Polymer composite hydrogel for treating bladder tumor as well as preparation method and application of polymer composite hydrogel
By using CuS nanoparticles and 808nm infrared-driven hydrogel nanomotors in bladder tumor treatment, the problem of nanodrug difficulty in penetrating the mucosal layer of the bladder wall is solved, achieving higher bioavailability and chemotherapy efficacy.
Patent Information
- Application Number
- CN202411845921.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-16
- Publication Date
- 2025-03-11
AI Technical Summary
Existing nanomedicines are difficult to penetrate the mucosal layer of the bladder wall, resulting in low bioavailability, limiting the development of chemokinetic therapy in bladder perfusion therapy.
CuS is used as the photothermal conversion nanoparticles and 808nm infrared rays are used as the driving light source to improve the ability of hydrogel nanomotors to penetrate the mucosal layer of the bladder wall, and promote in-depth penetration of drugs through autothermal phobia.
The bioavailability of nanodrugs and the efficacy of chemotherapy drugs are improved, and the penetration and efficacy of the drugs on the mucosal layer of the bladder wall are enhanced through higher energy density and temperature gradients.
Smart Images
Figure CN119587694A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of biomedicine, and in particular to a polymer composite hydrogel for treating bladder tumors, a preparation method and application thereof. Background Art
[0002] Bladder tumors are the most common tumors in the urinary system. Most of them are transitional cell carcinomas. They are most common on the lateral and posterior walls of the bladder, followed by the triangular area and the top. They can occur in multiple centers. Bladder tumors may be accompanied by tumors of the renal pelvis, ureter, and urethra successively or simultaneously. Different treatment plans can be adopted according to the specific situation of the bladder tumor, such as cystoscopic transurethral resection or radical cystectomy. Bladder instillation can maximize the exposure of the lesions to therapeutic drugs and can effectively reduce systemic toxic and side effects. Drugs for bladder instillation chemotherapy include gemcitabine, mitomycin C, epirubicin, pirarubicin, hydroxycamptothecin, doxorubicin, etc. Systemic chemotherapy is generally treated with gemcitabine combined with cisplatin.
[0003] In addition to chemotherapy drugs, nanomedicines have also been gradually used for intravesical instillation therapy in recent years. Among them, chemodynamic therapy (CDT) based on metal oxide nanoparticles converts highly expressed hydrogen peroxide in tumor cells into reactive oxygen species (ROS) for cell killing, which greatly avoids the toxic side effects caused by drug off-target, making it a promising method for intravesical instillation of bladder cancer. However, it is difficult for nanoparticles to break through the natural biological barrier formed by the mucosal layer of the bladder wall, resulting in low bioavailability of nanoformulations, which limits the further development of chemodynamic therapy in intravesical instillation therapy.
[0004] Self-propelled nanomotors are nanoparticles that can convert other energy into their own kinetic energy. Their autonomous movement helps to cross biological barriers and has deep tissue penetration. At the same time, they can promote the effective dispersion of particles in a local area. They are potential clinical drug delivery carriers. Currently reported nanomotors for bladder drug delivery are mainly urease-modified nanomotors, which use the high concentration of urea in the bladder microenvironment as fuel, and produce CO2 and NH3 concentration gradients after urease decomposition to drive the autonomous movement of particles. This type of motor structure relies on the natural asymmetric distribution of urease on the surface of nanoparticles, and the driving force generated is limited; secondly, the motor driven by enzymatic reaction depends on the concentration of chemical fuel. As the fuel is exhausted, the motor movement efficiency will be severely impaired; in addition, in the real bladder microenvironment, enzyme activity is difficult to maintain.
[0005] Professor Liu Ying of Nanjing University and Professor Guo Hongqian of Gulou Hospital led a research team to develop a 1064 nm near-infrared zone II light-driven hydrogel nanomotor for enhanced perfusion therapy of bladder cancer. The hydrogel nanomotor uses magnetic field effects and far-infrared zone II to achieve light-driven to break through the natural biological barrier formed by the bladder wall mucosa layer, effectively improving the bioavailability of rice preparations. However, the hydrogel nanomotor they developed has the following defects: it uses a far-infrared zone II light source as the driving light source. Since the longer the wavelength of infrared light, the stronger the penetration ability, but the weaker the energy, the correspondingly lower the photothermal conversion efficiency of nanoparticles, and the ability to use the photothermal conversion efficiency of nanoparticles to drive the thermal self-phoretic motion of the hydrogel nanomotor to penetrate the bladder wall mucosa layer is insufficient. Summary of the invention
[0006] In order to solve the above technical problems, the present invention provides a polymer composite hydrogel for treating bladder tumors. CuS is selected as nanoparticles for photothermal conversion in the polymer composite hydrogel. The highest photothermal conversion efficiency requires infrared light with a wavelength of 808nm as a driving light source, and near-infrared light with a wavelength of 808nm has a higher energy density, which improves the ability of hydrogel nanomotors to penetrate the bladder wall mucosal layer. At the same time, the higher energy density can increase the temperature of the bladder wall mucosa, thereby providing a working environment for chemotherapy drugs with higher efficacy.
[0007] In order to achieve the above technical effects, the present invention is implemented by the following technical solutions: A polymer composite hydrogel for treating bladder tumors is a hydrogel nanodroplet containing cisplatin, paclitaxel, Fe3O4@CuS NPs and coated with a lipid bilayer on the surface, which is obtained by mixing a hydrogel precursor solution and a lipid precursor solution through a flow focusing microfluidic mixing method.
[0008] Furthermore, the hydrogel precursor solution is prepared by mixing PEG-DA-575, Fe3O4@CuS, cisplatin, paclitaxel and a photoinitiator.
[0009] Furthermore, the lipid precursor solution is prepared from lecithin, cholesterol, DSPE-PEG, and DSPE-PEG-FA.
[0010] At the same time, the present invention also discloses a method for preparing a polymer composite hydrogel for treating bladder tumors, comprising the following steps: Preparation of S1, Fe3O4@CuS nanoparticles: (1) Add oleylamine into a flask and rotate and stir under a nitrogen environment, heat to a certain temperature while stirring, then dissolve Fe(acac)3 in oleylamine and N-methyl-2-pyrrolidone, and then inject it into the flask. After reacting for a certain period of time, slowly cool it, and then pour ethanol into the flask to obtain a black precipitate. Collect it after centrifugation to obtain Fe3O4 nanoparticles; (2) Dispersing Fe3O4 in cyclohexane and stirring the mixture under nitrogen atmosphere, then heating the mixture, adding oleylamine to the mixture, and reacting for a certain period of time to form a reaction mixture; adding copper chloride and sodium sulfide to the chloroform / oleylamine mixture, then adding the reaction mixture and stirring. After stirring for a certain period of time, the reaction mixture gradually turns dark green, centrifuging the reaction mixture, and washing with ethanol and chloroform after centrifugation to obtain Fe3O4@CuS nanoparticles with oleylamine as a stable ligand; (3) The obtained Fe3O4@CuS nanoparticles with oleylamine as a stabilizing ligand were dispersed in chloroform, mixed with DSPE-PEG-acrylate, and chloroform was added after a certain period of rotational stirring. After removing the chloroform under a nitrogen environment, a Fe3O4@CuS nanoparticle solution was obtained; S2. Preparation of hydrogel precursor solution: PEG-DA-575, Fe3O4@CuS nanoparticles, cisplatin, paclitaxel and photoinitiator were mixed in deionized water to obtain a hydrogel precursor solution; S3, preparation of lipid precursor solution: adding lecithin, cholesterol, DSPE-PEG and DSPE-PEG-FA together into chloroform and mixing, then drying under nitrogen environment to obtain a dry lipid film, dissolving the dry lipid film in isopropanol to obtain a lipid precursor solution; S4. Preparation of hydrogel nanodroplets: The lipid precursor solution is introduced into the central channel and flows at a lower flow rate through flow focusing microfluidic mixing, and the hydrogel precursor solution is introduced into the side channel at a higher flow rate. The central lipid precursor flow is hydrodynamically focused to obtain hydrogel nanodroplets containing cisplatin, paclitaxel, Fe3O4@CuS NPs and coated with a lipid bilayer on the surface.
[0011] The polymer composite hydrogel for treating bladder tumors provided by the present invention is used in preparing medicine for treating bladder tumors.
[0012] The beneficial effects of the present invention are as follows: CuS is selected as the nanoparticle for photothermal conversion in the polymer composite hydrogel provided by the present invention. The highest photothermal conversion efficiency requires infrared light with a wavelength of 808nm as the driving light source, and near-infrared light with a wavelength of 808nm has a higher energy density, which improves the ability of the hydrogel nanomotor to penetrate the bladder wall mucosal layer. At the same time, the higher energy density can increase the temperature of the bladder wall mucosa, thereby providing a working environment for chemotherapy drugs with higher efficacy. BRIEF DESCRIPTION OF THE DRAWINGS
[0013] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.
[0014] Figure 1 It is a flow chart of the preparation of polymer composite hydrogel for treating bladder tumors. DETAILED DESCRIPTION
[0015] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0016] The invention discloses a polymer composite hydrogel for treating bladder tumors, which is a hydrogel nanodroplet containing cisplatin, paclitaxel, and Fe3O4@CuS NPs and coated with a lipid bilayer on the surface, obtained by mixing a hydrogel precursor solution and a lipid precursor solution by flow focusing microfluidics.
[0017] In this embodiment, the hydrogel precursor solution is prepared by mixing PEG-DA-575, Fe3O4@CuS, cisplatin, paclitaxel and a photoinitiator.
[0018] In this embodiment, the lipid precursor solution is prepared from lecithin, cholesterol, DSPE-PEG, and DSPE-PEG-FA.
[0019] like Figure 1 As shown, the present invention also discloses a method for preparing a polymer composite hydrogel for treating bladder tumors, comprising the following steps: Preparation of S1, Fe3O4@CuS nanoparticles: (1) Add oleylamine into a flask and stir at 400 rpm under nitrogen atmosphere, heat to 300°C while stirring, then dissolve Fe(acac)3 in oleylamine and N-methyl-2-pyrrolidone, inject into the flask, react for 10 minutes, slowly cool to 60°C, pour ethanol into the flask to obtain a black precipitate, centrifuge at 10,000 rpm, and collect Fe3O4 nanoparticles after centrifugation; (2) Dispersing Fe3O4 in cyclohexane and stirring the mixture under nitrogen atmosphere, then heating the mixture to 70°C, adding oleylamine to the mixture, and reacting for 10 minutes to form a reaction mixture; adding copper chloride and sodium sulfide to the chloroform / oleylamine mixture, then adding the reaction mixture and stirring at a speed of 800 rpm. After stirring for 30 minutes, the reaction mixture gradually turns dark green, and the reaction mixture is centrifuged at a speed of 10,000 rpm. After centrifugation, the mixture is washed with ethanol and chloroform to obtain Fe3O4@CuS nanoparticles with oleylamine as a stable ligand; (3) The obtained Fe3O4@CuS nanoparticles with oleylamine as a stabilizing ligand were dispersed in chloroform, mixed with DSPE-PEG-acrylate, and stirred at 800 rpm for 12 h, then chloroform was added. After removing the chloroform under nitrogen atmosphere, a Fe3O4@CuS nanoparticle solution was obtained; S2. Preparation of hydrogel precursor solution: PEG-DA-575, Fe3O4@CuS nanoparticles, cisplatin, paclitaxel and photoinitiator were mixed in deionized water to obtain a hydrogel precursor solution; S3, preparation of lipid precursor solution: adding lecithin, cholesterol, DSPE-PEG and DSPE-PEG-FA together into chloroform and mixing, then drying under nitrogen environment to obtain a dry lipid film, dissolving the dry lipid film in isopropanol to obtain a lipid precursor solution; S4. Preparation of hydrogel nanodroplets: The lipid precursor solution is introduced into the central channel and flows at a lower flow rate through flow focusing microfluidic mixing, and the hydrogel precursor solution is introduced into the side channel at a higher flow rate. The central lipid precursor flow is hydrodynamically focused to obtain hydrogel nanodroplets containing cisplatin, paclitaxel, Fe3O4@CuS NPs and coated with a lipid bilayer on the surface.
[0020] The polymer composite hydrogel for treating bladder tumors provided by the present invention is used in preparing medicine for treating bladder tumors.
[0021] Cisplatin in the present invention is a commonly used chemotherapy drug that can inhibit the growth and division of tumor cells. Paclitaxel is a natural anti-tumor drug that can induce apoptosis and autophagy of tumor cells, thereby achieving the purpose of treating tumors. By co-loading cisplatin and paclitaxel in Fe3O4@CuS nanoparticles, the synergistic effect of the two drugs can be exerted at the same time, thereby improving the therapeutic effect.
[0022] The working principle of the polymer hydrogel of the present invention is as follows: Fe3O4 nanoparticles have good magnetism and can move under the action of a magnetic field, while CuS nanoparticles have good near-infrared photothermal effect, especially reaching a photothermal conversion efficiency of 50% under the irradiation of 805nm near-infrared light. The Fe3O4@CuS NPs composite nanoparticles are magnetic photothermal nanoparticles composed of Fe3O4 as a core and CuS as a shell. Fe3O4@CuS, cisplatin, and paclitaxel are encapsulated in a hydrogel wrapped with a lipid bilayer. Under the action of a magnetic field, Fe3O4@CuS aggregates to one side of the hydrogel nanoparticles to form an asymmetric structure. Under the irradiation of near-infrared light with a wavelength of 805 nm, the temperature of the CuS shell rises, and a temperature gradient is generated inside the hydrogel, thereby generating self-thermophoretic motion, promoting its distribution in the bladder and penetrating deeply into the mucosal layer of the bladder wall. The lecithin bilayer modified with folic acid (FA) wrapped in the outer layer of the hydrogel is used to target bladder cancer cells and improve the biocompatibility of the particles. FA After mediating cellular endocytosis, lipid molecules are degraded in lysosomes, and cisplatin and paclitaxel are released from the hydrogel, inducing tumor cell apoptosis and autophagy, thereby achieving the purpose of tumor treatment.
[0023] In the description of this specification, the description with reference to the terms "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.
Claims
1. A polymer composite hydrogel for treating bladder tumors, characterized in that: The hydrogel nanodroplets containing cisplatin, paclitaxel, Fe3O4@CuS NPs and coated with a lipid bilayer on the surface are obtained by mixing the hydrogel precursor solution and the lipid precursor solution through flow focusing microfluidics.
2. The polymer composite hydrogel for treating bladder tumors according to claim 1, characterized in that: The hydrogel precursor solution is prepared by mixing PEG-DA-575, Fe3O4@CuS, cisplatin, paclitaxel and a photoinitiator.
3. The polymer composite hydrogel for treating bladder tumors according to claim 2, characterized in that: The lipid precursor solution is prepared from lecithin, cholesterol, DSPE-PEG and DSPE-PEG-FA.
4. The method for preparing a polymer composite hydrogel for treating bladder tumors according to claim 1, characterized in that: The following steps are involved: Preparation of S1, Fe3O4@CuS nanoparticles: (1) Add oleylamine into a flask and rotate and stir under a nitrogen environment, heat to a certain temperature while stirring, then dissolve Fe(acac)3 in oleylamine and N-methyl-2-pyrrolidone, and then inject it into the flask. After reacting for a certain period of time, slowly cool it, and then pour ethanol into the flask to obtain a black precipitate. Collect it after centrifugation to obtain Fe3O4 nanoparticles; (2) Dispersing Fe3O4 in cyclohexane and stirring the mixture under nitrogen atmosphere, then heating the mixture, adding oleylamine to the mixture, and reacting for a certain period of time to form a reaction mixture; adding copper chloride and sodium sulfide to the chloroform / oleylamine mixture, then adding the reaction mixture and stirring. After stirring for a certain period of time, the reaction mixture gradually turns dark green, centrifuging the reaction mixture, and washing with ethanol and chloroform after centrifugation to obtain Fe3O4@CuS nanoparticles with oleylamine as a stable ligand; (3) The obtained Fe3O4@CuS nanoparticles with oleylamine as a stabilizing ligand were dispersed in chloroform, mixed with DSPE-PEG-acrylate, and chloroform was added after a certain period of rotational stirring. After removing the chloroform under a nitrogen environment, a Fe3O4@CuS nanoparticle solution was obtained; S2. Preparation of hydrogel precursor solution: PEG-DA-575, Fe3O4@CuS nanoparticles, cisplatin, paclitaxel and photoinitiator were mixed in deionized water to obtain a hydrogel precursor solution; S3, preparation of lipid precursor solution: adding lecithin, cholesterol, DSPE-PEG and DSPE-PEG-FA together into chloroform and mixing, then drying under nitrogen environment to obtain a dry lipid film, dissolving the dry lipid film in isopropanol to obtain a lipid precursor solution; S4. Preparation of hydrogel nanodroplets: The lipid precursor solution is introduced into the central channel and flows at a lower flow rate through flow focusing microfluidic mixing, and the hydrogel precursor solution is introduced into the side channel at a higher flow rate. The central lipid precursor flow is hydrodynamically focused to obtain hydrogel nanodroplets containing cisplatin, paclitaxel, Fe3O4@CuS NPs and coated with a lipid bilayer on the surface.
5. The polymer composite hydrogel for treating bladder tumors according to claim 1 is used in the preparation of drugs for treating bladder tumors.