CN109432062B - Drug-loaded electrospun fiber membrane and preparation method thereof - Google Patents
Drug-loaded electrospun fiber membrane and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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Abstract
The invention discloses a drug-loaded electro-spun fibrous membrane, which consists of an anti-tumor drug and a carrier material, and is characterized in that: the antitumor drug contains camptothecin and curcumin; the invention also discloses a preparation method of the fiber membrane. The fiber membrane is used as a brand-new anti-tumor drug carrier, has excellent biocompatibility and degradability, has good drug slow release performance, and has wide application prospect. The medicine has good biocompatibility and degradability, can be gradually released from a release carrier, so as to maintain stable and effective concentration, can effectively inhibit the growth of tumor cells, has excellent anti-tumor effect, and is convenient and fast in preparation method and low in cost.
Description
Technical Field
The invention relates to a drug-loaded electro-spun fibrous membrane and a preparation method thereof, in particular to an electro-spun fibrous membrane loaded with two anti-tumor drugs and a preparation method thereof.
Background
Cancer is one of the leading causes of death in humans, and chemotherapy is one of the leading methods of cancer treatment. Multidrug resistance in tumors is the biggest obstacle to current cancer chemotherapy. The research shows that: after the tumor cells in the growth period are contacted with the chemotherapeutic drug, the drug resistance is generated to the chemotherapeutic drug, and the cross drug resistance is generated to other drugs with different structures and functions. In clinic, about half of chemotherapy patients completely generate drug resistance to chemotherapy drugs, or even if the chemotherapy drugs are effective in a short time, the chemotherapy drugs immediately generate drug resistance, so that great difficulty is brought to the chemotherapy of tumors.
The use of a single chemical does not provide complete relief due to the adverse effects of cancer cell resistance and high dose or repeated administration. To overcome these problems, clinicians have adopted combination chemotherapy based on the combination of multiple drugs, which is an effective way to overcome the multidrug resistance of tumors. It has been reported that the use of combination chemotherapeutic drugs targeting different cellular signaling pathways can increase the genetic disturbance of cancer cell mutation and delay the adaptive process of cancer. Moreover, by adjusting the dosage of each drug, the simultaneous administration of multiple drugs can not only delay the adaptation process of cancer and related tumor cell mutation, reduce the side effects of the drugs, but also achieve the synergistic treatment effect.
Camptothecin (CPT) is a hydrophobic natural alkaloid extracted from camptotheca acuminata, and has broad-spectrum antitumor activity. CPT binds non-covalently to the DNA-topoisomerase I binary complex to form a CPT-topoisomerase I-DNA ternary complex, thereby inducing apoptosis in the cell. It has also been shown that CPT can also induce apoptosis in different cell types by activating the Fas pathway and the mitochondria-associated pathway, which allows the cell cycle to stay in the G2/M phase. Although CPT has been shown to have anti-tumor effects, its dose-limiting toxicity and limited therapeutic efficacy severely limit its clinical utility.
Disclosure of Invention
The invention aims to provide a drug-loaded electro-spun fibrous membrane, which is loaded with two anti-tumor drugs, namely camptothecin and curcumin.
The invention also aims to provide a preparation method of the electrospun fibrous membrane loaded with two antitumor drugs.
The technical scheme adopted by the invention is as follows:
a drug-loaded electrospun fiber membrane comprises antitumor drugs and carrier material, wherein the antitumor drugs comprise camptothecin and curcumin.
Further, the mass ratio of the antitumor drug to the carrier material is 1: 10-1: 20.
Further, the mass ratio of the camptothecin to the curcumin is 1: 7-7: 1.
Further, the carrier material is a biodegradable high polymer material modified with an amphiphilic substance, wherein the amphiphilic substance is PF127, and the biodegradable high polymer material is PLGA; preferably, the molecular weight of the PLGA is 1-10 ten thousand, and the ratio of the PLA to the PGA in the PLGA is 4: 1-1: 4.
Further, the mass ratio of PLGA to PF127 is 5: 1-1: 2.
The preparation method of the drug-loaded electrospun fiber membrane comprises the following steps:
1) dissolving camptothecin, curcumin, PLGA and PF127 in an organic solvent, and uniformly dissolving to obtain a high polymer electrospinning solution;
2) under the conditions of 25 ℃ and 30-50% of relative humidity, carrying out electrostatic spinning on the electrospinning liquid by using an electrostatic spinning instrument, and volatilizing an organic solvent to prepare a drug-loaded electrospun fibrous membrane;
3) and naturally drying the drug-loaded electrospun fiber membrane under the condition of keeping out of the sun.
Further, the organic solution is a mixed solution of dichloromethane and methanol.
Furthermore, the volume ratio of the dichloromethane to the methanol is 8: 2-8: 6.
Further, the mass fraction of PLGA in the high polymer electrospinning liquid is 12-18%.
Further, the technological parameters of the electrostatic spinning instrument are as follows: applying a voltage of 10-20 KV, a receiving distance of 6-10 cm, and a spinning advancing speed of 0.2-0.6 mL/min.
Curcumin (curmin, CUR) is a plant polyphenol with antioxidant, anti-inflammatory, tumor preventing and anticancer capabilities. Due to its unique properties, it is attracting increasing attention in the field of cancer therapy. It can inhibit various cell channels related to tumorigenesis and development; can interact with various intracellular and extracellular molecules related to tumorigenesis and metastasis, thereby inhibiting tumorigenesis and metastasis. In addition, the toxic and side effects of the CUR on human bodies are small, and the safe dose can be up to 8000 mg/day in clinical tests. The CUR is also a traditional Chinese medicine chemotherapy drug resistance reversal agent, has wide action targets, and can improve the sensitivity of drug-resistant cells to drugs and reverse the multidrug resistance of tumors in various ways. The synergistic therapeutic effects of CUR and various anticancer agents have been studied. Although CUR has many advantages, its use is limited by its poor oral bioavailability, poor water solubility and photosensitivity. In the invention, the camptothecin and the curcumin are combined for use, so that the problem that the clinical application of the camptothecin is severely limited due to the dose-limiting toxicity and the limited treatment effect of the camptothecin is solved. In addition, the electrospun fiber membrane is used as a carrier, so that the problems of low oral bioavailability, poor water solubility, poor photosensitivity and the like of curcumin are solved.
Poly (lactic-co-glycolic acid), PLGA, is an FDA-approved polymeric material that has attracted considerable attention due to its excellent biocompatibility, mechanical properties, ease of processing, controllability of degradation, and non-toxicity of byproducts. Has good biocompatibility and tensile strength, combines the high degradation speed of PGA and the high strength of PLA, and the degradation rate can be adjusted and controlled by changing the ratio of PLA to PGA. However, PLGA fibers typically exhibit very slow drug release characteristics due to their inherent hydrophobicity which hinders diffusion of the drug through the internal porous structure.
Pluronic F127(PF127) is an amphiphilic polymer polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer approved by FDA, and can carry out covalent modification on various hydrophilic functional groups, so that a functionalized substrate material with good water solubility can be obtained; meanwhile, PF127 has the characteristic of being adhered to a contact interface, has no obvious immune reaction, has good affinity and viscosity to chondrocytes, does not influence the metabolism of cells, and the degradation and absorption speed of the PF127 can be adjusted by changing the concentration of a solution. The hydrophilic biomaterial and the PLGA are co-spun, so that the hydrophilicity of the biomaterial can be effectively improved.
The invention has the beneficial effects that: the invention discloses an electrospun fibrous membrane of two antitumor drugs and a preparation method thereof, wherein the fibrous membrane is used as a brand-new antitumor drug carrier, has excellent biocompatibility and degradability, has good drug slow release performance, and has wide application prospect. The medicine has good biocompatibility and degradability, can be gradually released from a release carrier, so as to maintain stable and effective concentration, can effectively inhibit the growth of tumor cells, has excellent anti-tumor effect, and is convenient and fast in preparation method and low in cost.
Drawings
FIGS. 1 to 4 are scanning electron micrographs of PLGA-PF127 electrospun membranes under different conditions;
FIGS. 5 to 9 are scanning electron microscope photographs of different types of drug-loaded electrospun fiber membranes;
FIG. 10 shows the inhibition of colon tumor cells by drug-loaded electrospun fiber membranes.
Detailed Description
PLGA (PLA and PGA are 1:1, the molecular weight is 4.4 ten thousand) and PF127 are accurately weighed by a balance to account for 1000mg, and the PLGA and the PGA are dissolved in a mixed solution of dichloromethane and methanol (the volume ratio of the solution is 8:2) to prepare PLGA/PF127 with the gradient of the mass ratio of 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, the mass concentration of PLGA is 14%, the bottle mouth is sealed to prevent the solvent from volatilizing, and the solution is swirled until the solution is completely dissolved, thus obtaining the high polymer electrospinning solution. Respectively adjusting process control parameters of an electrospinning instrument (with an instrument input voltage of 3V and an instrument output voltage of 10KV) such as flow rate (0.2mL/min, 0.4mL/min and 0.6mL/min) and receiving distance (5cm, 6cm, 7cm, 8cm and 9cm) through electrostatic spinning to screen out optimal concentration: the fibrous membrane has good general appearance and uniform fiber in microscopic appearance. After the electro-spinning membrane is obtained, the electro-spinning membrane is placed on an ultra-clean workbench to be protected from light and dried naturally.
Representative scanning electron micrographs of PLGA-PF127 electrospun membranes under different conditions are shown in FIGS. 1-4, wherein the parameter conditions in FIG. 1 are that the PLGA/PF127 mass ratio is 5:1, the spinning advancing speed is 0.6mL/min, and the receiving distance is 8 cm;
the parameter conditions of FIG. 2 are PLGA/PF127 mass ratio of 3:1, spinning advancing speed of 0.2mL/min, receiving distance of 6 cm;
the parameter conditions of FIG. 3 are that the PLGA/PF127 mass ratio is 1:2, the spinning advancing speed is 0.4mL/min, and the receiving distance is 9 cm;
the parameter conditions of FIG. 4 were a PLGA/PF127 mass ratio of 4:1, a spinning advance speed of 0.4mL/min, and a take-up distance of 7 cm. By comparison, the parameter condition of fig. 4 is an optimal parameter condition.
Five groups of CPT and CUR samples with different mass ratios are selected to prepare the drug-loaded electro-spinning fibrous membrane. Wherein each group comprises PLGA 800mg and PF 127200 mg, and the total mass of each group is 80 mg. Five groups of drugs CPT: the mass ratio of the CUR is (A)1:0 respectively; (B)0: 1; (C)5: 1; (D)3: 1; (E)2: 1. The obtained solution was dissolved in a mixed solvent of methylene chloride and methanol (volume ratio 8:2) to give a PLGA mass concentration of 14%, and the bottle mouth was sealed to prevent solvent evaporation. And (5) vortexing by a vortexer until the solution is completely dissolved, and thus obtaining the spinning solution. And spinning the electrospinning solution by using an electrostatic spinning instrument by using the latex gloves as a receiver under the conditions of 25 ℃ and 30-50% of relative humidity. The input voltage is 3V, the output voltage is 10KV, the receiving distance is 7cm, the electrospinning liquid is 3mL, the spinning liquid advancing speed is 4mL/min, and the diameter of a spinning nozzle is 0.51 mm. After the electro-spinning membrane is obtained, the electro-spinning membrane is placed on an ultra-clean workbench to be protected from light and naturally dried, and the two drug-loaded fiber membranes with five different CPT and CUR proportions are prepared. As shown in FIGS. 5 to 9, the scanning electron microscope photographs and the diameter distribution of the electrospun fiber membranes PLGA-PF127-CPT, PLGA-PF127-CUR, PLGA-PF127-CPT/CUR (5:1), PLGA-PF127-CPT/CUR (3:1) and PLGA-PF127-CPT/CUR (2:1), respectively, are shown.
Detection of antitumor Effect
Test cells: mouse colon cancer CT-26 cells;
test materials: PLGA-PF127, PLGA-PF127-CPT, PLGA-PF127-CUR, PLGA-PF127-CPT/CUR (5:1), PLGA-PF127-CPT/CUR (3:1) and PLGA-PF127-CPT/CUR (2: 1);
the experimental method comprises the following steps: PLGA-PF127, PLGA-PF127-CPT, PLGA-PF127-CUR, PLGA-PF127-CPT/CUR (5:1), PLGA-PF127-CPT/CUR (3:1) and PLGA-PF127-CPT/CUR (2:1) were cut to 1cm × 1cm in size. Wherein PLGA-PF127 was UV sterilized for half an hour. The 6 kinds of fiber membranes are respectively placed in a 24-well plate, and 800 mu L of DMEM serum-free medium is added for pre-wetting for 1 h. After digesting the cells in the logarithmic growth phase with trypsin, the cell concentration was adjusted to 4X 10 with DMEM complete medium5Perml, add to 24-well plate at 37 ℃ with 5% CO2Culturing in an incubator. Each group was set with 3 more wells, cultured for 12, 24, 36h, medium and fibrous membrane were discarded, 0.8mL of MTT solution (0.5mg/mL) was added to each well, and culture was continued for 4 h. The culture was terminated, the cell supernatant was discarded, 800. mu.L of a dimethyl sulfoxide (DMSO) solution was added to each well, and the mixture was shaken at 120rpm on a shaker for 20min to dissolve the crystals sufficiently. The absorbance value (A) was measured for each well at an ELISA OD570nm570) The test was repeated 3 times. A of PLGA-PF127 electrospun fiber membrane with blank570For the reference frame, the relative activity of tumor cells was calculated separately. As shown in fig. 10, it is a photograph of the relative activity of tumor cells of the drug-loaded fiber membrane in different culture periods.
As can be seen from the figure, the cell activity ranges of the two anti-tumor drug-loaded electrospun fibrous membranes after being co-cultured with the cells for 12 hours, 24 hours and 36 hours are 74-62%, 61-39% and 43-31% respectively. The toxicity of the electrospun fibrous membrane carrying the two anti-tumor drugs to cells is gradually enhanced along with the extension of the culture time; however, the cell survival rates of the PLGA-PF127-CUR fiber membrane after being co-cultured with the cells for 12h, 24h and 36h are respectively 98%, 78% and 73%, which indicates that the inhibition effect of the membrane on the proliferation of colon cancer cells is not obvious. In addition, the cell activities of PLGA-PF127-CPT after 12h, 24h and 36h of co-culture with the cells are 48%, 42% and 37%, respectively, although the fiber membrane has a strong inhibition effect on the proliferation of the cells at the beginning, the inhibition effect on the proliferation of colon cancer cells is not obviously changed along with the prolonging of the culture time.
In conclusion, the two anti-tumor drug-loaded electrospun fibrous membranes have obvious inhibition effect on mouse colon cancer CT-26 cells under the condition of using less CPT, and show an upward trend on the toxicity of the cells along with the prolonging of time, and have stronger treatment effect in the long-term treatment of cancers.
Finally, it is noted that the above-mentioned embodiments illustrate rather than limit the invention, and that, while the invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (6)
1. A drug-loaded electrospun fiber membrane is composed of an anti-tumor drug and a carrier material, and is characterized in that: the antitumor drug contains camptothecin and curcumin; the mass ratio of the antitumor drug to the carrier material is 1: 10-1: 20; the mass ratio of the camptothecin to the curcumin is 1: 7-7: 1; the carrier material is a biodegradable high polymer material modified with an amphiphilic substance, wherein the amphiphilic substance is PF127, and the biodegradable high polymer material is PLGA; the molecular weight of the PLGA is 1-10 ten thousand, and the proportion of PLA to PGA in the PLGA is 4: 1-1: 4; the mass ratio of PLGA to PF127 was 5: 1-1: 2.
2. The method for preparing the drug-loaded electrospun fiber membrane of any one of claim 1, comprising the following steps:
1) dissolving camptothecin, curcumin, PLGA and PF127 in an organic solvent, and uniformly dissolving to obtain a high polymer electrospinning solution;
2) under the conditions of 25 ℃ and 30-50% of relative humidity, carrying out electrostatic spinning on the electrospinning liquid by using an electrostatic spinning instrument, and volatilizing an organic solvent to prepare a drug-loaded electrospun fibrous membrane;
3) and naturally drying the drug-loaded electrospun fiber membrane under the condition of keeping out of the sun.
3. The method of claim 2, wherein: the organic solution is a mixed solution of dichloromethane and methanol.
4. The production method according to claim 3, characterized in that: the volume ratio of the dichloromethane to the methanol is 8: 2-8: 6.
5. The method of claim 4, wherein: the mass fraction of PLGA in the high polymer electrospinning liquid is 12-18%.
6. The method of claim 5, wherein: the technological parameters of the electrostatic spinning instrument are as follows: applying a voltage of 10-20 KV, a receiving distance of 6-10 cm, and a spinning advancing speed of 0.2-0.6 mL/min.
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