Hydrophobic polymer micelles stable in aqueous solution and methods for their preparation

Abstract

The present application provides a kind of hydrophobic polymer colloidal particles existing stably in aqueous solution and its preparation method, comprising: S1, (PLA m ) f -(X n ) g The hetero-arm star copolymer of structure is dissolved in organic solvent to obtain polymer solution;Wherein, X is hydrophobic block;S2, water is dropped into polymer solution at the rate of [2.5% (v / v) ~ 12.5% (v / v)] / min, then the obtained mixture is added to 5-20 times volume of water for quenching to obtain assembly mixture;S3, remove organic solvent in assembly mixture to obtain hydrophobic polymer colloidal particles existing stably in aqueous solution.The method can successfully prepare hydrophobic polymer colloidal particles using hydrophobic polymer in water, and the prepared hydrophobic polymer colloidal particles can exist stably in aqueous solution.

Description

Technical Field

[0001] This invention belongs to the field of polymer preparation technology, specifically relating to a hydrophobic polymer particles that are stable in aqueous solution and a method for preparing the same. Background Technology

[0002] Since the advent of the world's first scanning tunneling microscope in the 1980s, nanomaterials have developed rapidly and are now widely and significantly applied in fields such as smart packaging, optoelectronic devices, and biomedicine. Among these applications, research on polymer self-assembled structures as nanomedicine carriers is extensive. Polymer nanomedicine carriers are mainly prepared through the self-assembly of amphiphilic block copolymers in selective solvents.

[0003] Studies have found that using hydrophobic oligomers as nanomedicine carriers can achieve high structural stability, making them less prone to dissociation under blood dilution and shear forces; and the drug loading capacity is higher than that of traditional amphiphilic polymer nanoparticles. However, in traditional polymer self-assembly, highly dispersed hydrophobic colloidal particles are thermodynamically unstable in aqueous solutions and tend to aggregate to reduce interfacial energy. Therefore, preparing nanoparticles in water using hydrophobic polymers is a challenge. Summary of the Invention

[0004] To address the problems of the prior art, the present invention provides a hydrophobic polymer particles that are stable in aqueous solution and a method for preparing the same. The method enables the successful preparation of hydrophobic polymer particles in water using hydrophobic polymers, and the prepared hydrophobic polymer particles are stable in aqueous solution.

[0005] This invention is achieved through the following technical solution:

[0006] A method for preparing hydrophobic polymer particles that are stable in aqueous solution, comprising:

[0007] S1, (PLA) m ) f -(X n ) g The hetero-arm star copolymer with the structure was dissolved in an organic solvent to obtain a polymer solution; wherein, X is a hydrophobic block;

[0008] S2, add water dropwise to the polymer solution at a rate of [2.5% (v / v) ~ 12.5% ​​(v / v)] / min, and then add 5 to 20 times the volume of water to quench the mixture to obtain the assembled mixture;

[0009] S3, remove the organic solvent from the assembly mixture to obtain hydrophobic polymer particles that are stable in aqueous solution.

[0010] Preferably, in step S1, (PLA)m ) f -(X n ) g In this case, f takes values ​​from 1 to 3, and g takes values ​​from 16 to 24.

[0011] Preferably, in step S1, X is polystyrene, polymethyl methacrylate, polymethyl methacrylate, polymethoxyethyl methacrylate, or polyacrylonitrile.

[0012] Preferably, in step S1, the concentration of the polymer solution is 1 mg / mL to 20 mg / mL.

[0013] Preferably, in step S1, the organic solvent is one or a mixture of several of tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, and cyclohexane.

[0014] Preferably, in step S2, the water content in the mixture is 23% to 40%.

[0015] Preferably, in step S3, the organic solvent in the assembly mixture is removed by means of open standing or dialysis.

[0016] A hydrophobic polymer particle that is stable in aqueous solution is prepared by the above-described preparation method.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] This invention provides a method for preparing hydrophobic polymer particles that can exist stably in aqueous solution. Water is dripped into the hydrophobic polymer solution at a relatively fast rate, resulting in faster particle assembly compared to traditional self-assembly, achieving rapid assembly. The mixture is then injected into a large volume of water for deep quenching, completely "freezing" the morphology of the hydrophobic polymer particles and ensuring stable dispersion in the aqueous solution. In traditional polymer self-assembly, highly dispersed hydrophobic colloidal particles are thermodynamically unstable in aqueous solution and tend to aggregate, reducing interfacial energy. However, the rapid self-assembly combined with deep quenching method of this invention is efficient and simple. The resulting hydrophobic colloidal particles, due to the absence of hydrophilic segments and the high glass transition temperature of the hydrophobic segments, exhibit tight chain packing and very low chain mobility in the aqueous medium, making them resemble "hard spheres." Therefore, when two particles collide, the collision time is much shorter than the chain exchange time required for fusion, and they quickly separate under thermal agitation. Thus, the obtained pure hydrophobic colloidal particles exhibit excellent stability in aqueous solution and maintain good dispersibility even after standing in a natural environment for 12 months. The present invention provides a method for preparing hydrophobic polymer particles that are stable in aqueous solution. This method is rapid, efficient, and simple. Using hydrophobic nanoparticles as nanomedicine carriers is expected to simultaneously improve the stability and drug loading of drug carriers, providing insights for promoting the clinical translation of nanomedicines.

[0019] Furthermore, the present invention (PLA) m ) f -(X n ) g Hydrophobic hetero-arm star copolymers have a high X block volume fraction. Because the molecular weight of their X hydrophobic arms is relatively small but the number of arms is large, chain entanglement caused by excessive chain length can be reduced while achieving a high molecular weight. Attached Figure Description

[0020] Figure 1 This is a transmission electron microscope image of the hydrophobic polymer particles of the present invention.

[0021] Figure 2 The polymer PLA in Example 7 of this invention 150 -(PS 51 ) 20 Cryo-electron microscopy images of assembled particles placed in the natural environment for 12 months.

[0022] Figure 3 The diagram shows the zeta potential distribution of the assembled particles in Examples 8 and 9 of this invention.

[0023] Figure 4 The polymer (PLA) in Examples 11 and 12 of this invention 40)3-(PMMA 23 ) 20 Transmission electron microscope image of assembled colloidal particles. Detailed Implementation

[0024] To further understand the present invention, the present invention will be described below with reference to embodiments. These descriptions are only for further explaining the features and advantages of the present invention and are not intended to limit the claims of the present invention.

[0025] The method for rapidly preparing hydrophobic polymer particles that can exist stably in aqueous solution provided by this invention includes the following steps:

[0026] 1) Will have (PLA) m ) f -(X n ) g The hetero-arm star copolymer of the structure was dissolved in a co-solvent of polylactic acid (PLA) and X hydrophobic block, and after thorough stirring, a polymer solution with a concentration of 1 mg / mL to 20 mg / mL was obtained.

[0027] 2) Using a syringe pump, deionized water is added dropwise to the polymer solution at a rate of [2.5% (v / v) to 12.5% ​​(v / v)] / min (the amount of water added per minute is 2.5% to 12.5% ​​of the polymer solution volume) to obtain a mixture with a water content of 23% to 40%; then, the mixture is quenched by adding a large amount of deionized water, wherein the volume of deionized water is 5 to 20 times that of the mixture, to obtain the final assembly mixture;

[0028] 3) The mixture was left to stand in a fume hood for two days or dialyzed for 48 hours to remove the organic solvent from the assembly mixture, resulting in hydrophobic polymer particles that are stable in aqueous solution.

[0029] Among them, (PLA) m ) f -(X n ) g This is a multi-branched star copolymer with f-arm polylactic acid and g-arm hydrophobic blocks, where f is 1–3 and g is 16–24; X is a hydrophobic block, whose structure can be polystyrene (PS), polymethyl methacrylate (PMMA), polymethyl methacrylate (PMA), polymethoxyethyl methacrylate, or polyacrylonitrile. m and n are the degrees of polymerization of PLA and X hydrophobic blocks, respectively. Cosolvents include, but are not limited to, one or more of tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, and cyclohexane.

[0030] In step 1), the preparation of the polymer solution is to ensure that the copolymer is uniformly dispersed in a certain system.

[0031] In step 2), deionized water is added to the polymer solution to form micelles. The assembly speed is [2.5% (v / v) ~ 12.5% ​​(v / v)] / min, which is faster than traditional self-assembly, thus achieving the purpose of rapid assembly.

[0032] In step 2), the water content is 23% to 40% to "freeze" the copolymer in the mixture, but the use of excessive water does not affect the preparation of assembled micelles.

[0033] In step 2), the mixture is added to a large amount of deionized water for deep quenching in order to completely "freeze" the morphology of the hydrophobic polymer particles and make them stably dispersed in the aqueous solution.

[0034] In step 3), volatile solvents such as tetrahydrofuran can be removed by allowing the solution to stand in an open container to evaporate. Non-volatile solvents such as 1,4-dioxane can be removed by dialysis in deionized water. The treatment time depends on factors such as the volume of the dialysis system, the volume of deionized water used for dialysis, the volatility of the solvent, and ventilation conditions; there is no specific time requirement.

[0035] Example 1:

[0036] Preparation of 21-arm hetero-arm star copolymer PLA 150 -(PS 51 ) 20 polymer solution

[0037] Take 10 mg of copolymer PLA 150 -(PS 51 ) 20 Dissolve in 10 mL of the co-solvent tetrahydrofuran, sonicate for 30 min and let stand overnight to prepare a 1 mg / mL polymer solution.

[0038] Example 2:

[0039] Preparation of 22-arm hetero-arm star copolymer (PLA) 50 )2-(PS 44 ) 20 polymer solution

[0040] Take 20 mg of copolymer (PLA) 50 )2-(PS 44 ) 20 Dissolve in 10 mL of the co-solvent tetrahydrofuran, sonicate for 30 min and let stand overnight to prepare a 2 mg / mL polymer solution.

[0041] Example 3:

[0042] Preparation of 22-arm hetero-arm star copolymer (PLA) 70 )2-(PS8)20 polymer solution

[0043] Take 60 mg of copolymer (PLA) 70 )2-(PS8) 20 Dissolve in 3 mL of the co-solvent tetrahydrofuran, sonicate for 30 min and let stand overnight to prepare a 20 mg / mL polymer solution.

[0044] Example 4:

[0045] Preparation of 23-arm hetero-arm star copolymer (PLA) 50 )3-(PS 31 ) 20 polymer solution

[0046] Take 10 mg of copolymer (PLA) 50 )3-(PS 31 ) 20 Dissolve in 10 mL of the co-solvent tetrahydrofuran, sonicate for 30 min and let stand overnight to prepare a 1 mg / mL polymer solution.

[0047] Example 5:

[0048] Preparation of 23-arm hetero-arm star copolymer (PLA) 40 )3-(PMMA 23 ) 20 polymer solution

[0049] Take 50 mg of copolymer (PLA) 40 )3-(PMMA 23 ) 20 Dissolve in 5 mL of co-solvent 1,4-dioxane, sonicate for 30 min and let stand overnight to prepare a 10 mg / mL polymer solution.

[0050] Example 6:

[0051] Preparation of 22-arm hetero-arm star copolymer (PLA) 65 )3-(PMA 18 ) 20 polymer solution

[0052] Take 10 mg of copolymer (PLA) 65 )3-(PMA 18 ) 20 Dissolve in 10 mL of co-solvent 1,4-dioxane, sonicate for 30 min and let stand overnight to prepare a 1 mg / mL polymer solution.

[0053] Example 7:

[0054] PLA 150-(PS 51 ) 20 Self-assembly of solutions

[0055] Using a syringe pump, 2 mL of the 1 mg / mL PLA prepared in Example 1 was injected at a rate of 250 μL / min. 150 -(PS 51 ) 20 Rapid self-assembly was achieved by injecting 0.6 mL of deionized water into the polymer solution, followed by rapid injection of the mixture into 20 mL of deionized water.

[0056] Example 8:

[0057] (PLA 50 )2-(PS 44 ) 20 Self-assembly of solutions

[0058] Using a syringe pump, 2 mL of the 1 mg / mL (PLA) solution prepared in Example 2 was injected at a rate of 250 μL / min. 50 )2-(PS 44 ) 20 Rapid self-assembly was achieved by injecting 0.6 mL of deionized water into the polymer solution, followed by rapid injection of the mixture into 10 mL of deionized water.

[0059] Example 9:

[0060] (PLA 70 )2-(PS8) 20 Self-assembly of solutions

[0061] Using a syringe pump, 2 mL of the 20 mg / mL (PLA) solution prepared in Example 3 was injected at a rate of 250 μL / min. 70 )2-(PS8) 20 Rapid self-assembly was achieved by injecting 0.6 mL of deionized water into the polymer solution, followed by rapid injection of the mixture into 20 mL of deionized water.

[0062] Example 10:

[0063] (PLA 50 )3-(PS 31 ) 20 Self-assembly of solutions

[0064] Using a syringe pump, 2 mL of the 1 mg / mL (PLA) solution prepared in Example 4 was injected at a rate of 250 μL / min. 50 )3-(PS 31 ) 20 Rapid self-assembly was achieved by injecting 0.6 mL of deionized water into the polymer solution, followed by rapid injection of the mixture into 20 mL of deionized water.

[0065] Example 11:

[0066] (PLA 40 )3-(PMMA 23 ) 20 Self-assembly of solutions

[0067] Using a syringe pump, 2 mL of the 10 mg / mL (PLA) prepared in Example 5 was injected at a rate of 50 μL / min. 40 )3-(PMMA 23 ) 20 Rapid self-assembly was achieved by injecting 0.86 mL of deionized water into the polymer solution, followed by rapid injection of the mixture into 20 mL of deionized water.

[0068] Example 12:

[0069] (PLA 40 )3-(PMMA 23 ) 20 Self-assembly of solutions

[0070] Using a syringe pump, 2 mL of the 10 mg / mL (PLA) prepared in Example 5 was injected at a rate of 50 μL / min. 40 )3-(PMMA 23 ) 20 Rapid self-assembly was induced by injecting 0.86 mL of deionized water into the polymer solution without quenching, serving as a control experiment.

[0071] Example 13:

[0072] (PLA 65 )3-(PMA 18 ) 20 Self-assembly of solutions

[0073] Using a syringe pump, 100 μL / min was injected into 2 mL of the 1 mg / mL (PLA) solution prepared in Example 6. 65 )3-(PMA 18 ) 20 Rapid self-assembly was achieved by injecting 0.86 mL of deionized water into the polymer solution, followed by rapid injection of the mixture into 40 mL of deionized water.

[0074] Example 14:

[0075] The assembled mixtures from Examples 7-10 were left to stand in a fume hood to obtain hydrophobic polymer particles that are stable in a pure water system.

[0076] Example 15:

[0077] The assembled mixtures from Examples 11-13 were transferred to a dialysis bag (MWCO 3500Da) and dialyzed with deionized water for 48 hours to remove the organic solvent, yielding hydrophobic polymer particles.

[0078] Figure 1 These are transmission electron microscope images of the assembled particles of the present invention. The scale bar is 200 nm. (a) is the polymer PLA in Example 7. 150 -(PS 51 ) 20 ((L 150 )-(S 51 ) 20 (a) Assembled particles, (b) are polymers (PLA) from Example 8. 50 )2-(PS 44 ) 20 ((L 50 )2-(S 44 ) 20 (c) is the polymer (PLA) used in Example 10, which is assembled into granules. 50 )3-(PS 31 ) 20 ((L 50 )3-(S 31 ) 20 Assembled colloidal particles. According to TEM image statistics, the sizes of the hydrophobic colloidal particles are 293±58nm(a), 281±60nm(b), and 253±47nm(c), and all have spherical morphology.

[0079] Figure 2 The polymer PLA in Example 7 150 -(PS 51 ) 20 Cryo-electron microscopy images of assembled particles after one year of rest in natural environment, scale bars at 1 μm (a) and 200 nm (b)–(c). Figure 1 In comparison, the size and morphology of the hydrophobic colloidal particles did not change significantly after being left to stand for a long time, indicating that the hydrophobic colloidal particles prepared by this invention can exist stably in aqueous solution.

[0080] Figure 3 The polymers (PLA) in Examples 8 and 9 50 )2-(PS 44 ) 20 ((L 50 )2-(S 44 ) 20 ) and (PLA 70 )2-(PS8) 20 ((L 70 )2-(S8) 20The Zeta potential distribution of the assembled colloidal particles is shown. Their Zeta potentials are -19.2mV and -18.6mV, respectively, both below -30mV (it is generally believed that when the Zeta potential is above ±30mV, the colloid is stable due to charge repulsion). Therefore, the colloidal particle is thermodynamically unstable and is kinetically stable. That is, when two colloidal particles collide, the interaction time between them is much shorter than the time required for chain exchange.

[0081] Figure 4 The polymer (PLA) in Examples 11 and 12 40 )3-(PMMA 23 ) 20 Transmission electron microscopy images of the assembled colloidal particles, scale bars at 1 μm (a) and 200 nm (b). The images show that the hydrophobic colloidal particles prepared by the rapid self-assembly combined with deep quenching method in Example 11 have a uniform spherical morphology and good dispersibility. Figure 4 (a)); In Example 12, the unquenched colloidal particles were spherical in shape and somewhat adhered to each other. Figure 4 (b) demonstrates that deep quenching is necessary for the formation of spherical nanoparticles.

Claims

1. A method for preparing hydrophobic polymer particles that are stable in aqueous solution, characterized in that, include: S1, (PLA) m ) f - (X n ) g The hetero-arm star copolymer with the structure was dissolved in an organic solvent to obtain a polymer solution; wherein, X is a hydrophobic block; (PLA) m ) f - (X n ) g middle f The value ranges from 1 to 3, and g ranges from 16 to 24; m and n are the degrees of polymerization of PLA and X hydrophobic blocks, respectively; S2, add water dropwise to the polymer solution at a rate of [2.5%(v / v)~12.5%(v / v)] / min, and then add 5~20 times the volume of water to quench the mixture to obtain the assembled mixture; S3, remove the organic solvent from the assembly mixture to obtain hydrophobic polymer particles that are stable in aqueous solution.

2. The method for preparing hydrophobic polymer particles stably existing in aqueous solution according to claim 1, characterized in that, In step S1, X is polystyrene, polymethyl methacrylate, polymethyl methacrylate, polymethoxyethyl methacrylate, or polyacrylonitrile.

3. The method for preparing hydrophobic polymer particles stably existing in aqueous solution according to claim 1, characterized in that, In step S1, the concentration of the polymer solution is 1 mg / mL to 20 mg / mL.

4. The method for preparing hydrophobic polymer particles stably existing in aqueous solution according to claim 1, characterized in that, In step S1, the organic solvent is one or a mixture of several of the following: tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, and cyclohexane.

5. The method for preparing hydrophobic polymer particles stably existing in aqueous solution according to claim 1, characterized in that, In step S2, the volume content of water in the mixture is 23%~40%.

6. The method for preparing hydrophobic polymer particles stably existing in aqueous solution according to claim 1, characterized in that, In step S3, the organic solvent in the assembly mixture is removed by open standing or dialysis.

7. A hydrophobic polymer particle that is stable in aqueous solution, characterized in that, It is prepared by any one of claims 1 to 6.

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