A composite photosensitive nanoparticle based on thulium oxide and its preparation method and application

Abstract

The present invention discloses a composite photosensitive nanoparticle based on thulium oxide, a preparation method and application thereof. The composite photosensitive nanoparticle is composed of a photosensitive thulium oxide core, mesoporous silica coated on the surface of the photosensitive thulium oxide core, and an active chemotherapy drug loaded on the mesoporous silica and coated with hyaluronic acid. After the composite photosensitive nanoparticle is coated with hyaluronic acid, the enrichment of the nanoparticle in tumor tissue can be improved. Under near-infrared laser irradiation, the core of the composite photosensitive nanoparticle can produce a large amount of in situ chemotherapy drugs in tumor cells. 1 O2 is used to kill tumor cells and at the same time trigger the release of active chemotherapy drugs in the mesoporous silica layer under the acidic microenvironment of the tumor to exert an anti-tumor effect, enabling tumor-targeted chemical-photodynamic combined therapy.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug-loaded nanoparticles, and in particular relates to a composite photosensitive nanoparticle based on thulium oxide, a preparation method thereof, and an application thereof. Background Art

[0002] In recent years, light-responsive composite nanomaterials have been widely studied for cancer diagnosis and treatment, and phototherapy has been proven to be an effective method for tumor ablation. When exposed to light of a specific wavelength, photosensitive materials absorb photons and convert the light energy into heat, raising the temperature of tumor tissue and thereby killing cancer cells locally. This is known as photothermal therapy (PTT). After absorbing photons, photosensitive materials transfer their energy to the oxygen surrounding the tissue, generating singlet oxygen or hydroxyl radicals with strong oxidative activity. These react with biomacromolecules (such as proteins, nucleic acids, and polysaccharides) in tissues and cells, causing structural or functional changes in these macromolecules, resulting in cytotoxicity and ultimately tumor cell damage and death. This is known as photodynamic therapy (PDT).

[0003] Nanomaterials that directly generate highly reactive reactive oxygen species (ROS) upon light irradiation play a crucial role in numerous fields, including photocatalysis, pollution control, fine chemical synthesis, and phototherapy for tumors. However, most existing materials lack the ability to be excited by relatively long-wavelength light, particularly the lower-energy near-infrared (NIR) light, severely limiting their further development in these areas. For example, NIR light accounts for over half (approximately 53%) of solar radiation, yet remains difficult to exploit in fields such as photocatalysis. In the biomedical field, ultraviolet and visible light are nearly incapable of penetrating the human body (1–2 mm), limiting existing applications such as photodynamic tumor therapy and photodynamic sterilization to superficial locations. NIR light, on the other hand, can penetrate depths of up to centimeters, but currently no materials are capable of directly generating ROS under NIR light. Researchers are limited to using nanoparticles loaded with traditional photosensitizers for photodynamic therapy. Therefore, the search for materials that can absorb NIR light to generate ROS holds significant research and application value.

[0004] Professor Tao Ke's team at Shanghai Jiao Tong University discovered that thulium oxide (Tm2O3) nanoparticles have the ability to generate reactive oxygen species under near-infrared light excitation ( J. Am. Chem. Soc . 2022, 144, 2455–2459), and further verified the value of this discovery through the application of tumor photodynamic therapy. Under the irradiation of near-infrared laser light source or low-power density non-laser light source, the growth of mouse tumors can be significantly inhibited. The findings of this study have laid a material foundation for the expansion of photodynamic therapy to deep lesions in the body.

[0005] Although phototherapy has developed rapidly and shown great potential, single-mode PDT or PTT therapy still faces some challenges, including limitations on superficial tumor types, hypoxic environments, recurrence and metastasis. Multifunctional nanomaterials based on light response offer the possibility of overcoming phototherapy barriers and expanding the application of phototherapy. In summary, the development of a multifunctional nanomaterial based on thulium oxide for combined tumor treatment has great application prospects. Summary of the Invention

[0006] The technical problem solved by the present invention is to provide a composite photosensitive nanoparticle based on thulium oxide and a preparation method thereof. The preparation process of the method is simple, and the prepared composite photosensitive nanoparticles have stable performance. It can be used as a new way to overcome the limitations of traditional photodynamic therapy, such as the decreased ability to produce reactive oxygen species caused by the easy aggregation and quenching of photosensitizers. At the same time, the composite photosensitive nanoparticles can deliver chemotherapy drugs with different drug activities to tumors in different locations, providing a possible platform for the development of efficient phototherapy combined with other therapies.

[0007] The present invention adopts the following technical solution to solve the above technical problems. A composite photosensitive nanoparticle based on thulium oxide is characterized in that: the composite photosensitive nanoparticle is composed of a photosensitive thulium oxide core, mesoporous silica coated on the surface of the photosensitive thulium oxide core, and an active chemotherapy drug loaded on the mesoporous silica and coated with hyaluronic acid. After the composite photosensitive nanoparticle is coated with hyaluronic acid, the enrichment of the nanoparticle in tumor tissue can be improved. Under near-infrared laser irradiation, the core of the composite photosensitive nanoparticle can produce a large amount of in situ chemotherapy drugs in tumor cells. 1 O2 is used to kill tumor cells and at the same time trigger the release of active chemotherapy drugs in the mesoporous silica layer under the acidic microenvironment of the tumor to exert an anti-tumor effect, thereby realizing tumor-targeted chemical-photodynamic combined therapy.

[0008] It is further defined that the active chemotherapy drug is one or more of doxorubicin (DOX), paclitaxel, gemcitabine, cisplatin, carboplatin or fluorouracil.

[0009] The method for preparing composite photosensitive nanoparticles based on thulium oxide of the present invention is characterized by the following specific steps:

[0010] Step S1: dissolving urea in water, adding thulium nitrate pentahydrate, heating and stirring to react, and centrifuging after the reaction to obtain a white solid product Tm(OH)CO3 precursor;

[0011] Step S2: The Tm(OH)CO3 precursor obtained in step S1 is dispersed in a solution containing hexadecyltrimethylammonium bromide (CTAB), H2O and ethanol, and then ammonia water is added. After stirring and mixing, tetraethyl silicate (TEOS) is added dropwise. The mixture is stirred and reacted at room temperature. After the reaction is completed, centrifugation is performed to obtain a white solid product Tm(OH)CO3@SiO2. The Tm(OH)CO3@SiO2 is then heated to 30-1000°C in an air atmosphere and calcined for 2-6 hours to obtain a white solid Tm2O3@mSiO2. The Tm2O3@SiO2 is then dispersed in water, and 3-aminopropyltriethoxysilane (APTES) is added. The mixture is reacted in a water bath. After the reaction is completed, the mixture is centrifuged and washed to obtain amino-modified Tm2O3@mSiO2.

[0012] Step S3: The amino-modified Tm2O3@mSiO2 obtained in step S2 is dispersed in a DOX aqueous solution, uniformly dispersed by ultrasonication, and then placed on a shaker for shaking reaction. After the reaction is completed, the Tm2O3@mSiO2-DOX is obtained by centrifugation and washing with water;

[0013] Step S4: The Tm2O3@mSiO2-DOX obtained in step S3 is dispersed in water, and hyaluronic acid (HA) is added. After stirring and dispersion, the mixture is centrifuged and washed with water to obtain the final product, composite photosensitive nanoparticles Tm2O3@mSiO2-DOX-HA.

[0014] It is further defined that the mass ratio of urea to thulium nitrate pentahydrate in step S1 is 1:10 to 10:1, preferably 5:2.

[0015] The invention relates to the use of thulium oxide-based composite photosensitive nanoparticles in the preparation of tumor-targeted chemo-photodynamic therapy drugs.

[0016] It is further specified that the composite photosensitive nanoparticles can directly generate a large amount of reactive oxygen species under 808nm laser irradiation to kill cancer cells, and at the same time trigger the release of the chemotherapy drug DOX in the mesoporous silica layer under the acidic microenvironment of tumor tissue and cells to achieve anti-tumor effects. The coated hyaluronic acid (HA) has the ability to target tumor cells and tissues overexpressing CD44, so the obtained Tm2O3@mSiO2-DOX-HA nanocomposite material can effectively accumulate in solid tumors.

[0017] The preparation method of the present invention differs from traditional encapsulation methods that encapsulate photosensitizers within nanocarriers. It not only overcomes the poor biocompatibility and difficult degradation issues of nanocarriers, but also enables rapid and precise release of chemotherapy drugs in tumor tissues and cells. Furthermore, the composite photosensitive nanoparticles produced by the present invention exhibit high light absorption capacity, strong water solubility and stability, and are simple to prepare. They can be used to deliver a variety of small molecule drugs to different tumor cells, providing a simple and effective universal therapeutic platform that enables efficient phototherapy and combined treatments.

[0018] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0019] 1. The composite photosensitive nanoparticles prepared by the present invention can co-deliver the photosensitizer core, which generates ROS activated by near-infrared radiation, and chemotherapeutic drugs to the tumor site, thereby improving the accumulation efficiency of the composite photosensitive nanoparticles at the tumor site and effectively reducing toxic side effects on normal cells.

[0020] 2. This invention can serve as a new approach to overcome the problems of traditional photodynamic therapy, such as reduced reactive oxygen species (ROS) production caused by the aggregation and quenching of photosensitizers, and limited tissue penetration depth of the excitation light.

[0021] 3. This invention proposes a feasible strategy for developing an effective tumor-targeted chemo-photodynamic combined therapy platform, which has good potential application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Schematic diagram of the preparation and application of composite photosensitive nanoparticles Tm2O3@mSiO2-DOX-HA.

[0023] Figure 2 Scanning electron microscope images of samples Tm(OH)CO3(a), Tm2O3@mSiO2(b), Tm2O3@mSiO2-DOX(c), and Tm2O3@mSiO2-DOX-HA(d).

[0024] Figure 3 This is the particle size distribution diagram of the composite photosensitive nanoparticles. The picture shows that the nanoparticles are spherical, with a particle size of about 113nm, and are uniform in size with a narrow particle size distribution.

[0025] Figure 4 Transmission electron microscopy images of samples Tm2O3@mSiO2 (a) and Tm2O3@mSiO2-DOX-HA (b) show that the obtained samples are spherical and have obvious core-shell structure.

[0026] Figure 5X-ray powder diffraction (XRD) patterns of samples Tm(OH)CO3 and Tm2O3@mSiO2.

[0027] Figure 6 Infrared spectra of samples HA, Tm2O3@mSiO2, Tm2O3@mSiO2-DOX, and Tm2O3@mSiO2-DOX-HA.

[0028] Figure 7 The ROS probe DPBF was mixed with Tm2O3@mSiO2, Tm2O3@mSiO2-DOX, and Tm2O3@mSiO2-DOX-HA and then irradiated with near-infrared 808nm laser for different times to produce 1 UV-visible spectroscopic spectrum of O2.

[0029] Figure 8 This is an experiment on the cell killing ability of different concentrations of DOX, Tm2O3@mSiO2, Tm2O3@mSiO2-DOX, and Tm2O3@mSiO2-DOX-HA on 4T1 cells under 808nm laser irradiation. DETAILED DESCRIPTION

[0030] The above contents of the present invention are further described in detail below through examples, but this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above contents of the present invention fall within the scope of the present invention. Example

[0031] Step S1: Synthesis of Tm(OH)CO3 precursor

[0032] Weigh 5 g of urea and dissolve it in 45 mL of secondary water. Stir until it is completely dissolved, then place it in an oil bath and heat it to 90°C and maintain it for 10 minutes. Then add 5 mL of an aqueous solution of thulium nitrate pentahydrate (0.4 g / mL) dropwise, maintain it at 90°C for 3 hours, then cool it to room temperature, centrifuge it, and wash it with water 3 times to obtain a white solid product Tm(OH)CO3 precursor.

[0033] Step S2: Synthesis of Tm2O3@mSiO2

[0034] 63mg of the Tm(OH)CO3 precursor was dispersed in a solution containing 0.15g of hexadecyltrimethylammonium bromide (CTAB), 40mL of H2O, and 30mL of ethanol. 500μL of ammonia was then added, and stirring continued for 10 minutes. After that, 50μL of tetraethylorthosilicate (TEOS) was added dropwise. After stirring at room temperature for 6 hours, the mixture was centrifuged and washed to obtain a white solid product, Tm(OH)CO3@SiO2. The white solid product, Tm(OH)CO3@SiO2, was then ground uniformly and placed in a vacuum tube high-temperature sintering furnace. Under air atmosphere, the temperature was raised to 800°C for 3 hours to obtain the white solid product, Tm2O3@mSiO2. The white solid product, Tm2O3@SiO2, was then dispersed in water, and 375μL of 3-aminopropyltriethoxysilane (APTES) was added. The mixture was stirred in a water bath for 3 hours, and then centrifuged and washed to obtain amino-modified Tm2O3@mSiO2.

[0035] Step S3: Synthesis of Tm2O3@mSiO2-DOX

[0036] 5 mg of amino-modified Tm2O3@SiO2 sample was dispersed in 2 mL of DOX aqueous solution (1 mg / mL), ultrasonically dispersed evenly, and then shaken on a shaker for 24 hours. Centrifuged and washed with water to obtain Tm2O3@mSiO2-DOX.

[0037] Step S4: Preparation of Tm2O3@mSiO2-DOX-HA

[0038] Take 5 mg of Tm2O3@mSiO2-DOX sample and disperse it in 5 mL of redistilled water. Then add 15 mg of hyaluronic acid (HA). After stirring at room temperature overnight, centrifuge and wash twice with redistilled water to obtain the final product, composite photosensitive nanoparticles Tm2O3@mSiO2-DOX-HA.

[0039] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for illustrating the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. Application of thulium oxide-based composite photosensitive nanoparticles in the preparation of tumor-targeted chemo-photodynamic therapy drugs, characterized by: The composite photosensitive nanoparticles can directly generate a large amount of reactive oxygen species under 808nm laser irradiation to kill cancer cells. At the same time, they trigger the release of the chemotherapy drug DOX in the mesoporous silica layer in the acidic microenvironment of tumor tissue and cells to achieve anti-tumor effects. The coated hyaluronic acid has a targeting ability for CD44-overexpressing tumor cells and tissues. Therefore, the obtained Tm2O3@mSiO2-DOX-HA nanocomposite material can effectively accumulate in solid tumors. The composite photosensitive nanoparticles are composed of a photosensitive thulium oxide core, mesoporous silica coated on the surface of the photosensitive thulium oxide core, and an active chemotherapy drug loaded on the mesoporous silica and coated with hyaluronic acid. The specific preparation steps are as follows: Step S1: dissolving urea in water, adding thulium nitrate pentahydrate, heating and stirring to react, and centrifuging after the reaction to obtain a white solid product Tm(OH)CO3 precursor; Step S2: dispersing the Tm(OH)CO3 precursor obtained in step S1 in a solution containing hexadecyltrimethylammonium bromide, H2O and ethanol, adding ammonia water, stirring and mixing, and then dropping tetraethyl silicate. Stirring and reacting at room temperature. After the reaction is completed, centrifuging to obtain a white solid product Tm(OH)CO3@SiO2. Then, heating Tm(OH)CO3@SiO2 to 800-1000°C in an air atmosphere and calcining for 2-6 hours to obtain a white solid Tm2O3@mSiO2. Subsequently, dispersing Tm2O3@SiO2 in water, adding 3-aminopropyltriethoxysilane, reacting in a water bath, and centrifuging and washing after the reaction to obtain amino-modified Tm2O3@mSiO2. Step S3: The amino-modified Tm2O3@mSiO2 obtained in step S2 is dispersed in a DOX aqueous solution, uniformly dispersed by ultrasonication, and then placed on a shaker for shaking reaction. After the reaction is completed, the Tm2O3@mSiO2-DOX is obtained by centrifugation and washing with water; Step S4: The Tm2O3@mSiO2-DOX obtained in step S3 is dispersed in water, hyaluronic acid is added, stirred and dispersed, centrifuged and washed with water to obtain the final product, composite photosensitive nanoparticles Tm2O3@mSiO2-DOX-HA.

2. The use according to claim 1, characterized in that: The mass ratio of urea to thulium nitrate pentahydrate in step S1 is 1:10 to 10:1.

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