IRGD-modified dual-drug-loading liposome and application thereof in radiotherapy sensitization of targeted glioblastoma

Abstract

The invention relates to an iRGD modified dual drug-loading liposome and an application of the iRGD modified dual drug-loading liposome in radiotherapy sensitization of targeted glioblastoma. The liposome is composed of HSPC, CHO-HP, DSPE-mPEG2000, and DSPE-PEG2000-MAL, and is loaded with Osimertinib (Osimertinib) and Bortezomib (Bortezomib) through a pH (Potential of Hydrogen) gradient method, and the preparation method of the liposome comprises the following steps: carrying out a reaction on the Osimertinib (Osimertinib) and the Bortezomib (Bortezomib) in the presence of a Osimertinib is used as an EGFR inhibitor, bortezomib is used as a proteasome inhibitor, and osimertinib and bortezomib synergistically enhance the radiotherapy sensitivity by weakening the DNA repair capability of tumor cells. The iRGD peptide on the surface of the liposome is combined with tumor cell specific receptors alpha v beta 3 and NRP1 in a targeting manner, so that the liposome is mediated to pass through tumor neovascularization and efficiently deliver drugs to tumor parts. Animal experiment results show that the enrichment of the liposome in tumor tissues is obviously higher than that of common liposome, and the drug release has good controllability. Compared with the prior art, the invention has obvious advantages in tumor targeting, drug delivery efficiency and radiotherapy sensitization effect, is suitable for combined treatment of radiotherapy drug-resistant glioblastoma, and has a wide clinical application prospect.

Description

Technical Field

[0001] The present invention relates to a drug delivery system, which is a dual drug-loaded liposome modified by iRGD, which is used to target glioblastoma and improve the radiosensitization effect. Specifically, the present invention combines the therapeutic effects of osimertinib and bortezomib to achieve dual-pathway inhibition of EGFR and NF-κB, and improves the clinical treatment effect of glioblastoma through targeted drug delivery and radiosensitization. Background Art

[0002] Glioblastoma (GBM) is a highly invasive and drug-resistant brain tumor. Traditional treatments such as surgical resection, radiotherapy and chemotherapy often have limited effects and are often accompanied by serious side effects. In particular, the resistance of tumor cells to radiotherapy has become a major challenge in treatment. Therefore, improving radiosensitivity has become a hot topic in current tumor treatment research. Osimertinib is an EGFR inhibitor that has been widely used in the treatment of EGFR mutation-related cancers. Studies have shown that osimertinib has a strong anti-tumor effect. There is extensive EGFR amplification in glioblastoma, and inhibiting its activity has good therapeutic prospects, but its application effect in glioblastoma is limited by drug delivery. Bortezomib is a proteasome inhibitor with anti-tumor effects. It can affect the radiosensitivity of tumors by affecting the DNA damage repair process. Summary of the invention

[0003] The purpose of the present invention is to provide an iRGD-modified dual-drug-loaded liposome, which can effectively target glioblastoma and improve the radiotherapy effect. Specifically, the liposome complex of the present invention includes the following technical features:

[0004] 1. Liposome matrix, loaded with two drugs, osimertinib and bortezomib, wherein:

[0005] oAs an EGFR inhibitor, osimertinib improves the therapeutic response of tumors mainly by inhibiting the proliferation and migration of tumor cells. By inhibiting the activation of EGFR in tumor cells after radiotherapy, it can affect the activation of its downstream molecule DNA-PKcs related to DNA damage repair, thereby improving the efficacy of radiotherapy. Based on its chemical properties, osimertinib is loaded in a lipid bilayer.

[0006] o Bortezomib, as a proteasome inhibitor, can significantly inhibit the activation of NF-κB in tumor cells during radiotherapy, thereby inhibiting the activation of DNA damage repair protein ATM, enhancing the radiosensitivity of tumor cells, and promoting the apoptosis of tumor cells. Based on its chemical properties, bortezomib is encapsulated inside liposomes.

[0007] 2. The iRGD peptide modified layer targets αvβ3 and NRP1, and is used to mediate the penetration of liposomes into neovascularization within tumors, targeting glioblastoma, and improving drug uptake through the high affinity and penetration of specific receptors on the surface of tumor cells. The liposome can effectively increase the concentration of the drug at the tumor site through the tumor targeting of the iRGD peptide, and significantly improve the radiosensitivity of the tumor during radiotherapy. Compared with the prior art, the present invention uses a combination strategy of dual drug loading and iRGD modification to deliver drugs to tumors and achieve dual-pathway inhibition, which not only improves the targeted delivery efficiency of osimertinib and bortezomib, but also enhances the sensitivity of tumors to radiotherapy, and has a stronger anti-tumor effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 .Schematic diagram of iRGD-modified dual drug-loaded liposomes.

[0009] This figure shows the structural composition and functional modification of iRGD-modified liposomes:

[0010] 1. The yellow spheres represent Bortezomib, which is encapsulated inside the liposomes.

[0011] 2. The light blue strip represents Osimertinib, which is embedded in the lipid bilayer membrane.

[0012] 3. The dark green round-headed strips represent HSPCs, which are the main components of the liposome bilayer membrane.

[0013] 4. Black bars represent CHO-HP, which is used to enhance membrane stability.

[0014] 5. The light pink round-headed long strip represents DSPE-mPEG2000, which provides the long circulation function of liposomes.

[0015] 6. The dark red round-headed bar represents DSPE-PEG2000-MAL, which is used to connect the iRGD peptide.

[0016] 7. The pink five-pointed star and connecting line represent the iRGD peptide modified on the surface of liposomes, which targets tumor cell-specific receptors

[0017] (such as αvβ3 and NRP1) to achieve precise delivery.

[0018] This figure intuitively shows the dual-drug loading and outer layer functionalization of liposomes, which helps to understand their synergistic mechanism in tumor targeting and drug release. DETAILED DESCRIPTION

[0019] The dual drug-loaded liposomes provided by the present invention have the following characteristics and embodiments:

[0020] 1. Preparation of Liposomes

[0021] o Using HSPC, CHO-HP, DSPE-mPEG2000, and DSPE-PEG2000-MAL as the basic ingredients,

[0022] Liposomes were prepared by thin film hydration method.

[0023] oOsimertinib and bortezomib were loaded using the pH gradient method.

[0024] o The iRGD peptide is linked to the maleimide group on the surface of the liposome through a covalent bond to ensure the stability of the peptide chain and the targeting of the liposome.

[0025] 2. Effects of iRGD modification

[0026] Through its unique tumor cell targeting effect, iRGD peptide can mediate the passage of liposomes through neovascularization within the tumor and bind to the surface of glioblastoma cells through tumor-associated receptors (such as αvβ3 integrin), significantly improving the cellular uptake rate and targeted delivery efficiency of liposomes.

[0027] 3. Radiotherapy sensitization effect

[0028] During radiotherapy, dual drug-loaded liposomes can enhance the radiosensitivity of tumor cells. By simultaneously inhibiting the activation of EGFR and NF-κB in tumor cells after radiotherapy, it can significantly inhibit the activation of DNA damage repair-related proteins (ATM and DNA-PKcs), inhibit the DNA repair ability of tumor cells, prolong the DNA damage process after radiotherapy, and thus improve the efficacy of radiotherapy.

[0029] 4. Distribution and drug release in vivo

[0030] Through experimental studies on in vivo mouse models, it was shown that the enrichment of the liposomes of the present invention in tumor tissues is significantly higher than that of ordinary liposomes, and the drug release exhibits sustained and controllable characteristics, thereby ensuring high concentration and long-term effect of the drug in the tumor area.

[0031] 5. Clinical Application

[0032] The iRGD-modified dual-drug-loaded liposomes of the present invention can be used for combined chemotherapy and radiotherapy treatment of glioblastoma, and have the potential to be used as a new targeted therapy strategy, and are particularly suitable for patients with radiotherapy-resistant glioblastoma.

Claims

1. An iRGD-modified dual-drug-loaded liposome complex comprising: i. a liposome matrix loaded with osimertinib and bortezomib as radiosensitizers; ii. an iRGD peptide modified layer, used to mediate the liposomes to pass through the new blood vessels into the tumor and target glioblastoma through specific binding; iii. It is characterized in that the liposome enhances the tumor cell uptake of the drug through the tumor penetrability and targeting properties of the iRGD peptide, achieves dual-pathway inhibition of tumor cells, and improves the radiosensitivity of the tumor during radiotherapy.

2. The liposome complex according to claim 1, wherein the size of the liposomes ranges from 100 to 150 nanometers to optimize in vivo distribution and tumor retention time.

3. The liposome complex according to claim 1 or 2, wherein the first radiosensitizer is osimertinib and the second radiosensitizer is bortezomib.

4. The liposome complex according to claim 1, wherein the iRGD peptide is modified on the liposome surface by covalent bonding to increase its stability in blood circulation.

5. The liposome complex according to claim 1, further comprising a DSPE-mPEG2000 component for achieving long-term circulation of the liposome in vivo.

6. Use of the iRGD-modified dual-drug-loaded liposome according to any one of claims 1 to 5 in the preparation of a pharmaceutical composition for radiosensitization, for treating glioblastoma and improving the efficacy of radiotherapy.

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