Application of polydextral lactic acid and polydextral lactic acid-glycolic acid copolymer in constructing micro / nanocarriers for antitumor drugs
By constructing a multifunctional anti-tumor drug delivery carrier based on PDLA and PDLGA, and utilizing the stereoconfigurational differences of dextrolactone, precise regulation of the tumor microenvironment can be achieved. This solves the problems of poor targeting and immunosuppression in existing tumor treatments, improves therapeutic efficacy, and activates anti-tumor immune responses.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HARBIN INST OF TECH
- Filing Date
- 2026-04-30
- Publication Date
- 2026-06-30
AI Technical Summary
In existing technologies, PLA and PLGA, as drug controlled-release carriers, suffer from poor tumor targeting, low drug utilization, and an irreversible immunosuppressive microenvironment in tumor treatment. Furthermore, they lack full utilization of the conformational differences between L- and D-lactate.
By employing polydextral lactic acid (PDLA) and polydextral lactic acid-glycolic acid copolymer (PDLGA) materials, and through the construction of multifunctional designs and functional regulation, and by adjusting the configurational differences of lactic acid, an anti-tumor drug delivery system is constructed. This achieves a differentiated technical solution for anti-tumor drug micro/nanocarriers, enabling differentiated regulation of biological systems and precise control of the tumor microenvironment, thereby improving the efficacy of tumor treatment.
It achieves precise regulation of the tumor microenvironment, improves the efficacy of tumor treatment, reduces potential toxic side effects, activates anti-tumor immune responses, and inhibits tumor growth.
Smart Images
Figure CN122297697A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomedical polymer materials and nanomedicine, specifically involving the clinical application of polydextral lactic acid (PDLA) and polydextral lactic acid-glycolic acid copolymer (PDLGA) in tumor treatment, and particularly involving their structural design, functional optimization and application methods in small molecule drug delivery and immune regulation. Background Technology
[0002] In recent years, cancer treatment has faced the dual challenges of insufficient efficacy and significant toxic side effects. Traditional treatments, such as chemotherapy, radiotherapy, and immunotherapy, while extending patient survival to some extent, still suffer from poor tumor targeting, low drug utilization, and the difficulty in reversing the immunosuppressive microenvironment. Biodegradable polymers such as polylactic acid (PLA) and polylactic-glycolic acid copolymer (PLGA) have been widely used as drug-controlled release carriers in clinical cancer treatment due to their good biocompatibility and biodegradability. However, the regulatory role of the L / D configuration difference of lactic acid, a classic biomedical material, in biological systems has not been fully understood and utilized. Existing technologies mainly focus on racemic or non-chiral PLA and PLGA systems, neglecting the potential impact of stereochemical differences in lactic acid monomers on their in vivo biological effects. Studies have shown that dextrorotatory lactic acid (D-lactic acid) and levorotatory lactic acid (L-lactic acid) differ in their metabolic pathways, enzyme recognition, and immune regulation. For example, different lactate configurations may have different effects on immune cells (such as macrophages and T cells) in the tumor microenvironment. Studies have shown that L-lactic acid can significantly inhibit the immune surveillance and clearance of tumor cells and promote tumor growth, while D-lactic acid can effectively enhance anti-tumor immune responses and inhibit tumor occurrence and development. However, there is currently a lack of systematic development on the application of poly-D-lactic acid (PDLA) and poly-D-lactic acid-glycolic acid copolymer (PDLGA) in the field of tumor therapy, especially a lack of comparison of the effects of L- and D-lactic acid PLA and PLGA in tumor therapy. Therefore, it is necessary to develop a novel material platform based on D-lactic acid for PDLA and PDLGA to achieve synergistic effects in drug delivery and tumor microenvironment regulation. Summary of the Invention
[0003] This invention aims to solve the following key technical problem: how to utilize the stereoconfiguration differences of the lactic acid components in poly-L-lactic acid (PLLA) and poly-L-lactic acid-glycolic acid copolymer (PLLGA) and poly-D-lactic acid (PDLA) and poly-D-lactic acid-glycolic acid copolymer (PDLGA) to achieve differentiated regulation of biological systems (especially the immune system), thereby constructing a novel anti-tumor drug delivery carrier screening system for clinical tumor treatment, improving the tumor treatment efficacy of such materials while reducing potential toxic side effects.
[0004] This invention proposes a PDLA and PDLGA polymer material system based on dextro-lactic acid for antitumor drug delivery and tumor therapy. By comparing the effects of PLA and PLGA composed of L / D lactic acid on the tumor immune microenvironment, the optimal lactic acid configuration of PLA and PLGA micro / nanocarriers for tumor therapy is screened to achieve precise regulation of the tumor microenvironment, thereby improving the efficacy of tumor therapy and expanding its clinical applications.
[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0006] Application of polydextral lactic acid and polydextral lactic acid-glycolic acid copolymer in the construction of antitumor drug micro / nanocarriers.
[0007] Furthermore, the antitumor drugs are small molecule chemotherapy drugs (including but not limited to doxorubicin, paclitaxel, camptothecin, etc.), small molecule photosensitizers (including but not limited to dihydroporphyrin E6, etc.), small molecule immunotherapeutic drugs (including but not limited to BMS-103, imiquimod, etc.), and small molecule radiosensitizers (including but not limited to iridoside, olaparib, etc.).
[0008] Furthermore, the particle size of the polydextral lactic acid and the polydextral lactic acid-glycolic acid copolymer is 10~5000 nm.
[0009] Micro- and nanoparticles with a particle size of 10–5000 nm based on PDLA or PDLGA rich in D-lactic acid units can be constructed. These particles can encapsulate small molecule drugs such as chemotherapeutic drugs, photosensitizers, immunomodulators, or radiosensitizers. The surface can be modified with targeting ligands (such as tumor-targeting peptides or antibody fragments). They also exhibit good blood circulation stability.
[0010] Furthermore, the effective concentration of the polydextral lactic acid and the polydextral lactic acid-glycolic acid copolymer is 1~500 mg / kg.
[0011] Furthermore, the micro / nano carrier is a pharmaceutically acceptable dosage form; the pharmaceutically acceptable dosage form is a tablet, granule, capsule, pill, syrup, suspension, powder, oral liquid, or injection.
[0012] Furthermore, the antitumor mechanism of the poly-D-lactic acid and poly-D-lactic acid-glycolic acid copolymer includes increasing the activity of effector T cells in the tumor microenvironment and increasing the concentration of cytokines such as IFN-γ at the tumor site. The material of this invention releases D-lactic acid during degradation, which has the following functions: regulating the local metabolic environment of the tumor; affecting the activity of immune cells (such as T cells); improving the tumor immunosuppressive microenvironment; and enhancing antitumor immunotherapy. Compared with PLA and PLGA constructed from L-lactic acid, PLA and PLGA constructed from D-lactic acid exhibit significantly improved tumor-suppressive effects. This is because D-lactic acid can effectively activate the antitumor immune response, while L-lactic acid inhibits the antitumor immune response.
[0013] The material of this invention can be used to construct multifunctional treatment platforms, including chemotherapy + immunotherapy, photodynamic therapy + immunotherapy, and radiotherapy + immunotherapy. Enhanced therapeutic effects are achieved through the synergistic effect of material degradation and drug release. Application methods include intravenous injection, local tumor injection, or implantable sustained-release systems.
[0014] Furthermore, the preparation method of the polydextral lactic acid and the polydextral lactic acid-glycolic acid copolymer is ring-opening polymerization (direct melt copolymerization).
[0015] Furthermore, PLA and PLGA polymers composed of lactic acid with different L / D configurations were prepared by ring-opening polymerization (direct melt copolymerization). Specifically, different configurations of lactide (for PLA preparation) or a mixture of lactide and glycolide with different configurations (for PLGA preparation) were mixed with an initiator (such as benzyl alcohol) and a catalyst (such as stannous octoate (Sn(Oct)2)) after dehydration. The mixture was then reacted at 130-160°C for 6-12 hours under nitrogen protection. After cooling to room temperature and dissolving the lactide, it was precipitated with ice-cold methanol to obtain PLA and PLGA polymers composed of lactic acid with different L / D configurations.
[0016] Furthermore, PDLA and PLGA micro / nanoparticles were prepared using an emulsion solvent evaporation method: PLA and PLGA polymers composed of lactic acid with different L / D configurations and antitumor drugs (such as doxorubicin, camptothecin, etc.) were dissolved in an organic phase such as dichloromethane, tetrahydrofuran, or ethyl acetate. The organic phase solution was then slowly added dropwise to deionized water, and the mixture was stirred at 100–1000 rpm for 3–6 hours at room temperature. The precipitate was collected by centrifugation to obtain PLA and PLGA micro / nanoparticles (i.e., drug-loaded nanocarriers). The particle size was adjusted by controlling the solvent type, stirring rate, and polymer concentration.
[0017] Furthermore, the construction of PDLGA involves copolymerizing D-lactic acid and glycolic acid to form PDLA-PLGA with a controllable ratio; adjusting the lactic acid / glycolic acid ratio (e.g., 50:50, 65:35, 75:25) to control the degradation rate; and regulating the composition of degradation products by changing the D-lactic acid content, thereby influencing the tumor microenvironment.
[0018] The beneficial effects of this invention compared to existing technologies are as follows: In the field of tumor treatment, PLA and PLGA materials composed of D-lactic acid have shown good effects in inhibiting tumor growth, prolonging the survival period of tumor-bearing mice, and activating anti-tumor immune responses. Compared with control group tumor-bearing mice that received local injections of PLA and PLGA composed of L-lactic acid, PLA and PLGA nanocarriers composed of D-lactic acid can significantly inhibit tumor growth in tumor-bearing mice and activate the anti-tumor activity of T cells. Attached Figure Description
[0019] Figure 1. (A) Transmission electron micrograph of PDLGA nanoparticles, (B) PDLGA nanoparticle size distribution, (C) Transmission electron micrograph of PLLGA nanoparticles, (D) PLLGA nanoparticle size distribution, (E) Rate of lactic acid production from the degradation of PDLGA and PLLGA, (F) and (G) Schematic diagram of the optical rotation of lactic acid produced from the degradation of PDLGA and PLLGA.
[0020] Figure 2 This is a diagram of an animal experimental protocol.
[0021] Figure 3 (B) Lactate content in tumors of tumor-bearing mice 20 days after injection of different doses of PDLGA and PLLGA nanoparticles, (C) Tumor growth curves of tumor-bearing mice after treatment with different doses of PDLGA nanoparticles, (D) Tumor growth curves of tumor-bearing mice after treatment with different doses of PLLGA nanoparticles.
[0022] Figure 4 (A) Growth and (B) area analysis of tumor organoids after treatment with PBS, PDLGA, and PLLGA, respectively. (C) CD3 content in tumors of tumor-bearing mice after treatment with PBS, PDLGA, and PLLGA, respectively. + CD4 + (D) Immunofluorescence staining of auxiliary T cells and flow cytometry analysis. (E) CD3 in tumors of tumor-bearing mice after treatment with PBS, PDLGA, and PLLGA, respectively. + CD8 +Immunofluorescence staining of active T cells and (F) flow cytometry quantitative analysis. (G) Flow cytometry quantitative analysis of cytotoxic T cells secreted by tumor-bearing mice after treatment with PBS, PDLGA, and PLLGA, respectively. (H, I) Concentrations of cytokines TNF-α and IL-6 in plasma of tumor-bearing mice after treatment with PBS, PDLGA, and PLLGA, respectively. Detailed Implementation
[0023] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments, but it is not limited thereto. Any modifications or equivalent substitutions to the technical solution of the present invention that do not depart from the spirit and scope of the technical solution of the present invention should be covered within the protection scope of the present invention.
[0024] Example 1:
[0025] This invention provides the application of PLGA composed of dextrorotatory lactic acid in constructing micro / nanocarriers for antitumor drugs and in tumor therapy. The antitumor drug is doxorubicin; the particle size of the poly(dextral lactic acid-glycolic acid) copolymer is 100-300 nm. The micro / nanocarrier is in the form of an injection.
[0026] The antitumor mechanism of the poly(D-lactic acid-glycolic acid) copolymer includes enhancing the activity of effector T cells in the tumor microenvironment and increasing the concentration of cytokines such as IFN-γ at the tumor site. During degradation, the material releases D-lactic acid, which has the following functions: regulating the local metabolic environment of the tumor; influencing the activity of immune cells (such as T cells); improving the tumor immunosuppressive microenvironment; and enhancing antitumor immunotherapy. Compared with PLA and PLGA constructed from L-lactic acid, PLA and PLGA constructed from D-lactic acid exhibit significantly improved tumor-suppressive effects. This is because D-lactic acid can effectively activate the antitumor immune response, while L-lactic acid inhibits it.
[0027] The poly(d-lactic acid-glycolic acid) copolymer is prepared by ring-opening polymerization. PLGA polymers with different L / D configurations of lactic acid are prepared using ring-opening polymerization (direct melt copolymerization). Specifically, a mixture of lactide and glycolide with different configurations (for PLGA preparation) is mixed with an initiator (such as benzyl alcohol) and a catalyst (such as stannous octoate (Sn(Oct)2)) after dehydration. The mixture is then reacted at 140-150°C for 10-12 hours under nitrogen protection. After cooling to room temperature and dissolving, the mixture is precipitated with ice-cold methanol to obtain PLGA polymers with different L / D configurations of lactic acid. The mass ratio of lactide to glycolide is 0.1-10:1; the mass ratio of lactide to catalyst is 500-2000:1; and the mass ratio of lactide to initiator is 10-1000:1.
[0028] PDLGA micro / nanoparticles were prepared using an emulsion solvent evaporation method: PLGA polymers composed of lactic acids with different L / D configurations and doxorubicin were dissolved in a dichloromethane organic phase. The organic phase solution was then slowly added dropwise to deionized water, and the mixture was stirred at 500–600 rpm for 4 hours at room temperature. The precipitate was collected by centrifugation to obtain PLGA micro / nanoparticles (i.e., drug-loaded nanocarriers). The particle size was adjusted by controlling the solvent type, stirring rate, and polymer concentration.
[0029] like Figure 1 As shown, both PDLGA and PLLGA can form micro / nano carriers with uniform particle size. Figure 1 AD). Under in vitro conditions, PDLGA and PLLGA showed similar efficiency in the in vitro degradation and release of lactic acid. Figure 1 E). PDLGA and PLLGA degradation products, lactic acid, exhibit opposite optical rotations: PDLGA degradation produces D-lactic acid, while PLLGA degradation produces L-lactic acid.
[0030] like Figure 2 and 3 As shown, different doses of PDLGA and PLLGA nanoparticles were injected into the tumors of 4T1 tumor-bearing mice. Figure 2 The results showed no significant difference in intratumoral lactate concentration after treatment with the two types of nanoparticles, indicating that different lactate configurations had no effect on the rate of lactate production from PLGA nanoparticle degradation. Figure 3 B). The study found that compared with the PBS control group, tumor growth rate was significantly reduced in tumor-bearing mice treated with PDLGA nanoparticles or D-lactic acid, and the tumor inhibition effect was positively correlated with the concentration of PDLGA nanoparticles, indicating that PDLGA nanoparticles themselves have an inhibitory effect on tumor growth, and this effect is caused by D-lactic acid produced after the degradation of PDLGA in vivo. Figure 3 C). Furthermore, compared to the PBS control group, tumor-bearing mice treated with PLLGA nanoparticles or L-lactic acid showed significantly increased tumor growth rates, and the tumor-promoting effect was positively correlated with the concentration of PLLGA nanoparticles, indicating that PLLGA nanoparticles themselves have a tumor-promoting effect, and this effect is caused by L-lactic acid produced after the degradation of PLLGA in vivo. Figure 3 D).
[0031] Further research revealed no significant difference between PDLGA and PLLGA in their effects on tumor cell growth and proliferation, indicating that the promoting / inhibiting effects of different lactate configurations on tumors are not achieved through direct action on tumor cells. Figure 4 A, B). However, the study found that compared with the PBS group, the proportion of active T cells in tumor-bearing mice treated with PDLGA nanoparticles was significantly increased, and the concentrations of anti-tumor cytokines such as TNF-α and IL-6 in plasma were significantly elevated. Figure 4(CI). Conversely, compared to the PBS group, the proportion of active T cells in tumor-bearing mice treated with PLLGA nanoparticles was significantly reduced, and the concentrations of anti-tumor cytokines such as TNF-α and IL-6 in plasma were significantly decreased. These results fully demonstrate that PLA or PLGA nanocarriers with different lactate configurations have completely opposite effects on the anti-tumor immune response. PLA or PLGA micro / nanocarriers composed of D-lactic acid can activate T cells in the tumor by degrading to produce D-lactic acid, thereby enhancing the anti-tumor immune response. Conversely, PLA or PLGA micro / nanocarriers composed of L-lactic acid can inhibit T cell activity in the tumor by degrading to produce L-lactic acid, thereby reducing the anti-tumor immune response. These results fully demonstrate that PLA and PLGA composed of different lactate configurations have completely opposite effects on tumor growth, therefore it is necessary to improve the efficacy of tumor treatment through precise regulation of the PLA and PLGA lactate configurations.
Claims
1. Application of polydextral lactic acid and polydextral lactic acid-glycolic acid copolymer in the construction of micro / nanocarriers for antitumor drugs.
2. The application according to claim 1, characterized in that: The antitumor drugs mentioned are small molecule chemotherapy drugs, small molecule photosensitizers, small molecule immunotherapeutic drugs, and small molecule radiosensitizers.
3. The application according to claim 1, characterized in that: The particle size of the polydextral lactic acid and the polydextral lactic acid-glycolic acid copolymer is 10~5000 nm.
4. The application according to claim 1, characterized in that: The effective concentration of the poly(D-lactic acid) and the poly(D-lactic acid-glycolic acid) copolymer is 1~500 mg / kg.
5. The application according to claim 1, characterized in that: The dosage forms of the micro / nano carriers are tablets, granules, capsules, pills, syrups, suspensions, powders, oral liquids, or injections.
6. The application according to claim 1, characterized in that: The antitumor mechanism of the polydextral lactic acid and polydextral lactic acid-glycolic acid copolymer includes increasing the activity of effector T cells in the tumor microenvironment and increasing the concentration of cytokines such as IFN-γ at the tumor site.
7. The application according to claim 1, characterized in that: The preparation method of the polydextral lactic acid and polydextral lactic acid-glycolic acid copolymer is ring-opening polymerization.
8. The application according to claim 7, characterized in that: The ring-opening polymerization method specifically involves mixing dextrorotatory lactide (D-lactide), or a mixture of D-lactide and glycolide, with an initiator and catalyst after removing water, and then reacting at 130-160°C for 6-12 hours under nitrogen protection. After cooling to room temperature and dissolving, the product is precipitated with ice-cold methanol to obtain PLA and PLGA polymers composed of D-lactic acid.
9. The application according to claim 1, characterized in that: PDLA and PDLGA micro / nanoparticles were prepared by emulsion solvent evaporation method: PLA and PLGA polymers composed of D-lactic acid and antitumor drugs were dissolved in an organic phase, and then the organic phase solution was slowly added dropwise to deionized water. The mixture was stirred at 100-1000 rpm for 3-6 hours at room temperature, and the precipitate was collected by centrifugation to obtain PLA and PLGA micro / nanoparticles composed of D-lactic acid (i.e., drug-loaded nanocarriers).
10. The application according to claim 1, characterized in that: Construction of PDLGA: D-lactic acid and glycolic acid are copolymerized to form PDLA-PLGA with a controllable ratio; the degradation rate is controlled by adjusting the lactic acid / glycolic acid ratio.