Polylactic acid-glycolic acid copolymer composite fiber membrane as well as preparation method and application thereof

Abstract

The invention discloses a poly (lactic acid-glycolic acid) copolymer composite fiber membrane as well as a preparation method and application thereof. The poly (lactic acid-glycolic acid) copolymer composite fiber membrane provided by the invention comprises a poly (lactic acid-glycolic acid) copolymer fiber matrix, a loaded chemotherapeutic drug and a copper-based metal organic framework, the loaded chemotherapeutic drugs comprise carmustine, carboplatin and etoposide; the copper-based metal organic framework is CuBDC; according to the invention, by optimizing the electrospinning liquid formula and the electrospinning process, the synergistic loading of the PLGA fiber membrane on the water-soluble drug, the hydrophobic drug and the copper-based MOF is successfully realized, and the problems of limited drug loading, short slow release period and single function of the current PLGA drug-loaded fiber membrane are solved.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of biomedical materials, and particularly relates to a polylactic glycolic acid copolymer composite fiber membrane and a preparation method and application thereof. BACKGROUND

[0002] As a biodegradable polymer material, polylactic glycolic acid copolymer (PLGA) has been widely concerned in the field of biomedical materials due to its good biocompatibility and controllable degradation rate, and has important application value in drug release carriers and tissue engineering scaffolds. Metal organic framework (MOF) material has unique advantages in drug delivery and catalysis due to its porous structure and functional designability. Combining PLGA and MOF to construct a composite fiber membrane has become one of the hot research directions in the field of biomedical materials in recent years.

[0003] The current PLGA drug-loaded fiber membrane has the following problems: drug loading is limited, it is difficult to simultaneously load water-soluble drugs (such as carboplatin) and hydrophobic drugs (such as etoposide); the release period is short: the traditional carrier degrades fast, and drug burst release is obvious; the function is single: it lacks the ability to synergistically control the release of trace elements. In the prior art, carboplatin is difficult to be effectively loaded by electrospinning because it is insoluble in organic solvents. Although MOF material has the effect of promoting angiogenesis, it has the problems of uncontrollable ion release and cytotoxicity risk. SUMMARY

[0004] The application aims to provide a polylactic glycolic acid copolymer composite fiber membrane and a preparation method and application thereof, so as to solve the problems of drug loading limitation, short release period and single function of the current PLGA drug-loaded fiber membrane.

[0005] In a first aspect, the application provides a polylactic glycolic acid copolymer composite fiber membrane, comprising: a polylactic glycolic acid copolymer fiber matrix, a loaded chemotherapeutic drug and a copper-based metal organic framework; the loaded chemotherapeutic drug comprises carmustine, carboplatin and etoposide; and the copper-based metal organic framework is CuBDC.

[0006] In a second aspect, the application provides a preparation method of a polylactic glycolic acid copolymer composite fiber membrane, comprising:

[0007] Step one, mixing tetrahydrofuran and N,N-dimethylformamide at a volume ratio of 2:1 to 4:1, and adding polylactic glycolic acid copolymer to prepare a 20% to 40% w / v solution;

[0008] Step two, sequentially adding carboplatin-NaCl aqueous solution, carmustine-methanol solution and etoposide;

[0009] Step three, performing an electrospinning process according to a first preset parameter;

[0010] Step four, Cu(CH3COO)2 reacts with Na2BDC in the aqueous phase for 1h to synthesize CuBDC;

[0011] Step five, dispersing CuBDC in polylactic acid glycolic acid copolymer / hexafluoroisopropanol solution;

[0012] Step six, electrospinning process according to the second preset parameter.

[0013] Optionally, in step one, 8mL of tetrahydrofuran and N,N-dimethylformamide are mixed in a volume ratio of 3:1, 2g of polylactic acid glycolic acid copolymer is added, and stirring is carried out for 12h.

[0014] Optionally, in step two, 2mL of 25mg / mL carboplatin-NaCl aqueous solution, 1mL of 50mg / mL carmustine-methanol solution, and 100mg of etoposide are sequentially added.

[0015] Optionally, in step three, the first preset parameter includes a voltage of 16-20kV, a receiving distance of 15-19cm, and a flow rate of 0.6-1mL / h.

[0016] Optionally, in step three, the first preset parameter includes a voltage of 16kV, a receiving distance of 15cm, and a flow rate of 0.8mL / h.

[0017] Optionally, in step five, CuBDC with 5%-20%w / w PLGA is dispersed in polylactic acid glycolic acid copolymer / hexafluoroisopropanol solution.

[0018] Optionally, in step five, CuBDC with 10%w / w PLGA is dispersed in polylactic acid glycolic acid copolymer / hexafluoroisopropanol solution.

[0019] Optionally, in step six, the second preset parameter includes a voltage of 13-15kV, a receiving distance of 12cm, and a flow rate of 1.0mL / h.

[0020] In a third aspect, the application provides a use of the polylactic acid glycolic acid copolymer composite fiber membrane described above in the preparation of a brain glioma sustained-release implant or a tissue engineering scaffold.

[0021] The application has the following beneficial effects: The polylactic acid glycolic acid copolymer composite fiber membrane, the preparation method and the application thereof successfully realize the synergistic loading of PLGA fiber membranes on water-soluble drugs, hydrophobic drugs and copper-based MOFs by optimizing the electrospinning liquid formula and the electrospinning process, effectively solve the problems that traditional PLGA drug-loaded fiber membranes are difficult to simultaneously load drugs with different properties and MOF materials have uncontrollable ion release and high risk of cytotoxicity, significantly improve the loading efficiency and sustained-release performance of drugs, prolong the drug release period, and reduce the cytotoxicity of the drug by Cu2+ The stable sustained release promotes angiogenesis, enhances the biocompatibility of the fibrous membrane, and is beneficial to promoting the adhesion and proliferation of hBMSCs, thereby providing a new effective approach for the preparation of a brain glioma sustained release implant or a tissue engineering scaffold. BRIEF DESCRIPTION OF DRAWINGS

[0022] In order to more clearly illustrate the technical solutions of the present application, the drawings needed in the embodiments will be briefly introduced below. Obviously, for those skilled in the art, other drawings can also be obtained without creative labor on the basis of these drawings.

[0023] Figure 1 SEM results of the PLGA fibrous membrane and the PLGA drug-loaded fibrous membrane, wherein (a) is the SEM result of the PLGA fibrous membrane, and (b) is the SEM result of the PLGA drug-loaded fibrous membrane;

[0024] Figure 2 XRD spectra of the PLGA fibrous membrane and the PLGA drug-loaded fibrous membrane;

[0025] Figure 3 Drug release curve;

[0026] Figure 4 Characterization of the PLGA / CuBDC fibrous membrane, wherein (a) is a powder X-ray diffraction spectrum of CuBDC; (b) is a scanning electron microscope image; (c) is a Fourier transform infrared spectrum; (d) is an X-ray diffraction curve; (e) is a thermogravimetric analysis spectrum of different scaffolds; (f) is a cumulative release curve of copper ions; (g) is a scanning electron microscope image, a digital photograph, and an energy spectrum analysis mapping of the composite scaffold; (h) is a scanning electron microscope image after 10 weeks of degradation;

[0027] Figure 5 In-vitro cell proliferation of the PLGA / CuBDC fibrous membrane;

[0028] Figure 6 Tumor inhibition effect of the multi-drug sustained release carrier on a nude mouse glioma model, wherein (a) is a 22-day tumor volume curve; (b) is a tumor weight curve. DETAILED DESCRIPTION

[0029] In order to make the objects, technical solutions and advantages of the present application clearer, the technical solutions of the present application will be described below in connection with specific embodiments of the present application and corresponding drawings. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the protection scope of the present application. The technical solutions provided by the embodiments of the present application are described in detail below in connection with the drawings.

[0030] Referring to Figures 1 to 6 The present application provides a polylactic acid glycolic acid copolymer composite fiber membrane, comprising: a polylactic acid glycolic acid copolymer fiber substrate, a loaded chemotherapeutic drug and a copper-based metal organic framework; the loaded chemotherapeutic drug comprises carmustine, carboplatin and etoposide; and the copper-based metal organic framework is CuBDC. A preparation method of the polylactic acid glycolic acid copolymer composite fiber membrane comprises the following steps.

[0031] In step one, tetrahydrofuran and N,N-dimethylformamide are mixed at a volume ratio of 2:1 to 4:1, and 20% to 40% w / v solution of polylactic acid glycolic acid copolymer is prepared by adding the polylactic acid glycolic acid copolymer.

[0032] In this embodiment, 8 mL of tetrahydrofuran and N,N-dimethylformamide are mixed at a volume ratio of 3:1, and 2 g of polylactic acid glycolic acid copolymer is added and stirred for 12 h.

[0033] In step two, carboplatin-NaCl aqueous solution, carmustine-methanol solution and etoposide are sequentially added.

[0034] In this embodiment, 2 mL of 25 mg / mL carboplatin-NaCl aqueous solution, 1 mL of 50 mg / mL carmustine-methanol solution and 100 mg of etoposide are sequentially added.

[0035] In step three, electrospinning process is performed according to first preset parameters.

[0036] In this embodiment, the first preset parameters include voltage 16 to 20 kV, receiving distance 15 to 19 cm, flow rate 0.6 to 1 mL / h, and receiving roller speed 450 rpm. Preferably, the voltage is 16 kV, the receiving distance is 15 cm, and the flow rate is 0.8 mL / h.

[0037] In step four, Cu(CH3COO)2 and Na2BDC are reacted in an aqueous phase for 1 h to synthesize CuBDC.

[0038] In step five, CuBDC is dispersed in polylactic acid glycolic acid copolymer / hexafluoroisopropanol solution.

[0039] In the present embodiment, CuBDC is dispersed in a polylactic acid glycolic acid copolymer / hexafluoroisopropanol solution at 5%-20% w / w PLGA. Preferably, CuBDC is dispersed in a polylactic acid glycolic acid copolymer / hexafluoroisopropanol solution at 10% w / w PLGA.

[0040] Step six, electrospinning process according to the second preset parameter.

[0041] In the present embodiment, the second preset parameter includes a voltage of 13-15 kV, a receiving distance of 12±2 cm, and a flow rate of 1.0 mL / h. The receiving wheel speed is 350 rpm.

[0042] Finally, post-processing is performed: vacuum drying at 37°C for 72 h to remove the solvent.

[0043] The product prepared by the present application has the following properties:

[0044] Drug loading: carmustine 67.8±3.2%, cisplatin 34.2±0.3%, etoposide 73.3±2.1%;

[0045] Sustained release performance: drug release >15 days, copper ion release >20 days (no burst release);

[0046] Biocompatibility: promotes hBMSCs adhesion and proliferation (PLGA / CuBDC L group is optimal).

[0047] Morphology characterization, see Figure 1 : fiber diameter 0.5-1.2 μm, drug uniformly wrapped;

[0048] Sustained release performance, see Figure 6 : BCNU sustained release for 15 days, cisplatin low release (restricted by hydrophobicity);

[0049] Cu 2+ sustained release, see Figure 4 f: stable release within 20 days, no burst release;

[0050] Biocompatibility, see Figure 5 : PLGA / CuBDC_L group cell proliferation rate increased by 50% (vs. pure PLGA).

[0051] In summary, the present application breaks through the bottleneck of loading water-soluble drugs by pre-dissolving cisplatin in an aqueous solution; PLGA synchronously loads drugs + MOF, which synergistically controls drug release and ion microenvironment; the double sustained release system (drug >15 days, Cu 2+ >20 days) solves the problems of fast degradation and high burst release of traditional carriers.

[0052] The above-described embodiments of the present application do not constitute a limitation on the scope of protection of the present application.

Claims

1. A polylactic acid-glycolic acid copolymer composite fiber membrane, characterized in that, include: The invention comprises a polylactic acid-glycolic acid copolymer fiber matrix, a loaded chemotherapeutic drug, and a copper-based metal-organic framework; the loaded chemotherapeutic drug includes carmustine, carboplatin, and etoposide; and the copper-based metal-organic framework is CuBDC.

2. A method for preparing a polylactic acid-glycolic acid copolymer composite fiber membrane as described in claim 1, characterized in that, include: Step 1: Mix tetrahydrofuran and N,N-dimethylformamide in a volume ratio of 2:1 to 4:1, and add polylactic acid glycolic acid copolymer to prepare a 20% to 40% w / v solution; Step 2: Add carboplatin-NaCl aqueous solution, carmustine-methanol solution, and etoposide in sequence; Step 3: Perform electrospinning according to the first preset parameters; Step 4: React Cu(CH3COO)2 with Na2BDC in an aqueous phase for 1 hour to synthesize CuBDC; Step 5: Disperse CuBDC in a polylactic acid glycolic acid copolymer / hexafluoroisopropanol solution; Step six: Perform electrospinning according to the second preset parameters.

3. The method for preparing a polylactic acid-glycolic acid copolymer composite fiber membrane as described in claim 2, characterized in that, In step one, tetrahydrofuran and N,N-dimethylformamide were mixed in a volume ratio of 3:1 for 8 mL, and 2 g of polylactic acid glycolic acid copolymer was added and stirred for 12 h.

4. The method for preparing a polylactic acid-glycolic acid copolymer composite fiber membrane as described in claim 2, characterized in that, In step two, add 2 mL of 25 mg / mL carboplatin-NaCl aqueous solution, 1 mL of 50 mg / mL carmustine-methanol solution, and 100 mg of etoposide in sequence.

5. The method for preparing a polylactic acid-glycolic acid copolymer composite fiber membrane as described in claim 2, characterized in that, In step three, the first preset parameters include a voltage of 16-20kV, a receiving distance of 15-19cm, and a flow rate of 0.6-1mL / h.

6. The method for preparing a polylactic acid-glycolic acid copolymer composite fiber membrane as described in claim 5, characterized in that, In step three, the first preset parameters include a voltage of 16kV, a receiving distance of 15cm, and a flow rate of 0.8mL / h.

7. The method for preparing a polylactic acid-glycolic acid copolymer composite fiber membrane as described in claim 2, characterized in that, In step five, 5%-20% w / w PLGA CuBDC is dispersed in a polylactic acid glycolic acid copolymer / hexafluoroisopropanol solution.

8. The method for preparing a polylactic acid-glycolic acid copolymer composite fiber membrane as described in claim 7, characterized in that, In step five, 10% w / w PLGA CuBDC is dispersed in a polylactic acid glycolic acid copolymer / hexafluoroisopropanol solution.

9. The method for preparing a polylactic acid-glycolic acid copolymer composite fiber membrane as described in claim 2, characterized in that, In step six, the second preset parameters include a voltage of 13-15kV, a receiving distance of 12cm, and a flow rate of 1.0mL / h.

10. The use of the polylactic acid glycolic acid copolymer composite fiber membrane as described in claim 1 in the preparation of sustained-release implants for gliomas or tissue engineering scaffolds.

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