Esophageal cancer targeting nano-tablet based on traditional Chinese medicine composition and preparation method of esophageal cancer targeting nano-tablet

Abstract

The invention discloses an esophageal cancer targeting nano-tablet based on a traditional Chinese medicine composition and a preparation method of the esophageal cancer targeting nano-tablet. The targeted nano tablet is prepared from the following refined extracts: a rhizoma paridis total saponin extract, a pseudobulbus cremastrae seu pleiones colchicine derivative extract, a panax notoginseng total saponin extract, a carthamin yellow extract, a thunberg fritillary bulb total alkaloid extract, frankincense-myrrh compound volatile oil, a resin extract and an astragaloside IV extract. The nano-carrier comprises a nano-carrier, a seaweed-laminarin composite extract, a processed rhizoma pinelliae total alkaloid extract and costus root volatile oil, and the costus root volatile oil serves as one of targeting ligands to be used for modifying the nano-carrier. The targeting property is strong: the dual-targeting ligand (costunolide-TOPK affinity peptide) on the surface of the nano-carrier can actively recognize and combine with a specific receptor of esophageal cancer cells, and meanwhile, due to the size (about 100-200 nanometers) of the carrier, the carrier is easy to enrich in tumor tissues through enhanced permeation and retention (EPR) effect, so that the modernization upgrading of the idea of'channel guiding medicine 'is realized.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology, and in particular to an esophageal cancer-targeting nanoparticle based on a traditional Chinese medicine composition and its preparation method. Background Technology

[0002] Esophageal cancer is a common malignant tumor of the digestive tract, with squamous cell carcinoma (ESCC) being the main pathological type. Traditional surgery and radiotherapy / chemotherapy have limitations, and the five-year survival rate for patients remains low. Traditional Chinese medicine has shown unique value in the comprehensive treatment of esophageal cancer, but traditional Chinese medicine formulas have problems such as unclear mechanisms of action, traditional dosage forms, poor targeting, and low bioavailability.

[0003] Many traditional Chinese medicine formulas contain herbs whose anti-tumor activity has been confirmed by modern pharmacological studies. For example, Paris rhizoma and its active ingredients (such as steroidal saponins) have been shown to inhibit the proliferation of various cancer cells; colchicine and its derivatives contained in Crestor pseudobulbus can interfere with microtubule polymerization and inhibit mitosis; and safflower yellow pigment in Carthami Flos has the effects of promoting blood circulation, removing blood stasis, anti-inflammation, and immunomodulation.

[0004] However, this original formula, when used as a traditional decoction or pill, has the following drawbacks: 1. The drug is distributed throughout the body, lacks targeting of esophageal lesions, and has a low effective concentration and short duration of action.

[0005] 2. The dosage form is crude, and the dissolution and bioavailability of the active ingredients are not high.

[0006] 3. Some ingredients may irritate the gastrointestinal tract.

[0007] 4. It lacks the support of a modern pharmacodynamic evaluation system, and its mechanism of action is unclear. Summary of the Invention

[0008] The purpose of this invention is to provide an esophageal cancer-targeting nanoparticle based on a traditional Chinese medicine composition and its preparation method. This tablet, through nanotechnology and polymer materials science, achieves active targeting and intelligent drug release to esophageal cancer tissue, thereby improving efficacy and reducing side effects.

[0009] The above-mentioned technical objective of the present invention is achieved through the following technical solution: An esophageal cancer-targeting nanoparticle based on a traditional Chinese medicine composition, wherein the targeted nanoparticle is composed of the following refined extracts: total saponin extract of Paris polyphylla, colchicine derivative extract of Cremastra appendiculata, total saponin extract of Panax notoginseng, safflower yellow pigment extract, total alkaloid extract of Fritillaria thunbergii, frankincense-myrrh complex volatile oil, resin extract, astragaloside A extract, seaweed-kelp polysaccharide complex extract, total alkaloid extract of processed Pinellia ternata, and volatile oil of Aucklandia lappa, wherein the volatile oil of Aucklandia lappa also serves as one of the targeting ligands for modifying the nanocarrier.

[0010] More preferably, the ingredients of the targeted nanoparticles are derived from extracts of traditional Chinese medicinal herbs including Paris polyphylla, Cremastra appendiculata, Panax notoginseng, Carthamus tinctorius, Fritillaria thunbergii, Boswellia carterii, Commiphora myrrha, Astragalus membranaceus, Sargassum fusiforme, Laminaria japonica, processed Pinellia ternata, and Aucklandia lappa.

[0011] This invention also provides a method for preparing esophageal cancer-targeting nanoparticles based on a traditional Chinese medicine composition, comprising the following steps: S1. Modern extraction and refining of active ingredients in traditional Chinese medicine; S1.1. Extraction of Paris polyphylla, Cremastra appendiculata, and Panax notoginseng using ultrasonic-assisted ethanol-water solution was carried out, followed by enrichment and purification using macroporous adsorption resin to obtain high-purity saponins and alkaloids. S1.2. Supercritical CO2 extraction technology is used for safflower, frankincense, myrrh, and safflower to obtain volatile oils and fat-soluble active ingredients, avoiding the destruction of heat-sensitive components. S1.3. Polysaccharide components were obtained from Astragalus membranaceus, seaweed, and kelp using hot water extraction combined with membrane filtration technology. S1.4, Fritillaria thunbergii and processed Pinellia ternata were soaked in 6 times the amount of dilute hydrochloric acid aqueous solution (pH=4) and then decocted. The total alkaloids were then purified by subsequent alkalization and extraction processes. S1.5. Spray dry all extracts to obtain a refined powder with good flowability for later use; S2. Constructing an esophageal mucosa-adhesive chitosan-gold nanocomposite carrier; S2.1 Synthesis of gold nanoparticle (AuNPs) core: Monodisperse gold nanoparticles with a particle size of approximately 15 nanometers were prepared by sodium citrate reduction method; S2.2 Construction of acid / ROS dual-response carrier shell: Chitosan (CS) and hyaluronic acid (HA) are sequentially encapsulated on the surface of gold nanoparticles by electrostatic adsorption. S2.3, Connecting Target Ligands: Through a carbodiimide (EDC) coupling chemical reaction, the main active ingredient in the volatile oil of Aucklandia lappa, costane lactone, and a polypeptide with affinity for TOPK, a marker of esophageal squamous cell carcinoma, are jointly grafted onto the hyaluronic acid chain. S3. Preparation of drug-loaded nanoparticles: The purified extract mixture prepared in S1 and the blank esophageal mucosa adhesive chitosan-gold nanocomposite carrier prepared in S2 were dissolved together in deionized water and drug-loaded nanoparticles were prepared by ultrasonic-emulsification. By controlling the ratio of carrier to drug, a high drug loading capacity was achieved. S4. Tablet forming and packaging; S4.1 The drug-loaded nanoparticle suspension obtained in step 3 is mixed with microcrystalline cellulose as a filler, sodium cross-linked carboxymethyl cellulose as a disintegrant, and magnesium stearate as a lubricant. S4.2. The mixture is pressed into a circular tablet core using a dry compression process. S4.3. Coat the tablet core with Opadry film coating premix to form a protective film; S4.4 Pack the finished tablets in aluminum-plastic blister packaging and store them in a cool, dry place.

[0012] In summary, the present invention has the following beneficial effects: Firstly, this invention has strong targeting: the dual-targeting ligand (auslane lactone-TOPK affinity peptide) on the surface of the nanocarrier can actively recognize and bind to specific receptors of esophageal cancer cells. At the same time, the size of the carrier itself (about 100-200 nanometers) makes it easy to accumulate in tumor tissue through enhanced permeation and retention (EPR) effects, realizing a modern upgrade of the "guide drug" concept.

[0013] Secondly, this invention enables intelligent drug release: the carrier structure is responsive to the tumor microenvironment (weakly acidic, high ROS), and can rapidly release drugs at cancerous sites while remaining stable in normal tissues, thereby reducing systemic toxicity.

[0014] Thirdly, this invention enables multi-modal synergistic treatment: the gold nanoparticle core provides the potential for radiosensitization, while the multiple components of traditional Chinese medicine exert anti-tumor, immunomodulatory (such as enhancing NK cell activity), and angiogenesis inhibition (by inhibiting targets such as VEGFR2) effects through multiple pathways, thus achieving synergistic treatment. Attached Figure Description

[0015] Figure 1 This is a flowchart of the preparation process in this invention. Detailed Implementation

[0016] The present invention will be further described in detail below with reference to the accompanying drawings.

[0017] Example 1: An esophageal cancer-targeting nanoparticle based on a traditional Chinese medicine composition. The targeted nanoparticle is composed of the following refined extracts: total saponin extract of Paris polyphylla, colchicine derivative extract of Cremastra appendiculata, total saponin extract of Panax notoginseng, yellow pigment extract of Carthamus tinctorius, total alkaloid extract of Fritillaria thunbergii, frankincense-myrrh complex volatile oil, resin extract, astragaloside A extract, seaweed-kelp polysaccharide complex extract, total alkaloid extract of processed Pinellia ternata, and volatile oil of Aucklandia lappa. The Aucklandia lappa volatile oil also serves as one of the targeting ligands for modifying the nanocarrier. Each extract component is derived from extracts of traditional Chinese medicinal herbs including Paris polyphylla, Cremastra appendiculata, Panax notoginseng, Carthamus tinctorius, Fritillaria thunbergii, frankincense, myrrh, astragalus, seaweed, kelp, processed Pinellia ternata, and Aucklandia lappa.

[0018] A method for preparing esophageal cancer-targeting nanoparticles based on a traditional Chinese medicine composition, such as... Figure 1 As shown, it includes the following steps: S1. Modern extraction and refining of active ingredients in traditional Chinese medicine; S1.1 For Paris polyphylla, Cremastra appendiculata, and Panax notoginseng, ultrasonic-assisted extraction with an ethanol-water solution was performed, followed by enrichment and purification using macroporous adsorption resin to obtain high-purity saponins and alkaloids. The specific operation method is as follows: Paris polyphylla, Panax notoginseng, and Cremastra appendiculata were pulverized and ultrasonically extracted three times with 8 times the volume of 70% ethanol, 45 minutes each time. The extracts were combined, the ethanol was recovered, and the extract was concentrated to a paste. The paste was then loaded onto an AB-8 type macroporous resin column, first eluted with water to remove impurities, then eluted with 70% ethanol. The ethanol eluent was collected, concentrated under reduced pressure, and spray-dried to obtain a refined powder.

[0019] S1.2. Supercritical CO2 extraction technology is used to extract volatile oils and fat-soluble active ingredients from safflower, frankincense, myrrh, and costus root, avoiding the destruction of heat-sensitive components. The specific operation method is as follows: supercritical CO2 extraction is performed on safflower, frankincense, myrrh, and costus root at a pressure of 25 MPa and a temperature of 45°C for 2 hours. The extract is collected to obtain refined oil.

[0020] S1.3. For Astragalus membranaceus, seaweed, and kelp, hot water extraction combined with membrane filtration was used to obtain polysaccharide components. The specific procedure was as follows: Astragalus membranaceus, seaweed, and kelp were decocted three times with 12 times their volume of water, each time for 1.5 hours. The decoctions were combined and concentrated to a relative density of 1.10 (60℃). Three times their volume of 95% ethanol was added for precipitation, and the mixture was allowed to stand overnight. The supernatant was collected, the ethanol was recovered, and the mixture was concentrated and spray-dried to obtain refined polysaccharide powder.

[0021] S1.4, Fritillaria thunbergii, and processed Pinellia ternata were soaked in 6 times the amount of dilute hydrochloric acid aqueous solution (pH=4) and then decocted. The total alkaloids were then purified by alkalization and extraction processes and spray-dried.

[0022] S2. Constructing an esophageal mucosa-adhesive chitosan-gold nanocomposite carrier; S2.1 Synthesis of gold nanoparticle (AuNPs) core: Monodisperse gold nanoparticles with a particle size of approximately 15 nanometers were prepared by sodium citrate reduction method; S2.2 Construction of acid / ROS dual-response carrier shell: Chitosan (CS) and hyaluronic acid (HA) are sequentially encapsulated on the surface of gold nanoparticles by electrostatic adsorption. S2.3, Connecting Target Ligands: Through a carbodiimide (EDC) coupling chemical reaction, the main active ingredient in the volatile oil of Aucklandia lappa, costane lactone, and a polypeptide with affinity for TOPK, a marker of esophageal squamous cell carcinoma, are jointly grafted onto the hyaluronic acid chain. S3. Preparation of drug-loaded nanoparticles: The purified extract mixture prepared in S1 and the blank esophageal mucosa adhesive chitosan-gold nanocomposite carrier prepared in S2 were dissolved together in deionized water and drug-loaded nanoparticles were prepared by ultrasonic-emulsification. By controlling the ratio of carrier to drug, a high drug loading capacity was achieved. S4. Tablet forming and packaging; S4.1 The drug-loaded nanoparticle suspension obtained in step 3 is mixed with microcrystalline cellulose as a filler, sodium cross-linked carboxymethyl cellulose as a disintegrant, and magnesium stearate as a lubricant. S4.2. The mixture is pressed into a circular tablet core using a dry compression process. S4.3. Coat the tablet core with Opadry film coating premix to form a protective film; S4.4 Pack the finished tablets in aluminum-plastic blister packaging and store them in a cool, dry place.

[0023] This specific embodiment is merely an explanation of the present invention and is not intended to limit the invention. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they are within the scope of the claims of the present invention.

Claims

1. An esophageal cancer-targeting nanoparticle based on a traditional Chinese medicine composition, characterized in that, The targeted nanoparticles are composed of the following refined extracts: total saponin extract of Paris polyphylla, colchicine derivative extract of Cremastra appendiculata, total saponin extract of Panax notoginseng, yellow pigment extract of safflower, total alkaloid extract of Fritillaria thunbergii, frankincense-myrrh complex volatile oil, resin extract, astragaloside A extract, seaweed-kelp polysaccharide complex extract, total alkaloid extract of processed Pinellia ternata, and volatile oil of Aucklandia lappa. The volatile oil of Aucklandia lappa also serves as one of the targeted ligands for modifying the nanocarrier.

2. The esophageal cancer-targeting nanoparticle based on a traditional Chinese medicine composition according to claim 1, characterized in that, The targeted nanoparticles are derived from extracts of traditional Chinese medicinal herbs, including Paris polyphylla, Cremastra appendiculata, Panax notoginseng, Carthamus tinctorius, Fritillaria thunbergii, Boswellia carterii, Commiphora myrrha, Astragalus membranaceus, Sargassum fusiforme, Laminaria japonica, processed Pinellia ternata, and Aucklandia lappa.

3. The method for preparing esophageal cancer-targeting nanoparticles based on a traditional Chinese medicine composition according to claim 2, characterized in that, Includes the following steps: S1. Modern extraction and refining of active ingredients in traditional Chinese medicine; S1.

1. Extraction of Paris polyphylla, Cremastra appendiculata, and Panax notoginseng using ultrasonic-assisted ethanol-water solution was carried out, followed by enrichment and purification using macroporous adsorption resin to obtain high-purity saponins and alkaloids. S1.

2. Supercritical CO2 extraction technology is used for safflower, frankincense, myrrh, and safflower to obtain volatile oils and fat-soluble active ingredients, avoiding the destruction of heat-sensitive components. S1.

3. Polysaccharide components were obtained from Astragalus membranaceus, seaweed, and kelp using hot water extraction combined with membrane filtration technology. S1.4, Fritillaria thunbergii and processed Pinellia ternata were soaked in 6 times the amount of dilute hydrochloric acid aqueous solution (pH=4) and then decocted. The total alkaloids were then purified by subsequent alkalization and extraction processes. S1.

5. Spray dry all extracts to obtain a refined powder with good flowability for later use; S2. Constructing an esophageal mucosa-adhesive chitosan-gold nanocomposite carrier; S2.1 Synthesis of gold nanoparticle (AuNPs) core: Monodisperse gold nanoparticles with a particle size of approximately 15 nanometers were prepared by sodium citrate reduction method; S2.2 Construction of acid / ROS dual-response carrier shell: Chitosan (CS) and hyaluronic acid (HA) are sequentially encapsulated on the surface of gold nanoparticles by electrostatic adsorption. S2.3, Connecting Target Ligands: Through a carbodiimide (EDC) coupling chemical reaction, the main active ingredient in the volatile oil of Aucklandia lappa, costane lactone, and a polypeptide with affinity for TOPK, a marker of esophageal squamous cell carcinoma, are jointly grafted onto the hyaluronic acid chain. S3. Preparation of drug-loaded nanoparticles: The purified extract mixture prepared in S1 and the blank esophageal mucosa adhesive chitosan-gold nanocomposite carrier prepared in S2 were dissolved together in deionized water and drug-loaded nanoparticles were prepared by ultrasonic-emulsification. By controlling the ratio of carrier to drug, a high drug loading capacity was achieved. S4. Tablet forming and packaging; S4.1 The drug-loaded nanoparticle suspension obtained in step 3 is mixed with microcrystalline cellulose as a filler, sodium cross-linked carboxymethyl cellulose as a disintegrant, and magnesium stearate as a lubricant. S4.

2. The mixture is pressed into a circular tablet core using a dry compression process. S4.

3. Coat the tablet core with Opadry film coating premix to form a protective film; S4.4 Pack the finished tablets in aluminum-plastic blister packaging and store them in a cool, dry place.

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