyl rhodamine as synthetic monomers;
the allylrhodamine has a structure shown as a formula (I'):
wherein R is 1 、R 2 、R 3 、R 4 Each independently selected from one of hydrogen, alkyl, cycloalkyl and hydroxyalkyl, R 5 、R 6 、R 7 And R 8 Each independently selected from one of hydrogen, alkyl, cycloalkyl, amino, halo, hydroxyalkyl, heterocycloalkyl, each R 9 ' independently of one another, is a substituted or unsubstituted allyl, each R 10 Each independently selected from at least one of hydrogen, isothiocyanate, alkyl, cycloalkyl and hydroxyalkyl, m is an integer from 1 to 5, n is an integer from 0 to 4, and the sum of m and n is not more than 5.
In the temperature-sensitive fluorescent nano material provided by the embodiment of the invention, allylrhodamine is a fluorescent molecular labeling monomer, and chemical labeling is realized by polymerizing the allylrhodamine with monomers such as N-isopropylacrylamide and the like, so that the rhodamine-labeled poly N-isopropylacrylamide temperature-sensitive nano gel is prepared.
It can be understood that the expression "prepared by using at least N-isopropylacrylamide and allylrhodamine as synthetic monomers" means that synthetic monomers other than N-isopropylacrylamide and allylrhodamine can be added in the synthesis of the rhodamine-labeled poly N-isopropylacrylamide type temperature-sensitive nanogel, and are not limited to two monomers, namely N-isopropylacrylamide and allylrhodamine. For example, rhodamine-labeled poly-N-isopropylacrylamide temperature-sensitive nanogel is formed by copolymerizing N-isopropylacrylamide (serving as a main monomer), a comonomer and allylrhodamine (a fluorescence labeling monomer), wherein the fluorescence labeling monomer is one of the monomers.
Specifically, allylrhodamine provides a reactive group (double bond of allyl) to be used as one of monomers for synthesizing poly N-isopropylacrylamide temperature-sensitive nanogel, so that fluorescent molecules are successfully and chemically grafted onto the temperature-sensitive nanogel.
In some embodiments, the allylrhodamine is one of allylrhodamine B, allylrhodamine isothiocyanate B, and allylrhodamine 6G.
In the formula (I'), R 9 ' is a substituted or unsubstituted allyl group. It is understood that the unsubstituted allyl group is-CH 2 -CH＝CH 2 And substituted allyl is a derivative group in which at least one hydrogen atom is replaced by a substituent, such as: -CH 2 -CH＝CH-CH 3 、-CH 2 -C(CH 3 )＝CH 2 、-CH(CH 3 )-CH＝CH-CH 3 And the like. In some embodiments, the substituent on the substituted allyl isAn alkyl group having 5 or less carbon atoms.
The poly N-isopropyl acrylamide temperature-sensitive nano gel is a cross-linked polymer formed by taking N-isopropyl acrylamide as a main monomer, and besides the allyl rhodamine and the main monomer (N-isopropyl acrylamide), the monomers participating in copolymerization also comprise other monomers, and in some embodiments, the other monomers of the poly N-isopropyl acrylamide temperature-sensitive nano gel comprise at least one of acrylic acid, N-N-propyl acrylamide, methyl methacrylate, hydroxyethyl methacrylate and acrylamide.
The poly-N-isopropyl acrylamide temperature-sensitive nanogel is a cross-linked polymer, and is cross-linked and copolymerized under the action of a cross-linking agent to form a cross-linked polymer with a three-dimensional network structure, which is different from the traditional linear polymer. The cross-linking agent can be selected from one or more of N, N '-methylene bisacrylamide, N' -ethylene bisacrylamide, 1, 3-propylene bisacrylamide, ethylene diacrylate, diethylene glycol diacrylate, triethylene glycol diacrylate, trimethylolpropane triacrylate and pentaerythritol triacrylate.
Based on the above examples, the weight ratio of allylrhodamine to N-isopropylacrylamide is (4-6): 4000-6000. Therefore, the fluorescence characteristic of the temperature-sensitive fluorescent nano material is ensured.
In the embodiment of the invention, allyl rhodamine B marked poly (N-isopropyl acrylamide-co-butyl methacrylate) is used as a test sample, the stability and the physical and chemical properties of the temperature-sensitive nanogel are respectively tested, and the following results are found: the temperature-sensitive fluorescent nano material has the characteristic of high chemical stability, and does not influence the original physical and chemical properties of the temperature-sensitive nano gel, such as gelation temperature, particle size distribution, viscosity, embolism strength and the like. In addition, the lowest effective detection limit of the temperature-sensitive fluorescent nano material reaches 0.61mg/L, and the method is favorable for exploring the whole body metabolism condition of the temperature-sensitive nano gel vascular embolization agent in the process of treating the complete liver cancer.
On the basis of the technical scheme of the temperature-sensitive fluorescent nano material, the embodiment of the invention also provides a preparation method of the temperature-sensitive fluorescent nano material, which comprises the following steps: forming a synthesis system of poly N-isopropyl acrylamide temperature-sensitive nanogel, and carrying out polymerization reaction; wherein the synthesis system comprises a monomer mixture comprising at least: n-isopropylacrylamide and allylrhodamine.
According to the method provided by the embodiment of the invention, the allyl rhodamine is added into the synthesis system of the poly N-isopropyl acrylamide temperature-sensitive nanogel, so that monomers such as the allyl rhodamine and the N-isopropyl acrylamide are polymerized to synthesize the poly N-isopropyl acrylamide temperature-sensitive nanogel, the fluorescent molecules are successfully and chemically grafted onto the temperature-sensitive nanogel, the preparation process steps are simplified, and the synthesized temperature-sensitive fluorescent nanomaterial is high in chemical stability and does not influence the original physical and chemical properties of the temperature-sensitive nanogel, such as gelation temperature, particle size distribution, viscosity, embolism intensity and the like.
Specifically, the step of forming the synthesis system of the poly-N-isopropylacrylamide temperature-sensitive nanogel mainly refers to the construction of a material system before reaction, for example, the monomer mixture, the surfactant and the crosslinking agent required by the reaction are mixed in a reaction solvent.
Wherein, the composition of the monomer mixture can be flexibly adjusted according to the type of the poly-N-isopropylacrylamide temperature-sensitive nano-gel to be synthesized. In some embodiments, the monomer mixture further comprises other monomers including at least one of acrylic acid, N-propyl acrylamide, methyl methacrylate, butyl methacrylate, hydroxyethyl acrylate, acrylamide. Thus, poly-N-isopropylacrylamide polymers labeled with synthetic fluorescent molecules, such as poly (NIP-co-AA), poly (NIP-co-NNP), poly (NIP-co-MMA), poly (NIP-co-BMA), poly (NIP-co-HEMA), poly (NIP-co-HEA), and poly (NIP-co-AAm), and the like.
The embodiment of the invention does not specifically limit the types and sources of the surfactant, the cross-linking agent and the reaction solvent, and can be adjusted according to the characteristics of the poly-N-isopropylacrylamide temperature-sensitive nanogel to be synthesized. In some embodiments, the surfactant is selected from sodium lauryl sulfate, the reaction solvent is selected from hydrophilic systems such as water, physiological saline, phosphate buffered saline, and the like, and the crosslinker is selected from N, N '-methylenebisacrylamide, N' -ethylenebisacrylamide, 1, 3-propylenediacrylamide, ethyleneglycol diacrylate, diethylene glycol diacrylate, triethylene glycol diacrylate, trimethylolpropane triacrylate, pentaerythritol triacrylate, and the like.
And carrying out polymerization reaction to enable all monomers and the cross-linking agent to carry out cross-linking copolymerization under the catalysis of the initiator, thereby preparing the temperature-sensitive fluorescent nano material. The polymerization reaction of the embodiment of the present invention is mainly a free radical polymerization reaction of an alkene monomer, and thus, the initiator is mainly selected from azo type, peroxy type and redox type initiators capable of initiating a free radical polymerization reaction, such as potassium persulfate or ammonium persulfate in some embodiments.
Taking MBA cross-linked poly (NIP-co-BMA) as an example, the preparation method of the temperature-sensitive fluorescent nano material provided by the embodiment of the invention can be as follows:
adding N-isopropyl acrylamide, allyl rhodamine, sodium dodecyl sulfate and MBA into a three-necked bottle provided with a reflux condenser tube and an air guide device, dissolving the mixture by using ultrapure water under magnetic stirring, introducing high-purity nitrogen into the reaction system for 20-40 min, heating the reaction system to 65-75 ℃, adding an initiator potassium persulfate, and adding N into the mixture 2 Reacting for 0.5-1h at 65-75 ℃ in the atmosphere, adding butyl methacrylate, continuing to react for 4-5 h to obtain turbid suspension, dialyzing and purifying the suspension in ultrapure water, and freeze-drying to obtain freeze-dried powder, namely the target product.
In the embodiment of the invention, the preparation method of the allylrhodamine comprises the following steps:
s011, reacting rhodamine, allyl halide and alkali;
s012, adding a precipitator after the reaction is finished, mixing, filtering, collecting filtrate, and drying the filtrate;
wherein the rhodamine has a structure shown as a formula (I):
R 1 、R 2 、R 3 、R 4 each independently selected from one of hydrogen, alkyl, cycloalkyl and hydroxyalkyl, R 5 、R 6 、R 7 And R 8 Each independently selected from one of hydrogen, alkyl, cycloalkyl, amino, halo, hydroxyalkyl and heterocycloalkyl, and each R 9 Each independently selected from one of hydrogen, alkyl, cycloalkyl, hydroxyalkyl and heterocycloalkyl, and each R 10 Each independently selected from at least one of hydrogen, isothiocyanate, alkyl, cycloalkyl and hydroxyalkyl, m is an integer from 1 to 5, n is an integer from 0 to 4, and the sum of m and n is not more than 5.
Specifically, in step S011, rhodamine provides a reactive group: carboxyl and/or ester group to form-COO under catalysis of base - . Rhodamine has a structure shown as a formula (I), and through reaction, allyl is used for substituting R 9 And allylrhodamine is formed. In some embodiments, the rhodamine is one of rhodamine B, rhodamine isothiocyanate B, and rhodamine 6G.
The allylic haloalkenes contain at least one double bond and at least one halogen atom is attached to a saturated carbon atom separated from an unsaturated carbon atom by a single bond. Under the catalysis of base, the halogen atom of allyl halide is separated to form a carbonium ion intermediate, -COO - Reacts with a carbonium ion intermediate to introduce allyl into rhodamine. In addition to the above examples, the allylrhodamine formed after the reaction is allylrhodamine B, allylisothiocyanato rhodamine B, allylrhodamine 6G, and the like, correspondingly.
In some embodiments, the substituent on the double bond in the allylic haloalkene is hydrogen or an alkyl group having 5 or fewer carbon atoms. In a specific embodiment, the allylic haloalkene is selected from one of 3-bromo-1-propene, 3-chloro-1-propene, 3-iodo-1-propene, 3-bromo-1-butene, 3-iodo-1-butene, 3-chloro-1-butene, 3-bromo-2-methyl-1-propene, 3-chloro-2-methyl-1-propene, and 3-iodo-2-methyl-1-propene. The allyl halogenated alkene can well dissolve rhodamine, alkali and allyl rhodamine generated by reaction, and has moderate reaction activity with rhodamine, so that the reaction is controllable. Meanwhile, the melting point, the boiling point and the viscosity are moderate, and the volatile organic silicon compound is easy to remove by heating and volatilization.
The base is used as a catalyst to promote the reaction of rhodamine containing carboxyl and/or ester group and allyl halide so as to introduce allyl into the rhodamine, and can neutralize acid formed by the reaction of the rhodamine and the allyl halide so as to promote the forward movement of the reaction. In some embodiments, the base is selected from at least one of anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous lithium carbonate, anhydrous sodium bicarbonate, anhydrous potassium bicarbonate, anhydrous lithium bicarbonate. The sources of the alkali are wide, the reaction condition of the alkali and the acid is mild, and the operation is convenient. Meanwhile, the carbonates are selected to be anhydrous carbonates, which can promote the forward movement of the reaction to a certain extent.
On the basis of the above embodiment, the amounts of rhodamine, allylic haloalkene and alkali are adjusted, and the reaction conditions are adjusted to ensure that the reaction has higher conversion rate.
In some embodiments, the molar ratio of rhodamine, allylic haloalkene, and base is 1 (8-12) to (0.5-6). Thus, the rhodamine and the allyl halogenated alkene are fully reacted, and the conversion rate of the reaction can reach 100%. In specific examples, when 1 mole of rhodamine is used, the allylic haloalkene is used in an amount of 8 moles, 9 moles, 10 moles, 11 moles, or 12 moles, and the base is used in an amount of 0.5 moles, 1.1 moles, 1.8 moles, 2.3 moles, 3.5 moles, 4.3 moles, 5.6 moles, or 6 moles.
In some embodiments, the reacting comprises: reacting for 20-30 hours at 60-85 ℃ under the conditions of sealing and avoiding light. On one hand, the reaction is controlled to be carried out in a closed and light-proof environment, so that the solvent is prevented from volatilizing in the reaction process, and the fluorescent characteristic of the rhodamine is prevented from being influenced by external illumination for a long time. On the other hand, the reaction is controlled to be carried out at 60-85 ℃ for 20-30 hours, so as to ensure that the rhodamine and the allyl halogenated alkene are fully reacted, and the conversion rate of the reaction can reach 100%. In specific examples, the reaction temperature is 60 ℃, 65 ℃, 71 ℃, 76 ℃, 81 ℃ or 85 ℃ and the reaction time is 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours or 30 hours.
In step S012, a precipitating agent is added after the reaction is finished, and the precipitating agent is selected from organic solvents that do not dissolve the alkali and the byproducts formed by the reaction in which the alkali participates, so that the byproducts are precipitated in the process of mixing treatment, thereby achieving the purpose of purifying the target product. Meanwhile, the precipitator is a volatile organic solvent, so that the allyl halide which does not participate in the reaction is heated and removed together with the precipitator in the drying process, and the allyl rhodamine is basically obtained after the drying process. In some embodiments, the precipitating agent is at least one of absolute ethanol, absolute acetone, and absolute methanol. The precipitating agents can well dissolve allylrhodamine and allylic haloalkene, have boiling points higher than that of the allylic haloalkene, and can take away unreacted allylic haloalkene in the heating volatilization process. In addition, the precipitants do not dissolve carbonates such as anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous lithium carbonate and the like and products formed by the reaction of the carbonates and the halogen acid, and the purity of the products is favorably improved.
Adding a precipitator for mixing treatment, so that the precipitator is fully and uniformly mixed with all components in the system, and the alkali which is not dissolved by the precipitator and the product formed by the alkali participating in the reaction are precipitated and separated out.
The amount of the precipitant should be able to remove impurities (alkali and byproducts formed by the alkali participating in the reaction) in the system, and the embodiment of the present invention is not specifically limited herein.
The step of adding the precipitant to perform the mixing treatment may take part in the conventional operations in the art, for example, a method of mechanical stirring or ultrasound after adding the precipitant.
Filtering to remove the precipitate, wherein the collected filtrate mainly contains allylrhodamine, a reactant solvent, a precipitating agent and the like. And then, drying the filtrate to remove the reaction solvent together with the precipitant by heating and volatilization, so that the dried product is the target product allyl rhodamine.
The step of drying the filtrate can be performed by conventional procedures in the art, such as vacuum low-temperature concentration or heating concentration. In some embodiments, the step of drying the filtrate comprises: the filtrate is concentrated to dryness at 50-70 ℃.
The method for preparing the allylrhodamine, provided by the embodiment of the invention, can be used for efficiently synthesizing the allylrhodamine, and has the advantages of simplified process steps, high conversion rate and high product purity. Compared with the prior art, it has following advantage:
(1) The allyl haloalkene is simultaneously used as a reaction substrate and a reaction solvent, so that the rhodamine is promoted to be fully contacted with the allyl haloalkene, the conversion rate of synthesizing the allyl rhodamine B from the rhodamine B is greatly improved, and the conversion rate of the reaction reaches 100 percent through experimental verification;
(2) The allyl halogenated alkene is easy to remove by heating after the reaction is finished, so that the problem that excessive time and labor cost are needed for removing DMF (dimethyl formamide) serving as a reaction solvent in the prior art is solved;
(3) After the reaction is finished, a precipitator is added for mixing treatment to remove alkali and byproducts formed by the participation of the alkali in the reaction, the step of separation and purification by column chromatography is omitted, and allyl haloalkene which does not participate in the reaction is carried out in the drying process, so that the purification process is greatly simplified.
The allylrhodamine prepared by the method for preparing allylrhodamine disclosed by the embodiment of the invention has high purity and no impurity residue (the residual impurity is allyltype halogenated alkene or has certain biotoxicity), and the method is applied to labeling to obtain the fluorescent poly-N-isopropylacrylamide temperature-sensitive nanogel and has high safety.
In order to make the above implementation details and operations of the present invention clearly understood by those skilled in the art, and to make the progress of the temperature-sensitive fluorescent nanomaterial and the preparation method thereof significantly apparent, the following examples illustrate the implementation of the present invention.
Example 1
S11, synthesizing allyl rhodamine B
(1) Adding rhodamine B, 3-bromo-1-propylene and anhydrous sodium carbonate into a penicillin bottle according to the molar ratio of rhodamine B (HPLC grade, 99%, shanghai Mecline), 3-bromo-1-propylene (AR, 98%, shanghai Mecline) and anhydrous sodium carbonate of 1;
(2) Adding absolute ethyl alcohol after the reaction in the step S111 is finished, fully mixing and stirring, filtering, and collecting filtrate; and (3) carrying out rotary evaporation on the filtrate at the temperature of 60 ℃ until the filtrate is dried, and collecting a solid product, namely the allyl rhodamine B.
S12, synthesizing allyl rhodamine B marked poly (NIP-co-BMA)
Adding 2.2632g of N-isopropylacrylamide, 2.2632mg of allylrhodamine B, 0.032g of sodium dodecyl sulfate and 0.0324g of N, N' -methylenebisacrylamide into a three-necked bottle provided with a reflux condenser and an air guide device, dissolving the mixture by using ultrapure water under magnetic stirring, introducing high-purity nitrogen into the reaction system for 30min, heating the reaction system to 65 ℃, adding 0.0952g of potassium persulfate, and adding the mixture into N 2 Reacting for 1h at 75 ℃ in the atmosphere, adding 0.168mL of butyl methacrylate, continuing to react for 4h, dialyzing and purifying the reaction solution in ultrapure water, and freeze-drying to obtain the freeze-dried powder, namely the target product.
Example 2
S21, synthesizing allyl rhodamine 6G
(1) Adding rhodamine 6G, 3-iodine-1-propylene and anhydrous potassium carbonate into a penicillin bottle according to the molar ratio of rhodamine 6G (HPLC grade, 99%, shanghai Mecline), 3-iodine-1-propylene (AR, 98%, shanghai Mecline) and anhydrous potassium carbonate being 1;
(2) Adding acetone after the reaction in the step 2.1 is finished, fully mixing and stirring, filtering, and collecting filtrate; and (3) carrying out rotary evaporation on the filtrate at 70 ℃ until the filtrate is dried, and collecting a solid product, namely the allyl rhodamine 6G.
S22, synthesizing allyl rhodamine 6G marked poly (NIP-co-AAm)
2.263G N-isopropyl acrylamide, 0.014G acrylamide (AAm), 3.395mg allyl rhodamine 6G, 0.03G sodium dodecyl sulfate and 0.031g N, N' -methylene bisacrylamide were put into a three-necked flask equipped with a reflux condenser and an air guide, dissolved with ultrapure water under magnetic stirring, and then high-purity nitrogen was introduced into the reaction system for 30min, the reaction system was heated to 70 ℃, 0.0452G potassium persulfate was added, and the mixture was stirred in N 2 Reacting for 4.5h in the atmosphere, dialyzing and purifying the reaction solution in ultrapure water, and freeze-drying to obtain the freeze-dried powder which is the target product.
Example 3
S31, synthesizing allyl rhodamine isothiocyanate B
(1) Adding rhodamine isothiocyanate rhodamine B, 3-bromo-1-butene and anhydrous lithium carbonate into a penicillin bottle according to the molar ratio of rhodamine isothiocyanate rhodamine B (HPLC grade, 99 percent, shanghai Mecline), 3-bromo-1-butene (AR, 98 percent, shanghai Mecline) and anhydrous lithium carbonate of 1.5, covering the cover of the penicillin bottle, and heating to 60 ℃ under the conditions of sealing and keeping out of the sun to react for 35 hours;
(2) Adding methanol after the reaction in the step 3.1 is finished, fully mixing and stirring, filtering, and collecting filtrate; and (3) carrying out rotary evaporation on the filtrate at 50 ℃ until the filtrate is dried, and collecting a solid product, namely the allyl rhodamine isothiocyanate rhodamine B.
S32, synthesizing allyl rhodamine isothiocyanate B marked poly (NIP-co-NNP)
Adding 1.488g of N-isopropyl acrylamide, 0.182g of N-N-propyl acrylamide (NNPAAm), 1.042mg of allyl rhodamine B isothiocyanate and 0.03g of sodium dodecyl sulfate into a three-necked bottle provided with a reflux condenser tube and an air guide device, dissolving the mixture by using ultrapure water under magnetic stirring, introducing high-purity nitrogen into the reaction system for 30min, adding 0.05g of ammonium persulfate, heating the reaction system to 65 ℃, reacting for 5h, dialyzing and purifying the reaction liquid in the ultrapure water, and freeze-drying the reaction liquid to obtain the freeze-dried powder, namely the target product.
Comparative example 1
This comparative example synthesizes poly (NIP-co-BMA) not labeled with allylrhodamine B according to step S12 of example 1, and the synthesis method is different from that of example 1 in that: in step S12, allylrhodamine B is not added. The synthesized product is regarded as temperature-sensitive nanogel before labeling.
Test example
1. The particle size, PDI, viscosity, complex shear modulus, and macroscopic morphology of the temperature-sensitive nanogels of example 1 and comparative example 1 (i.e., temperature-sensitive nanogels before and after fluorescent labeling) were measured, respectively, and the results are shown in table 1 and fig. 1.
As shown by the result, the temperature-sensitive nanogel before and after fluorescent labeling has no obvious difference in particle size between 25 ℃ and 37 ℃ after being diluted by 25 times, the particle size uniformity (PDI) is good, and the fact that the grafting of the allylrhodamine B does not influence the particle size and uniformity of the temperature-sensitive nanogel can be inferred. The comparison result of the liquid viscosity of the temperature-sensitive nanogel at 25 ℃ and the gel-state complex shear modulus at 37 ℃ shows that the grafting of the allyl rhodamine B has no influence on the two key indexes.
TABLE 1 Performance indexes of temperature-sensitive nanogels before and after fluorescence labeling
| Performance index | Comparative example 1 | Example 1 |
| Particle size (nm) at 25 ℃ | 219.1 | 216.2 |
| 25℃，PDI | 0.063 | 0.019 |
| Particle size (nm) at 37 ℃ | 88.87 | 89.88 |
| 37℃，PDI | 0.011 | 0.017 |
| Viscosity (mPas) at 25 DEG C | 38.19 | 39.89 |
| Complex shear modulus (Pa) at 37 deg.C | 85.31 | 86.38 |
2. Diluting the temperature-sensitive nanogel after the fluorescence labeling according to multiple times, and performing E m ＝580nm、E x In the range of 0.61-4.88mg/L under the condition of =500nm, the linear relation between the concentration and the fluorescence intensity is detected, as can be seen from figure 2, the linear relation between the gel and the fluorescence intensity is good, and the coefficient R is determined by linear regression 2 ＝0.9999。
Table 2 shows that the lowest effective detection concentration of the gel reaches 0.61mg/L, and the result shows that the temperature-sensitive nanogel after being fluorescently labeled has quantitative tracing capacity under trace concentration.
TABLE 2 detection table for concentration and fluorescence intensity of fluorescence-labeled temperature-sensitive nanogel
3. Research on external elution behavior and long-term stability of temperature-sensitive nanogel after fluorescent labeling
Selecting an elution system consisting of a four-channel peristaltic pump and a digital display constant-temperature water bath, keeping the temperature of the sample and the water for injection for elution at 37 ℃, and setting 4 groups of parallel samples, wherein each group is 200 mu L; setting the speed of water for injection at 500 mu L/min, collecting elution solution times, and taking points according to the initial dense point and the later loose point. After the elution is finished, 4 groups of samples are detected, and the fluorescence intensity and the linear relation of the samples under different dilution concentrations are consistent with those before the elution.
At E m ＝580nm，E x And under the condition of 500nm, detecting the fluorescence intensity of the eluent collected at different time points, and simulating whether the temperature-sensitive nanogel has a monomer or oligomer eluted from a gel network to influence the normal metabolic tracing judgment of the temperature-sensitive nanogel after the temperature-sensitive nanogel completes embolism at the focus position in a gel state. The control group had an average fluorescence intensity value of-2.929 for water for injection. From the results in Table 3, it can be judged that no fluorescent substance was eluted from the gel network in the sample. The fluorescence intensity can effectively reflect the metabolic concentration of the temperature-sensitive nanogel.
TABLE 3 detection table for in vitro elution of temperature-sensitive nanogels after fluorescent labeling
4. Taking the allylrhodamine B synthesized in the step S11, and 3-bromo-1-propene and rhodamine B to perform nuclear magnetic resonance detection respectively, wherein the hydrogen spectra are shown in FIG. 3, and Table 4 shows the results of identifying each hydrogen signal in FIG. 3. The result shows that step S11 of example 1 successfully synthesizes allylrhodamine B, allyls are bonded to rhodamine B, and the hydrogen spectrum signal is clear, which reflects that the synthesized allylrhodamine B has higher purity.
TABLE 4
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A temperature-sensitive fluorescent nanomaterial, comprising: the rhodamine-labeled poly N-isopropyl acrylamide temperature-sensitive nanogel is prepared by at least taking N-isopropyl acrylamide and allyl rhodamine as synthetic monomers;
the allylrhodamine has a structure shown as a formula (I'):
wherein R is 1 、R 2 、R 3 、R 4 Each independently selected from one of hydrogen, alkyl, cycloalkyl and hydroxyalkyl, R 5 、R 6 、R 7 And R 8 Each independently selected from one of hydrogen, alkyl, cycloalkyl, amino, halo, hydroxyalkyl, heterocycloalkyl, each R 9 ' independently of one another, is a substituted or unsubstituted allyl, each R 10 Each independently selected from at least one of hydrogen, isothiocyanate, alkyl, cycloalkyl and hydroxyalkyl, m is an integer from 1 to 5, n is an integer from 0 to 4, and the sum of m and n is not more than 5.
2. The temperature-sensitive fluorescent nanomaterial according to claim 1, wherein a substituent on the substituted allyl group is an alkyl group having 5 or fewer carbon atoms; and/or
The synthetic monomer also comprises other monomers, and the other monomers comprise at least one of acrylic acid, N-N-propyl acrylamide, methyl methacrylate, butyl methacrylate, hydroxyethyl acrylate and acrylamide.
3. The temperature-sensitive fluorescent nanomaterial according to claim 1, wherein the allylrhodamine is one of allylrhodamine B, allylrhodamine isothiocyanate B, and allylrhodamine 6G.
4. The temperature-sensitive fluorescent nanomaterial according to any one of claims 1 to 3, wherein the weight ratio of the allylrhodamine to the N-isopropylacrylamide is (4-6): 4000-6000).
5. A preparation method of the temperature-sensitive fluorescent nano-material according to any one of claims 1 to 4, characterized in that the preparation method comprises the following steps: forming a synthesis system of poly N-isopropyl acrylamide temperature-sensitive nanogel, and carrying out polymerization reaction;
wherein the synthesis system comprises a monomer mixture comprising at least: n-isopropylacrylamide and allylrhodamine.
6. The method of claim 5, wherein the monomer mixture further comprises other monomers, and the other monomers comprise at least one of acrylic acid, N-N-propyl acrylamide, methyl methacrylate, butyl methacrylate, hydroxyethyl acrylate, and acrylamide.
7. The method according to claim 5, wherein the method for producing allylrhodamine comprises:
reacting rhodamine, allyl halide and alkali;
adding a precipitator after the reaction is finished, mixing, filtering, collecting filtrate, and drying the filtrate;
wherein the rhodamine has a structure shown as a formula (I):
R 1 、R 2 、R 3 、R 4 each independently selected from one of hydrogen, alkyl, cycloalkyl and hydroxyalkyl, R 5 、R 6 、R 7 And R 8 Each independently selected from one of hydrogen, alkyl, cycloalkyl, amino, halo, hydroxyalkyl and heterocycloalkyl, and each R 9 Each independently selected from one of hydrogen, alkyl, cycloalkyl, hydroxyalkyl and heterocycloalkyl, and each R 10 Each independently selected from at least one of hydrogen, isothiocyanate, alkyl, cycloalkyl and hydroxyalkyl, m is an integer from 1 to 5, n is an integer from 0 to 4, and the sum of m and n is not more than 5.
8. The process according to claim 7, wherein the allylic haloalkene has at least one double bond, and at least one halogen atom is bonded to a saturated carbon atom which is separated from an unsaturated carbon atom by a single bond, and the double bond is substituted by hydrogen or an alkyl group having 5 or less carbon atoms.
9. The production method according to claim 7, wherein the base is at least one selected from the group consisting of anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous lithium carbonate, anhydrous sodium hydrogen carbonate, anhydrous potassium hydrogen carbonate, and anhydrous lithium hydrogen carbonate; and/or
The precipitant is at least one of absolute ethyl alcohol, absolute acetone and absolute methanol.
10. The method of claim 7, wherein the reacting comprises: reacting for 20-30 hours at 60-85 ℃ under the condition of sealing and avoiding light; and/or
The molar ratio of the rhodamine to the allyl halogenated alkene to the base is 1 (8-12) to 0.5-6.
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