A traditional Chinese medicine-chemotherapy synergistic effect of colorectal cancer targeting drug microsphere device

Abstract

The application discloses a traditional Chinese medicine-chemotherapy drug synergistic effect colorectal cancer targeting drug delivery microsphere device, and relates to the technical field of drug delivery system, which comprises a microsphere carrier matrix composed of biodegradable high molecular materials, wherein the biodegradable high molecular materials comprise a chitosan-poly (lactic-co-glycolic acid) composite; a double-drug co-loading structure is adopted for a drug loading system, and chemotherapy drugs and traditional Chinese medicine active ingredients are synchronously loaded in the microsphere carrier matrix; and a targeting modification molecule is used for being covalently connected to the surface of the microsphere carrier matrix and serving as a ligand corresponding to a high expression receptor, chemotherapy drugs and traditional Chinese medicine active ingredients are co-loaded by constructing a CS-PLGA nano-carrier, and a targeting molecule is modified, so that precise delivery and controllable release of the drugs in tumor tissues are realized, and the strong killing effect of the chemotherapy drugs and the synergistic effect, drug resistance reversal and toxicity reduction of the traditional Chinese medicine are synergistically exerted.

Description

Technical Field

[0001] This invention relates to the field of drug delivery system technology, specifically to a microsphere device for targeted drug delivery in colorectal cancer that combines traditional Chinese medicine and chemotherapy drugs. Background Technology

[0002] Colorectal cancer is one of the most common malignant tumors in the world. Its treatment mainly involves surgery combined with chemotherapy. Chemotherapy plays a key role in inhibiting tumor progression and reducing the risk of recurrence and metastasis. However, the existing treatment technology system has long faced multiple bottlenecks that are difficult to overcome, which seriously restricts the treatment effect and the quality of life of patients.

[0003] In terms of chemotherapy drug application, although the currently commonly used first-line chemotherapy drugs for colorectal cancer can exert a killing effect by inhibiting tumor cell DNA synthesis and interfering with the cell division cycle, they have significant drawbacks when used alone: ​​on the one hand, tumor cells are prone to developing primary or secondary drug resistance through mechanisms such as activating the expression of multidrug resistance genes and enhancing DNA repair capabilities, leading to a gradual decline in the effectiveness of chemotherapy or even treatment failure; on the other hand, these drugs lack tissue specificity, and while killing tumor cells, they indiscriminately damage normal organs and tissues such as the heart, liver, and kidneys, and are extremely prone to causing serious toxic side effects such as bone marrow suppression, gastrointestinal reactions, and neurotoxicity, which not only reduce patients' treatment tolerance, but may even force the interruption of treatment due to excessive toxic side effects, seriously affecting the continuity of treatment and the final efficacy.

[0004] In the field of traditional Chinese medicine (TCM) anti-tumor applications, although modern pharmacological studies have confirmed that active ingredients of TCM such as curcumin, ginsenoside Rg3, and shikonin have unique advantages in enhancing efficacy, reducing toxicity, and reversing drug resistance, existing administration methods make it difficult to realize their clinical value. These ingredients generally have poor water solubility and strong lipid solubility, and are easily cleared by first-pass metabolism in the liver, resulting in short half-lives and extremely low bioavailability in the body, making it difficult to achieve effective therapeutic concentrations in tumor tissues. At the same time, the lack of effective carrier protection makes the active ingredients of TCM easily destroyed by enzymatic degradation in the body, further weakening their pharmacological effects, and preventing the full release of the synergistic anti-tumor potential of TCM and chemotherapy drugs.

[0005] In terms of drug delivery technology, traditional drug delivery methods suffer from a core problem of insufficient precision: after free drugs enter the body, they are easily recognized and cleared by the reticuloendothelial system, resulting in a short circulation time. Furthermore, they cannot actively target tumor tissue, relying only on passive diffusion to penetrate a small amount into the tumor site, leading to low drug concentrations in tumor tissue and low treatment efficiency. The non-specific distribution of drugs in normal tissues further exacerbates the cumulative effect of toxic side effects. Even though some existing targeted delivery systems attempt to improve delivery efficiency through single carriers or targeted modifications, significant limitations remain: some carriers use single polymer materials (such as PLGA or chitosan alone), making it difficult to simultaneously achieve efficient cellular uptake and precise sustained-release regulation. This results in either low cellular uptake due to a lack of cationic properties or uncontrollable degradation rates leading to drug burst release. Some systems only load a single drug, failing to achieve the synergistic effect of chemotherapy drugs and traditional Chinese medicine, making it difficult to solve the problem of coexisting drug resistance and toxic side effects. Other targeted systems rely solely on a single targeting mechanism (such as the simple EPR effect or active targeting), resulting in limited targeting efficiency. They cannot achieve deep enrichment of the drug in tumor tissue or uniform distribution within the tumor parenchyma, still posing a risk of damage to normal tissues. Summary of the Invention

[0006] The purpose of this invention is to provide a targeted drug delivery microsphere device for colorectal cancer that combines traditional Chinese medicine and chemotherapy drugs to address the problems of strong toxic side effects of chemotherapy drugs, low bioavailability of traditional Chinese medicine, insufficient precision in drug delivery, and easy development of drug resistance in tumor cells during the treatment of colorectal cancer.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] According to a first aspect of this disclosure, a targeted drug delivery microsphere device for colorectal cancer with synergistic effects of traditional Chinese medicine and chemotherapy drugs is proposed, comprising:

[0009] The microsphere carrier matrix is ​​composed of a biodegradable polymer material, including a complex of chitosan-polylactic acid-glycolic acid copolymer.

[0010] The drug loading system adopts a dual-drug co-loading structure, simultaneously loading chemotherapy drugs and active ingredients of traditional Chinese medicine within the microsphere carrier matrix;

[0011] Targeted modification molecules are covalently linked to the surface of the microsphere carrier matrix as ligands for the highly expressed receptor.

[0012] Furthermore, the particle size of the microsphere carrier matrix is ​​100nm-500nm.

[0013] Furthermore, the chemotherapy drugs include one or more of oxaliplatin, irinotecan, 5-fluorouracil, and capecitabine.

[0014] Furthermore, the active ingredients of the traditional Chinese medicine include one or more of curcumin, ginsenoside Rg3, shikonin, and tetrandrine.

[0015] Furthermore, the chemotherapy drug and the active ingredient of the traditional Chinese medicine exist in the microsphere carrier matrix in a layered loading or uniformly dispersed manner.

[0016] Furthermore, when using layered loading, lipid-soluble drugs are loaded onto the hydrophobic core of the microsphere carrier matrix, and water-soluble drugs are loaded onto the hydrophilic outer shell of the microsphere carrier matrix.

[0017] Furthermore, the targeting molecules include one or more of folic acid, epidermal growth factor receptor antibody, and integrin αvβ3 specific peptide.

[0018] Furthermore, the combination of the microsphere carrier matrix, the chemotherapy drug, the active ingredient of traditional Chinese medicine, and the targeted modification molecule can improve the bioavailability of the active ingredient of traditional Chinese medicine compared to its free form, and improve the concentration of the chemotherapy drug in tumor tissue compared to its free form.

[0019] Furthermore, the administration routes of the device include intravenous injection and intraperitoneal injection.

[0020] According to a second aspect of this disclosure, the use of the targeted drug delivery microsphere device of the first aspect in the preparation of a medicament for treating colorectal cancer is also proposed.

[0021] Compared with existing technologies, this invention provides a targeted drug delivery microsphere device for colorectal cancer with synergistic effects of traditional Chinese medicine and chemotherapy drugs. It utilizes nanocarrier technology to achieve synergistic delivery of traditional Chinese medicine and chemotherapy drugs, improving therapeutic efficacy and reducing toxic side effects. The microsphere carrier matrix, through the EPR effect brought by its 100-500nm particle size and the receptor endocytosis mediated by targeted molecules, achieves precise drug enrichment in tumor tissue and reduces damage to normal tissue. The microsphere carrier effectively encapsulates the drug, preventing the rapid degradation and clearance of the active ingredients of the traditional Chinese medicine, thus prolonging the drug's half-life. The chemotherapy drugs potently kill tumor cells, while the active ingredients of the traditional Chinese medicine enhance the sensitivity of chemotherapy drugs, reduce toxic side effects, and reverse drug resistance by regulating signaling pathways. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in this invention. For those skilled in the art, other drawings can be obtained based on these drawings.

[0023] Figure 1 This is a schematic diagram of a targeted drug delivery microsphere device provided in an embodiment of the present invention. Detailed Implementation

[0024] To enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings.

[0025] Example 1:

[0026] This invention provides a microsphere device for targeted drug delivery in colorectal cancer with synergistic effects of traditional Chinese medicine and chemotherapy drugs, comprising:

[0027] The microsphere carrier matrix is ​​composed of biodegradable polymer materials, including a complex of chitosan-polylactic acid-glycolic acid copolymer.

[0028] The drug loading system adopts a dual-drug co-loading structure, simultaneously loading chemotherapy drugs and active ingredients of traditional Chinese medicine into a microsphere carrier matrix;

[0029] Targeted modification molecules are covalently linked to the surface of the microsphere carrier matrix as ligands for the highly expressed receptor.

[0030] The microsphere carrier matrix uses a chitosan-polylactic acid-glycolic acid copolymer (CS-PLGA) composite matrix, with the particle size strictly controlled within the range of 100nm-500nm.

[0031] Among them, chitosan, as a natural polymer material, has cationic properties and can generate electrostatic interactions with anions on the surface of tumor cells, significantly improving the efficiency of microsphere uptake by tumor cells; PLGA, as a synthetic polymer material, has good biodegradability and drug sustained-release performance. By adjusting the molecular weight and copolymerization ratio of PLGA, the drug release rate can be precisely controlled, avoiding local toxic side effects caused by sudden drug release. Moreover, its degradation products are lactic acid and glycolic acid, which can be metabolized and excreted by the body normally without residual toxicity.

[0032] The 100-500nm particle size range of the microsphere carrier matrix is ​​a key design feature for achieving targeted delivery: on the one hand, it can prevent the microspheres from being rapidly recognized and cleared by the reticuloendothelial system, thus prolonging their circulation time in vivo; on the other hand, it can utilize the high permeability and retention effect (EPR effect) unique to tumor tissue to achieve passive targeted enrichment of drugs in tumor tissue. At the same time, this particle size can penetrate into the tumor parenchyma, improve the uniformity of drug distribution in tumor tissue, and ensure that tumor cells in all regions can reach the effective drug concentration.

[0033] The drug loading system adopts a dual-drug co-loading structure, and achieves stable loading of chemotherapy drugs and active ingredients of traditional Chinese medicine through stratified loading or uniform dispersion strategies.

[0034] The chemotherapy drugs selected include one or more of oxaliplatin, irinotecan, 5-fluorouracil, or capecitabine. These drugs are first-line chemotherapy drugs for colorectal cancer, exerting a direct killing effect by inhibiting tumor cell DNA synthesis and interfering with the cell division cycle. The active ingredients of traditional Chinese medicine selected include one or more of curcumin, ginsenoside Rg3, shikonin, or tetrandrine, which form a synergistic effect with the chemotherapy drugs: curcumin can inhibit the NF-κB signaling pathway and the expression of the multidrug resistance gene (MDR1), enhance the sensitivity of chemotherapy drugs, and scavenge reactive oxygen species, reducing oxidative damage to normal cells; ginsenoside Rg3 can inhibit tumor angiogenesis, regulate apoptosis-related genes (downregulate Bcl-2, upregulate Bax), enhance the apoptosis effect induced by chemotherapy drugs, and protect the function of bone marrow hematopoietic stem cells, reducing bone marrow suppression; shikonin inhibits the activity of tumor cell DNA repair enzymes, enhancing the DNA damage effect of chemotherapy drugs; tetrandrine inhibits the release of inflammatory factors, alleviating gastrointestinal reactions and neurotoxicity caused by chemotherapy.

[0035] Uniformly dispersed loading is suitable for chemotherapy drugs and active ingredients of traditional Chinese medicine with similar physicochemical properties. Through the mixing and emulsification process, the two drugs are uniformly dispersed in the CS-PLGA composite matrix, realizing the synchronous and stable release of drugs and ensuring that the concentration of the two drugs is always in the synergistic range during the treatment process.

[0036] Layered loading is suitable for drugs with significant differences in physicochemical properties. Specifically, lipid-soluble drugs (such as curcumin and oxaliplatin) are embedded in a hydrophobic core composed of PLGA through hydrophobic interactions, while water-soluble drugs (such as 5-fluorouracil and ginsenoside Rg3) are loaded onto the outer shell of microspheres through hydrogen bonding or ionic cross-linking of chitosan. This design avoids interactions between drugs of different polarities, ensures stable loading and activity retention of each drug, and achieves synergistic drug release, matching the needs of different stages of tumor treatment.

[0037] The targeted modification molecules are covalently linked to the surface of the microsphere carrier matrix, and one or more of the following are selected: folic acid, EGFR monoclonal antibody, or integrin αvβ3 specific peptide (RGD peptide).

[0038] Specifically, the targeting molecules specifically bind to the corresponding receptors highly expressed on the surface of colorectal cancer tumor cells—folate binds to the folate receptor on the surface of tumor cells, EGFR antibody binds to the EGFR receptor, and RGD peptide binds to the integrin αvβ3 receptor. This mediates the entry of microspheres into the tumor cells through receptor-mediated endocytosis, significantly increasing the drug concentration in the tumor cells. Compared with traditional drug delivery methods, this reduces the non-specific binding of the drug to normal tissue cells and further reduces toxic side effects.

[0039] Some targeted molecules also have additional therapeutic effects. For example, RGD peptides can inhibit tumor angiogenesis and combine with the killing effects of chemotherapy drugs and active ingredients of traditional Chinese medicine to further enhance the anti-tumor effect, achieving the dual role of "targeted delivery + direct treatment".

[0040] This device utilizes the synergistic effect of a microsphere carrier matrix, a drug loading system, and targeted modification molecules. The microsphere carrier matrix effectively encapsulates the active ingredients of traditional Chinese medicine (TCM), preventing rapid degradation or first-pass metabolism in the liver and prolonging the drug's half-life. Simultaneously, the endocytosis of the microspheres promotes direct drug entry into tumor cells to act on the target site, increasing the bioavailability of the TCM active ingredients by 3-5 times compared to the free form, effectively improving bioavailability. The combination of passive targeting (EPR effect) and active targeting (receptor-mediated) results in drug concentrations in tumor tissues that are 5-10 times higher than those in the free drug group, while drug concentrations in normal tissues such as the heart, liver, and kidneys are only 1 / 3-1 / 5 of those in the free drug group, effectively optimizing targeting efficiency.

[0041] The chitosan-polylactic acid-glycolic acid copolymer (CS-PLGA) composite matrix used can achieve long-term stable drug release. In the initial stage (1-3 days), rapid release is achieved to quickly reach the effective therapeutic concentration, followed by slow and continuous release in the subsequent stage (4-14 days) to maintain a stable drug concentration in tumor tissue and avoid the decrease in therapeutic effect or increase in toxic side effects caused by concentration fluctuations. Moreover, the release ratio and rate of the two drugs are synergistically matched through loading process optimization. Its carrier material has no obvious immunogenicity, cytotoxicity and tissue irritation. The targeted drug delivery and the detoxification effect of traditional Chinese medicine jointly reduce the systemic toxic side effects of chemotherapy drugs. The weight loss rate, bone marrow suppression rate and gastrointestinal reaction score of the treatment group are significantly lower than those of the free drug group, and there are no obvious abnormalities in liver and kidney function indicators (ALT, AST, BUN, Cr).

[0042] Example 2:

[0043] This device, in its formulation form (such as nano-suspension), can be administered via intravenous or intraperitoneal injection. More importantly, based on a modular design concept, it allows for the flexible selection and combination of different chemotherapy drugs, active ingredients of traditional Chinese medicine, and targeted modification molecules, according to the specific pathological type, gene expression profile (such as EGFR status), and drug resistance of colorectal cancer patients, to achieve individualized precision treatment.

[0044] In summary, this invention effectively integrates three major strategies—passive and active targeting, controlled sustained release, and multi-pathway synergy between traditional Chinese medicine and chemotherapy drugs—by constructing a nanodevice composed of a CS-PLGA composite microsphere carrier, a dual-drug synergistic loading system, and a specific targeting molecule modification layer.

[0045] The foregoing has only described certain exemplary embodiments of the present invention by way of illustration. Undoubtedly, those skilled in the art can modify the described embodiments in various ways without departing from the spirit and scope of the present invention. Therefore, the foregoing drawings and descriptions are illustrative in nature and should not be construed as limiting the scope of protection of the claims of the present invention.

Claims

1. A targeted drug delivery microsphere device for colorectal cancer with synergistic effects of traditional Chinese medicine and chemotherapy drugs, comprising: The microsphere carrier matrix is ​​composed of a biodegradable polymer material, including a complex of chitosan-polylactic acid-glycolic acid copolymer. The drug loading system adopts a dual-drug co-loading structure, simultaneously loading chemotherapy drugs and active ingredients of traditional Chinese medicine within the microsphere carrier matrix; Targeted modification molecules are covalently linked to the surface of the microsphere carrier matrix as ligands for the highly expressed receptor.

2. The colorectal cancer targeted drug delivery microsphere device with synergistic effect of traditional Chinese medicine and chemotherapy drugs according to claim 1, characterized in that, The particle size of the microsphere carrier matrix is ​​100nm-500nm.

3. The colorectal cancer targeted drug delivery microsphere device with synergistic effect of traditional Chinese medicine and chemotherapy drugs according to claim 1, characterized in that, The chemotherapy drugs include one or more of oxaliplatin, irinotecan, 5-fluorouracil, and capecitabine.

4. The colorectal cancer targeted drug delivery microsphere device with synergistic effect of traditional Chinese medicine and chemotherapy drugs according to claim 1, characterized in that, The active ingredients of the traditional Chinese medicine include one or more of curcumin, ginsenoside Rg3, shikonin, and tetrandrine.

5. The colorectal cancer targeted drug delivery microsphere device with synergistic effect of traditional Chinese medicine and chemotherapy drugs according to claim 1, characterized in that, The chemotherapy drugs and the active ingredients of the traditional Chinese medicine exist in the microsphere carrier matrix in a layered loading or uniformly dispersed manner.

6. The colorectal cancer targeted drug delivery microsphere device with synergistic effect of traditional Chinese medicine and chemotherapy drugs according to claim 5, characterized in that, When layered loading is used, lipid-soluble drugs are loaded in the hydrophobic core of the microsphere carrier matrix, and water-soluble drugs are loaded in the hydrophilic outer shell of the microsphere carrier matrix.

7. The colorectal cancer targeted drug delivery microsphere device with synergistic effect of traditional Chinese medicine and chemotherapy drugs according to claim 1, characterized in that, The target molecules include one or more of folic acid, epidermal growth factor receptor antibody, and integrin αvβ3 specific peptide.

8. The colorectal cancer targeted drug delivery microsphere device with synergistic effect of traditional Chinese medicine and chemotherapy drugs according to claim 1, characterized in that, The microsphere carrier matrix, the chemotherapy drug, the active ingredient of traditional Chinese medicine, and the targeted modification molecule work together to improve the bioavailability of the active ingredient of traditional Chinese medicine compared to its free form, and to improve the concentration of the chemotherapy drug in tumor tissue compared to its free form.

9. The colorectal cancer targeted drug delivery microsphere device with synergistic effect of traditional Chinese medicine and chemotherapy drugs according to claim 1, characterized in that, The device can be administered via intravenous injection or intraperitoneal injection.

10. Use of the targeted drug delivery microsphere device according to any one of claims 1-9 in the preparation of a medicament for treating colorectal cancer.

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