Thixotropic small molecule gels, methods of making and uses thereof
The thixotropic small molecule gel factor synthesized by liquid-phase amide condensation solves the problem of synthetic complexity, achieves efficient targeted drug release and reduces toxic side effects, and can be applied in drug delivery and biomedicine.
Patent Information
- Application Number
- CN202411846675.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-16
- Publication Date
- 2025-11-07
- Estimated Expiration
- 2044-12-16
AI Technical Summary
Existing technologies make it difficult to synthesize thixotropic small molecule gels simply and conveniently, hindering their application in fields such as drug delivery, especially the targeted release of anticancer drugs.
Gel factors with hydrophobic alkyl chains and hydrophilic dipeptide sequences were synthesized by liquid-phase amide condensation. These gels then self-assembled to form thixotropic small molecule gels, which were used to load anticancer drugs and achieve pH-responsive release.
It achieves high shear thixotropic recovery rate, reduces drug toxicity and side effects, and has injectability and pH-responsive release characteristics, making it widely applicable in controlled-release drug formulations, cell culture, and tissue engineering.
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Figure CN119661630B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the technical field of gel drug carriers, and relates to a thixotropic small-molecule gel, a preparation method and application thereof. BACKGROUND
[0002] Small-molecule gels are a kind of three-dimensional network structure formed by capturing solvent molecules through non-covalent interactions such as hydrogen bonding, π-π stacking, hydrophobic interaction and van der Waals force. Compared with polymer gels, this kind of gel has attracted more and more attention from researchers in various fields due to its easily modified structure, sensitive stimulus response characteristics and reversibility. Peptide-based small-molecule gels have good biocompatibility and biodegradability, and have been widely used in cell culture, drug delivery, tissue repair and other biomedical fields. Gels with thixotropy are a very advantageous type of small-molecule gels, and there is an urgent need for them in many fields such as drug delivery. The toxic and side effects of anticancer drugs have always been a major factor threatening the lives of cancer patients. Injectable gel drug delivery carriers can directly inject drugs into the lesion site to achieve targeted release and reduce the toxic and side effects of drugs.
[0003] However, due to the complexity of the self-assembly process and its mechanism, the thixotropy of small-molecule gels is an advantageous property that can be encountered but not sought. Designing thixotropic gels with target application scenarios is still a major challenge to the application of small-molecule gels.
[0004] Therefore, there is a need for a method for simply and conveniently synthesizing thixotropic small-molecule gels to solve the above technical problems. SUMMARY
[0005] The thixotropic small-molecule gel of the present application is formed by self-assembly of a gelator in a solvent. The structure of the gelator used is composed of a hydrophobic alkyl chain and a hydrophilic dipeptide sequence. The gelator can form a small-molecule gel with thixotropy, providing a reference for the design of thixotropic small-molecule gels from the perspective of molecular structure design. At the same time, as a thixotropic gel material, it realizes the loading of anticancer drugs and forms an injectable drug-loaded gel, providing a reference for the research in the field of injectable gel drug delivery.
[0006] The technical scheme adopted by the present application to solve the technical problem is: a thixotropic small-molecule gel formed by self-assembly of a small-molecule gelator in a solvent. The small-molecule gelator used has a structure shown in formula (I):
[0007]
[0008] In formula (I), x = 8-18, y = 1-5,
[0009] In formula (I), R includes:
[0010]
[0011] Preferably, the small molecule gelator is synthesized by liquid phase amide condensation method, the synthesis method comprising the following steps:
[0012] Mixing tryptophan or phenylalanine or tyrosine, glycine or alanine or aminobutyric acid or amino valeric acid or amino hexanoic acid, alkyl amine, condensation reagent, additive and organic solvent to carry out amide condensation reaction, and the final product is the small molecule gelator.
[0013] The structural compound of the alkyl amine has the structure shown in formula (V):
[0014] In the formula, x = 8-18.
[0015] Preferably, the condensation reagent in the step includes dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI), onium salts, organic phosphorus, s-triazine derivatives, carbonyl diimidazole. The additive includes N-hydroxy-7-azabenzotriazole HOAt, 1-hydroxybenzotriazole HOBt, 4-dimethylaminopyridine DMAP, N-hydroxysuccinimide HOSu, 1H,1H-pentafluoropropanol PfpOH; the solvent includes N,N-dimethylformamide DMF, dichloromethane DCM, tetrahydrofuran THF, acetonitrile.
[0016] Preferably, in the step, the molar ratio of amino acid (tryptophan or phenylalanine or tyrosine or glycine or alanine or aminobutyric acid or amino valeric acid or amino hexanoic acid): condensation reagent or additive: amine (H2N-(CH2) x-1 CH3) is 1:0.8-1.2:1.5-2.5, wherein the value range of x is 8-18.
[0017] Preferably, in the step, the temperature of the amide condensation reaction is 0-60℃.
[0018] Preferably, in the preparation of thixotropic small molecule gel, the final product gelator is dissolved in a solvent to form a gel after self-assembly.
[0019] More preferably, the solvent includes water, dimethyl sulfoxide DMSO, N,N-dimethylformamide DMF, methanol, ethanol, acetone, benzene, toluene, xylene and a solvent mixed in any proportion of any two or more of the above.
[0020] More preferably, the concentration of the gelator used is greater than or equal to 0.2% w / v.
[0021] The application also discloses application of the thixotropic small molecule gel, which uses the thixotropic small molecule gel as a carrier of active drugs, and can successfully load drugs for treating various diseases such as cardiovascular and cerebrovascular diseases, cancer, hypertension, diabetes, inflammation, and neurological diseases. The active drug preparation can be directly delivered to a lesion site by using a syringe, and is released in response to the pH of the microenvironment of the lesion site, so that the target controlled release of the drug is realized, and the toxic and side effects of the drug are reduced. The thixotropic small molecule gel can also be applied to the construction of a cell culture environment or the preparation of a tissue engineering product.
[0022] The application has the following beneficial effects:
[0023] 1. The application synthesizes a series of gel factors by a simple and easy-to-operate liquid phase amide condensation method, and the synthesized gel factors have a hydrophilic dipeptide end and a hydrophobic alkyl chain end, and have wide application potential as amphiphilic materials.
[0024] 2. The gel prepared by the simple and easy-to-operate method has a shear thixotropic recovery rate of up to 96%.
[0025] 3. The application can be applied to the field of drug controlled release preparation products, realizes loading of anticancer drugs, and realizes pH stimulus response release of the drugs; has the combined characteristics of injectability and pH stimulus response release, greatly reduces the toxic and side effects of free drugs. Meanwhile, the application also has wide application potential in the fields of cell culture, tissue repair, and other biological medicines. BRIEF DESCRIPTION OF DRAWINGS
[0026] Figure 1 GTC is a gel factor of the thixotropic small molecule gel, a preparation method and application thereof 16 Gel pictures prepared in different solvents
[0027] Figure 2 GTC is a gel factor of the application 16 Gel electron microscope pictures prepared in 50% DMSO / H2O
[0028] Figure 3 GTC is a gel factor of the application 16 Gel thixotropy characterization picture of the prepared gel with a 96% recovery rate
[0029] Figure 4 GTC is a gel factor of the application 16 Gel picture of the gel loaded with anticancer drug DOX
[0030] Figure 5 GTC is a gel factor of the application 16 Characterization picture of the pH response release behavior of the gel to anticancer drug DOX DETAILED DESCRIPTION
[0031] The related art in the present application will be described clearly and completely in conjunction with the drawings of the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments of the present application, all the other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.
[0032] Reference Figures 1 to 5 is given below, embodiments of a thixotropic small-molecule gel GTC 16 , a preparation method thereof and applications thereof.
[0033] Embodiments
[0034] Gelator GTC 16 Chemical structure
[0035]
[0036] Preparation process of small-molecule gelator GTC 16
[0037] The series of small-molecule gelators are synthesized by a liquid-phase peptide synthesis method. The synthesis steps are as follows:
[0038] (1) Preparation of Boc-Trp-C 16 . 1.52 g (5 mmol, 1 eq.) of BOC-L-tryptophan was dissolved in 10 mL of DMF, and an ice bath was used at 0°C. Then, 0.76 g (5 mmol, 1 eq.) of HOBT and 1.00 g (5 mmol, 1 eq.) of DCC were added. After 1-2.5 h (or later), 2.41 g (10 mmol, 2 eq.) of hexadecylamine H2N-(CH2) 15 CH3 dissolved in 20 mL of ethyl acetate was added. The reaction was carried out in an ice bath for 2.5 h, and then gradually lowered to room temperature for 3 days. After post-treatment, the white target intermediate Boc-Trp-C 16 was obtained.
[0039] (2) Preparation of NH2-Trp-C 16 . 12.29 g (21.23 mmol) of Boc-Trp-C 16 was dissolved in dry 45 mL of DCM solvent (2 eq), and then 45 mL (2 eq) of trifluoroacetic acid was added.
[0040] The reaction was carried out for 40-50 mins. After post-treatment, the white target intermediate NH2-Trp-C 16 was obtained.
[0041] (3) Preparation of Boc-Gly-Trp-C 16 Boc-Gly-Trp-C 16 was prepared as follows: 1.58 g (9 mmol) of Boc-glycine was dissolved in 10 mL of DMF in an ice bath at 0°C. Then 1.22 g (9 mmol) of HOBt and 2.06 g (10 mmol) of DCC were added. Subsequently, 4.3 g (10 mmol) of H2N-Trp-C
[0042] H2N-Trp-C 16 .
[0043] (4) Preparation of H2N-Gly-Trp-C 16 (abbreviation: GTC 16 ) was prepared as follows: 1.64 g (2.96 mmol) of Boc-Gly-Trp-C 16 was added to a round bottom flask, and 12 mL (4 eq) of formic acid was added. The reaction was carried out for 4 h.
[0044] The final product H2N-Gly-Trp-C 16 was obtained after work-up.
[0045] Method for preparing the gel:
[0046] 10 mg of the gel factor GTC 16 synthesized by the above method was first completely dissolved in 0.5 mL of DMSO, and then 0.5 mL of H2O was added to the above mixed solution, so that the volume ratio of DMSO:H2O in the mixed solvent was 5:5. A semi-transparent gel GTC 16 was formed after standing for less than 1 minute.
[0047] The gel GTC 16 prepared by the above method became a fluid state after being destroyed by external force, and returned to the original solid gel state after standing for a while, indicating that the gel had good thixotropy.
[0048] In the gel factor synthesis method in this example:
[0049] Boc-glycine can be replaced by Boc-alanine, Boc-aminobutyric acid, Boc-aminopentanoic acid, or Boc-aminohexanoic acid.
[0050] Boc-tryptophan can be replaced by Boc-phenylalanine or Boc-tyrosine.
[0051] Hexadecylamine can be replaced by octylamine, nonylamine, decylamine, dodecylamine, tetradecylamine, or octadecylamine.
[0052] Amide condensing agent DCC can be replaced by DIC, EDCI
[0053] Catalyst HOBT can be replaced by DMAP.
[0054] The preparation method of the gel includes, but is not limited to, heating-cooling cycle method, solvent trigger method, pH trigger method, etc. The gel prepared by the gelator in the embodiment can be applied.
[0055] The mixing of various solutions in the gel preparation process mentioned in the embodiment does not have a sequence, and the gel with a self-assembly structure can be finally formed.
[0056] The good solvent DMSO used in the embodiment can be replaced by DMF, methanol, ethanol, acetone.
[0057] The ratio of the good solvent to the poor solvent in the embodiment can be in the range of 0-1.
[0058] The gelator GTC used in the embodiment 16 The concentration can be selected in the range of ≥0.2% w / v.
[0059] The ratio of the solvent DMSO / H2O used in the embodiment can be 1:9-8:2.
[0060] Example
[0061] Preparation method of drug-loaded gel carrier:
[0062] 10 mg of gelator GTC 16 was first completely dissolved in 0.5 mL of DMSO to form solution A, and then 0.5 mL of aqueous solution B containing 1 mg of drug doxorubicin (DOX) was added to the above mixed solution A to form mixed solution C. The drug-loaded gel GTC 16 / DOX was formed by standing solution C.
[0063] Characterization and thixotropy test of the gel:
[0064] (1) The gel prepared in the example was photographed, and the physical map obtained is shown in Figure 1 , which Figure 1 demonstrates the GTC 16 gel diagram formed in various ratios of DMSO / H2O solvent.
[0065] (2) The gel prepared in the example was freeze-dried and then tested by SEM, and the results are shown in Figure 2 . The gel forms a dense three-dimensional network structure and can load active drugs and the like.
[0066] (3) The thixotropic properties of the fresh gel in the example were characterized, and the results are shown in Figure 3 The gel maintained good solid characteristics in the low shear rate mode, became liquid after a large stress damage, and returned to 96% of the original gel after the stress damage was removed. This indicates that the gel has very good shear thixotropic properties and has application potential in a variety of application scenarios.
[0067] (4) The drug-loaded gel prepared in the above application example was photographed, and the physical map obtained is shown in Figure 4 As can be seen from Figure 4 , the drug-loaded gel still forms a good gel.
[0068] (5) The in vitro drug release of the drug-loaded gel prepared in the above application example was characterized, as shown in Figure 5
[0069] The drug-loaded gel achieves pH-stimulated release behavior in different pH PBS solutions.
[0070] The drug loading in this embodiment includes but is not limited to anticancer drugs such as DOX and CPT.
[0071] The key of the present embodiment is that 1, the series of gelator molecules are composed of dipeptide sequences and alkyl chain connections. 2, the gelator is dissolved in water or other solvents and self-assembled. 3, the gel can be applied to the thixotropic gel material scenario. 4, the gel is applied to the fields of drug delivery, cell culture, tissue engineering, etc.
[0072] In summary, the present application synthesizes a series of gelators by a simple and easy-to-operate liquid phase condensation method. The synthesized gelators have a hydrophilic peptide end and a hydrophobic alkyl chain end, and have wide application potential as amphiphilic materials. The gel formed by the gelator has thixotropic properties, and can be applied to the loading of anticancer drugs and pH-stimulated controlled release.
[0073] It should be emphasized that: the above is only a preferred embodiment of the present application, and does not limit the present application in any form. Any simple modification, equivalent change and modification of the above embodiment according to the technical essence of the present application still belongs to the scope of the technical solution of the present application.
Claims
1. A thixotropic small molecule gel, characterized in that, The small molecule gel is formed by self-assembly of a small molecule gelator in a solvent, the small molecule gelator has the following structure:
2. The method for preparing the thixotropic small molecule gel according to claim 1, characterized in that, The small molecule gelator is synthesized by a liquid phase amide condensation method, and the synthesis method comprises the following steps: Trp, Gly, hexadecylamine, condensation reagent, additive and organic solvent are mixed to perform amide condensation reaction, and the final product is the small molecule gelator.
3. A method of preparing a thixotropic small molecule gel according to claim 2, characterized in that, The condensation reagent comprises dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC), 1-(3-dimethyl aminopropyl)-3-ethyl carbodiimide (EDCI), onium salt, organic phosphorus, s-triazine derivative, carbonyl diimidazole; the additive comprises N-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 4-dimethyl aminopyridine (DMAP), N-hydroxy succinimide (HOSu), 1H, 1H-pentafluoropropanol (PfpOH); and the solvent comprises N,N-dimethyl formamide (DMF), dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile.
4. The method for preparing a thixotropic small molecule gel according to claim 2, characterized in that, The molar ratio of the amino acid: condensing agent or additive: hexadecylamine H2N-(CH2) 16 CH3was 1:0.8-1.2:1.5-2.
5. The amino acid comprises Trp and Gly.
5. The method for preparing a thixotropic small molecule gel according to claim 2, characterized in that, The amide condensation reaction temperature is 0-60 DEG C.
6. The method for preparing a thixotropic small molecule gel according to claim 2, characterized in that, In preparation of the thixotropic small molecule gel, the final product gelator is dissolved in a solvent to form a gel after self-assembly.
7. A method of preparing a thixotropic micromolecular gel according to claim 6, characterized in that, The solvent comprises water, dimethyl sulfoxide (DMSO), N,N-dimethyl formamide (DMF), methanol, ethanol, acetone, benzene, toluene, xylene and a solvent mixture of any two or more of the above in any proportion.
8. Application of the thixotropic small molecule gel prepared by the preparation method of any one of claims 2 to 7 in preparation of a drug controlled release preparation.