Fabric for adjuvant treatment of breast cancer and method for its production

Abstract

The application belongs to the field of textiles, and discloses a fabric for adjuvant therapy of breast cancer and a preparation method thereof. The preparation method comprises the following steps: firstly, preparing a fluorouracil FU and collagen tripeptide CTP compound FU-CTP, incorporating the compound into a core layer spinning solution, preparing a core-shell nanofiber membrane through electrospinning, and finally obtaining the fabric for adjuvant therapy of breast cancer. The fabric can release the compound FU-CTP in the form of micelles, CTP can carry FU, promote the transdermal penetration ability of FU, and enrich FU in the local breast to reach a therapeutic concentration, so that most side effects such as gastrointestinal side effects and bone marrow suppression caused by oral and intravenous administration of FU can be reduced.

Description

Technical Field

[0001] This invention belongs to the field of textiles, specifically relating to a fabric for adjuvant treatment of breast cancer and its preparation method. Background Technology

[0002] Fluorouracil (FU) has shown efficacy against various tumors, including gastrointestinal tumors, breast cancer, ovarian cancer, choriocarcinoma, cervical cancer, liver cancer, bladder cancer, skin cancer (topical application), and vulvar leukoplakia (topical application). It can be used alone or in combination with other drugs as adjuvant therapy for breast cancer and gastrointestinal tumors, and also for palliative care of some non-surgical malignancies, particularly those of the gastrointestinal tract, breast, head and neck, liver, urinary system, and pancreas. However, FU side effects may include gastrointestinal reactions and clinical symptoms such as bone marrow suppression, anemia, and allergies. Common routes of FU administration are oral and intravenous injection, thus unavoidable side effects on the gastrointestinal tract and bone marrow. Summary of the Invention

[0003] In view of this, the purpose of the present invention is to provide a fabric for adjuvant treatment of breast cancer and a method for preparing the same. The fabric can release the complex FU-CTP in the form of micelles. CTP can carry FU and promote its transdermal penetration ability, thereby enriching FU locally in the breast to achieve a therapeutic concentration. This can reduce most of the side effects such as gastrointestinal side effects and bone marrow suppression caused by oral and intravenous administration of FU.

[0004] To address the aforementioned technical problems, this invention provides a fabric for adjuvant treatment of breast cancer and a method for preparing the same, comprising the following steps:

[0005] S1. Preparation of FU-CTP complex: Fluorouracil and collagen tripeptide were dissolved together in 1-2 w / v% acetic acid solution, then chitosan was added, and after thorough stirring and dissolution, the mixture was spray-dried to obtain the FU-CTP complex.

[0006] S2. Preparation of spinning solution: The FU-CTP composite obtained in step S1 and polyvinylpyrrolidone are added to water and stirred thoroughly to obtain the core spinning solution.

[0007] S3. Add egg yolk lecithin and polylactic acid to a mixed solution of dichloromethane and ethanol, stir thoroughly to obtain shell spinning solution;

[0008] S4. Electrospun membrane preparation: The core spinning solution and the shell spinning solution are coaxially electrospun to obtain a core-shell nanofiber membrane with a nanofiber diameter of 700-900nm. After hot pressing, a fabric with a thickness of 400-800μm for adjuvant treatment of breast cancer is obtained.

[0009] Furthermore, in step S1, the chitosan has a weight-average molecular weight of 100,000-150,000 and a degree of deacetylation of 75-85%.

[0010] Furthermore, in step S1, the feeding ratio of fluorouracil, collagen tripeptide, acetic acid solution and chitosan is (520-650) mg:(1.12-1.40) g:100 ml:(1.0-2.0) g.

[0011] Furthermore, in step S2, the weight-average molecular weight of the polyvinylpyrrolidone is 24,000-58,000.

[0012] Furthermore, in step S2, the ratio of FU-CTP complex, polyvinylpyrrolidone and water is (2-5)g:(15-20)g:100ml.

[0013] Furthermore, in step S3, the volume ratio of dichloromethane to ethanol in the mixed solution of dichloromethane and ethanol is 5:5-7:3.

[0014] Furthermore, in step S3, the polylactic acid has a weight-average molecular weight of 15,000-24,000.

[0015] Furthermore, in step S3, the feeding ratio of egg yolk lecithin, polylactic acid, and the mixed solution of dichloromethane and ethanol is (100-200) mg: (3-5) g: 100 ml.

[0016] Furthermore, in step S4, the coaxial electrospinning conditions are: voltage 10-15kV, distance 13-16cm, core layer spinning solution flow rate 1.2-1.5ml / h, and shell layer spinning solution flow rate 0.7-1.0ml / h.

[0017] The present invention also provides a fabric prepared by the above preparation method for adjuvant treatment of breast cancer.

[0018] Compared to existing technologies, this invention utilizes the hydrogen bonds in collagen tripeptides to form a biuret-like structure, coupling with fluorouracil via hydrogen bonds. Furthermore, under the action of amino-cationized chitosan, the ring strain formed by the collagen tripeptides is released, enhancing the stability of the FU-CTP complex. In use, the affinity of the collagen tripeptides for the skin allows fluorouracil to be carried percutaneously, accumulating at therapeutic concentrations of FU locally in the breast. Moisture accumulation on the skin surface dissolves polyvinylpyrrolidone in the fibrous core, releasing the FU-CTP complex from its fibrous shell. This FU is then coated with egg yolk lecithin and released onto the skin surface. The combined action of lecithin and CTP significantly improves the percutaneous absorption of FU, enabling the formation of high FU concentrations around subcutaneous breast tumors without causing bone marrow suppression or gastrointestinal adverse reactions. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of a biuret-like structure in collagen tripeptides.

[0020] Figure 2 A scanning electron microscope image of the fabric prepared for adjuvant treatment of breast cancer in Example 1;

[0021] Figure 3 Transmission electron micrograph of the fabric fibers used in adjuvant therapy for breast cancer prepared in Example 1;

[0022] Figure 4 The results of transdermal permeability tests on the fabrics used in the examples and comparative examples are shown. Detailed Implementation

[0023] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims of the present invention.

[0024] This invention provides a method for preparing a fabric for adjuvant treatment of breast cancer, comprising the following steps:

[0025] S1. Preparation of FU-CTP complex: Fluorouracil and collagen tripeptide were dissolved together in 1-2 w / v% acetic acid solution, then chitosan was added, and after thorough stirring and dissolution, the mixture was spray-dried to obtain the FU-CTP complex.

[0026] This invention mimics the bend formed by proline or hydroxyproline in the repetitive collagen tripeptide GXY sequence of collagen, utilizing the hydrogen bond formed by the amino group H of glycine and the carbonyl group O of X, with one collagen tripeptide forming one hydrogen bond. This cyclic structure will, on one hand, form a biuret-like structure (…). Figure 1 This structure can couple with fluorouracil via hydrogen bonding to form the FU-CTP complex. Under the action of amino-cationized chitosan, the ring strain formed by GXY is released, enhancing the stability of the FU-CTP complex.

[0027] S2. Preparation of spinning solution: The FU-CTP composite obtained in step S1 and polyvinylpyrrolidone are added to water and stirred thoroughly to obtain the core spinning solution.

[0028] S3. Add egg yolk lecithin and polylactic acid to a mixed solution of dichloromethane and ethanol, stir thoroughly to obtain shell spinning solution;

[0029] S4. Electrospun membrane preparation: The core spinning solution and the shell spinning solution are coaxially electrospun to obtain a core-shell nanofiber membrane with a nanofiber diameter of 700-900nm. After hot pressing, a fabric with a thickness of 400-800μm for adjuvant treatment of breast cancer is obtained.

[0030] Example 1

[0031] A fabric for adjuvant therapy of breast cancer and its preparation method, comprising the following steps:

[0032] 1. Preparation of FU-CTP complex: 600 mg of fluorouracil and 1.30 g of collagen tripeptide were dissolved together in 100 ml of 1.5 w / v acetic acid solution, and then 1.5 g of chitosan with a weight average molecular weight of 120,000 and a degree of deacetylation of 80% was added. After thorough stirring and dissolution, the mixture was spray-dried to obtain the FU-CTP complex.

[0033] 2. Preparation of spinning solution: Add 4g of the FU-CTP composite obtained in step 1 and 18g of polyvinylpyrrolidone with a weight average molecular weight of 42000 to 100ml of water, stir thoroughly to obtain the core spinning solution; add 160mg of egg yolk lecithin and 4g of polylactic acid with a weight average molecular weight of 20000 to 100ml of a mixed solution of dichloromethane and ethanol in a volume ratio of 6:4, stir thoroughly to obtain the shell spinning solution.

[0034] 3. Electrospun membrane preparation: Coaxial electrospinning was performed using the core spinning solution and shell spinning solution obtained in step 2. The electrospinning conditions were: voltage 12kV, distance 15cm, core spinning solution flow rate 1.4ml / h, and shell spinning solution flow rate 0.8ml / h, to obtain a core-shell nanofiber membrane with a nanofiber diameter of 850nm. After hot pressing, a fabric with a thickness of 700μm for adjuvant treatment of breast cancer was obtained. Figure 2 These are scanning electron microscope images. Figure 3 The image shows a transmission electron microscope (TEM) image of the fiber, which has a diameter of 850±26 nm and an inner diameter of 550±23 nm, with a uniform thickness distribution.

[0035] Example 2

[0036] A fabric for adjuvant therapy of breast cancer and its preparation method, comprising the following steps:

[0037] 1. Preparation of FU-CTP complex: 520 mg of fluorouracil and 1.12 g of collagen tripeptide were dissolved together in 100 ml of 1 w / v acetic acid solution, and then 1 g of chitosan with a weight average molecular weight of 100,000 and a degree of deacetylation of 75% was added. After thorough stirring and dissolution, the mixture was spray-dried to obtain the FU-CTP complex.

[0038] 2. Preparation of spinning solution: Add 2g of the FU-CTP composite obtained in step 1 and 15g of polyvinylpyrrolidone with a weight average molecular weight of 24000 to 100ml of water, stir thoroughly to obtain the core spinning solution; add 100mg of egg yolk lecithin and 3g of polylactic acid with a weight average molecular weight of 15000 to 100ml of a mixed solution of dichloromethane and ethanol in a volume ratio of 7:3, stir thoroughly to obtain the shell spinning solution.

[0039] S3. Electrospun membrane preparation: Coaxial electrospinning was performed using the core spinning solution and shell spinning solution obtained in step 2. The electrospinning conditions were: voltage 10kV, distance 13cm, core spinning solution flow rate 1.2ml / h, and shell spinning solution flow rate 0.7ml / h, to obtain a core-shell nanofiber membrane with a nanofiber diameter of 700nm. After hot pressing, a fabric with a thickness of 400μm for adjuvant treatment of breast cancer was obtained.

[0040] Example 3

[0041] A fabric for adjuvant therapy of breast cancer and its preparation method, comprising the following steps:

[0042] 1. Preparation of FU-CTP complex: 650 mg of fluorouracil and 1.40 g of collagen tripeptide were dissolved together in 100 ml of 2 w / v acetic acid solution, and then 2 g of chitosan with a weight average molecular weight of 150,000 and a degree of deacetylation of 85% was added. After thorough stirring and dissolution, the mixture was spray-dried to obtain the FU-CTP complex.

[0043] 2. Preparation of spinning solution: Add 5g of the FU-CTP composite obtained in step 1 and 20g of polyvinylpyrrolidone with a weight average molecular weight of 58000 to 100ml of water, stir thoroughly to obtain the core spinning solution; add 200mg of egg yolk lecithin and 5g of polylactic acid with a weight average molecular weight of 24000 to 100ml of a mixed solution of dichloromethane and ethanol in a volume ratio of 5:5, stir thoroughly to obtain the shell spinning solution.

[0044] 3. Electrospun membrane preparation: The core spinning solution and shell spinning solution obtained in step 2 were used for coaxial electrospinning. The electrospinning conditions were 15kV voltage, 16cm distance, core spinning solution flow rate of 1.5ml / h, and shell spinning solution flow rate of 1ml / h to obtain a core-shell nanofiber membrane with a nanofiber diameter of 900nm. After hot pressing, a fabric with a thickness of 800μm for adjuvant treatment of breast cancer was obtained.

[0045] Comparative Example 1 (without collagen tripeptide)

[0046] A fabric and its preparation method, comprising the following steps:

[0047] 1. Preparation of FU-CS complex: 600 mg of fluorouracil was dissolved in 100 ml of 1.5 w / v acetic acid solution, and then 1.5 g of chitosan with a weight average molecular weight of 120,000 and a degree of deacetylation of 80% was added. After thorough stirring and dissolution, the mixture was spray-dried to obtain the FU-CS complex.

[0048] 2. Preparation of spinning solution: Add 4g of the FU-CS composite obtained in step 1 and 18g of polyvinylpyrrolidone with a weight average molecular weight of 42000 to 100ml of water, stir thoroughly to obtain the core spinning solution; add 160mg of egg yolk lecithin and 4g of polylactic acid with a weight average molecular weight of 20000 to 100ml of a mixed solution of dichloromethane and ethanol in a volume ratio of 6:4, stir thoroughly to obtain the shell spinning solution.

[0049] 3. Electrospun membrane preparation: Coaxial electrospinning was performed using the core spinning solution and shell spinning solution obtained in step 2. The electrospinning conditions were: voltage 12kV, distance 15cm, core spinning solution flow rate 1.4ml / h, and shell spinning solution flow rate 0.8ml / h, to obtain a core-shell nanofiber membrane with a nanofiber diameter of 850nm. The membrane was then hot-pressed to obtain a fabric with a thickness of 700μm.

[0050] Comparative Example 2 (Chitosan-free)

[0051] A fabric and its preparation method, comprising the following steps:

[0052] 1. Preparation of FU-CTP complex: 600 mg of fluorouracil and 1.30 g of collagen tripeptide were dissolved together in 100 ml of 1.5 w / v acetic acid solution. After thorough stirring and dissolution, the solution was spray-dried to obtain the FU-CTP complex.

[0053] 2. Preparation of spinning solution: Add 4g of the FU-CTP composite obtained in step 1 and 18g of polyvinylpyrrolidone with a weight average molecular weight of 42000 to 100ml of water, stir thoroughly to obtain the core spinning solution; add 160mg of egg yolk lecithin and 4g of polylactic acid with a weight average molecular weight of 20000 to 100ml of a mixed solution of dichloromethane and ethanol in a volume ratio of 6:4, stir thoroughly to obtain the shell spinning solution.

[0054] 3. Electrospun membrane preparation: Coaxial electrospinning was performed using the core spinning solution and shell spinning solution obtained in step 2. The electrospinning conditions were: voltage 12kV, distance 15cm, core spinning solution flow rate 1.4ml / h, and shell spinning solution flow rate 0.8ml / h, to obtain a core-shell nanofiber membrane with a nanofiber diameter of 850nm. The membrane was then hot-pressed to obtain a fabric with a thickness of 700μm.

[0055] Comparative Example 3 (Lecithin without Egg Yolk)

[0056] A fabric and its preparation method, comprising the following steps:

[0057] 1. Preparation of FU-CTP complex: 600 mg of fluorouracil and 1.30 g of collagen tripeptide were dissolved together in 100 ml of 1.5 w / v acetic acid solution, and then 1.5 g of chitosan with a weight average molecular weight of 120,000 and a degree of deacetylation of 80% was added. After thorough stirring and dissolution, the mixture was spray-dried to obtain the FU-CTP complex.

[0058] 2. Preparation of spinning solution: Add 4g of the FU-CTP composite obtained in step 1 and 18g of polyvinylpyrrolidone with a weight average molecular weight of 42000 to 100ml of water, stir thoroughly to obtain the core spinning solution; add 4g of polylactic acid with a weight average molecular weight of 20000 to 100ml of a mixed solution of dichloromethane and ethanol in a volume ratio of 6:4, stir thoroughly to obtain the shell spinning solution.

[0059] 3. Electrospun membrane preparation: Coaxial electrospinning was performed using the core spinning solution and shell spinning solution obtained in step 2. The electrospinning conditions were: voltage 12kV, distance 15cm, core spinning solution flow rate 1.4ml / h, and shell spinning solution flow rate 0.8ml / h, to obtain a core-shell nanofiber membrane with a nanofiber diameter of 850nm. The membrane was then hot-pressed to obtain a fabric with a thickness of 700μm.

[0060] Transdermal permeation test

[0061] The transdermal permeability of fluorouracil in the fabrics of Examples 1-3 and Comparative Examples 1-3 was determined using a TK-12B transdermal diffusion assay instrument. Eight-week-old SD rats were euthanized by depilating their backs and cervically dislocating. Skin samples of approximately 2.5cm × 2.5cm in size were immediately harvested from the back, and subcutaneous mucosa and adipose tissue were scraped away. The skin was rinsed with physiological saline until the wash was clear. The harvested skin was then soaked in physiological saline and stored in a refrigerator as spare rat skin for in vitro transdermal experiments.

[0062] Experimental parameter settings: water bath temperature 37±0.5℃, stirring speed 250 r·min -1 The effective diffusion area is 2.92 cm². 2 The receiving cell volume was 7 ml, and the receiving medium was physiological saline containing 20% ​​ethanol. The test fabric was soaked in artificial sweat, excess moisture was absorbed with absorbent paper, and then applied to the keratin layer of mouse skin for fixation. The concentration of fluorouracil in the receiving cell at 12 h and 24 h was determined by high-performance liquid chromatography (HPLC), and the cumulative transdermal permeation Q was calculated. The results are shown in [Figure number missing]. Figure 4 .

[0063] Depend on Figure 4 It can be seen that the fabric prepared in the example can rapidly permeate fluorouracil drug through the skin, with a cumulative permeation of 30 μg·cm³ in 12 hours. -2It can reach 60 μg·cm⁻¹ in 24 hours. -2 The above methods are highly beneficial for locally increasing drug concentration around subcutaneous tumors, while avoiding the side effects of intravenous and oral fluorouracil injection. In contrast, although the fabric prepared in the comparative example also contains fluorouracil in its fibers, its transdermal permeability is poor. The reason for this is that Comparative Example 1 lacks collagen tripeptide; fluorouracil cannot utilize the biuret-like structure of collagen tripeptide to obtain the FU-CTP complex, and collagen tripeptide is crucial for the transdermal permeability of fluorouracil, thus significantly limiting its permeability. Comparative Example 2 lacks chitosan; without the stabilizing effect of amino-cationized chitosan, the ring strain of CTP in the FU-CTP complex is strong, weakening the binding of fluorouracil to CTP. CTP cannot assist in the transdermal permeability of FU, thus reducing the permeability of fluorouracil. The fabric fiber in Comparative Example 3 lacks egg yolk lecithin in its shell layer; the FU-CTP complex diffusing outward from the core layer cannot be coated by egg yolk lecithin before being released to the body surface. A lack of lecithin reduces the compatibility of the FU-CTP complex with the stratum corneum of the skin, and also significantly affects the transdermal absorption performance of fluorouracil.

[0064] This invention provides a fabric for adjuvant treatment of breast cancer and a method for its preparation. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for preparing a fabric for adjuvant therapy of breast cancer, characterized in that, Includes the following steps: Preparation of S1.FU-CTP complex: Fluorouracil and collagen tripeptide were dissolved together in 1-2 w / v% acetic acid solution, then chitosan was added, and after thorough stirring and dissolution, the mixture was spray-dried to obtain FU-CTP complex. S2. Preparation of spinning solution: The FU-CTP composite obtained in step S1 and polyvinylpyrrolidone are added to water and stirred thoroughly to obtain the core spinning solution. S3. Add egg yolk lecithin and polylactic acid to a mixed solution of dichloromethane and ethanol, stir thoroughly to obtain shell spinning solution; S4. Electrospun membrane preparation: The core spinning solution and the shell spinning solution are coaxially electrospun to obtain a core-shell nanofiber membrane with a nanofiber diameter of 700-900nm. After hot pressing, a fabric with a thickness of 400-800μm for adjuvant treatment of breast cancer is obtained.

2. The production method according to claim 1, characterized by, In step S1, the chitosan has a weight-average molecular weight of 100,000-150,000 and a degree of deacetylation of 75-85%.

3. The preparation method according to claim 1, characterized in that, In step S1, the feeding ratio of fluorouracil, collagen tripeptide, acetic acid solution and chitosan is (520-650) mg:(1.12-1.40) g:100 ml:(1.0-2.0) g.

4. The method of claim 1, wherein, In step S2, the weight-average molecular weight of the polyvinylpyrrolidone is 24,000-58,000.

5. The preparation method according to claim 1, characterized in that, In step S2, the ratio of FU-CTP complex, polyvinylpyrrolidone and water is (2-5)g:(15-20)g:100ml.

6. The method of claim 1, wherein, In step S3, the volume ratio of dichloromethane to ethanol in the mixed solution of dichloromethane and ethanol is 5:5-7:

3.

7. The preparation method according to claim 1, characterized in that, In step S3, the polylactic acid has a weight-average molecular weight of 15,000-24,000.

8. The method of claim 1, wherein, In step S3, the feeding ratio of egg yolk lecithin, polylactic acid and the mixed solution of dichloromethane and ethanol is (100-200) mg: (3-5) g: 100 ml.

9. The method of claim 1, wherein, In step S4, the coaxial electrospinning conditions are: voltage 10-15kV, distance 13-16cm, core layer spinning solution flow rate 1.2-1.5ml / h, and shell layer spinning solution flow rate 0.7-1.0ml / h.

10. A fabric for adjuvant treatment of breast cancer is prepared by the preparation method according to any one of claims 1 to 9.

Images