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CN-122005788-A - Application of polyamino acid material in tumor microwave thermal therapy sensitization

CN122005788ACN 122005788 ACN122005788 ACN 122005788ACN-122005788-A

Abstract

The invention provides an application of polyamino acid material in tumor microwave thermal therapy sensitization. The invention applies the polyamino acid material to the field of tumor microwave thermal therapy sensitization for the first time, and can specifically target tumors based on excellent biosafety, specific tumor targeting and good microwave sensitization, thereby selectively heating tumor areas and remarkably improving the treatment efficiency of cancers. The preparation method can realize excellent tumor treatment effect, does not generate potential physiological toxicity to organisms, and has good clinical application value.

Inventors

  • MENG XIANWEI
  • DING JIANXUN
  • WU QIONG
  • LI MINGLU
  • CHEN ZENGZHEN
  • CHEN XUESI

Assignees

  • 中国科学院理化技术研究所

Dates

Publication Date
20260512
Application Date
20260122

Claims (10)

  1. 1. Use of a modified polyamino acid for the preparation of a medicament for treating tumors, wherein the modified polyamino acid is a polyamino acid comprising in a side chain of the polyamino acid a structure represented by the following formula (I): -E-PEG, (I) Wherein PEG is polyethylene glycol and E is a peptide fragment responsive to matrix metalloproteinase, e.g. selected from a peptide fragment responsive to matrix metalloproteinase 2 or a peptide fragment responsive to matrix metalloproteinase 9; Preferably, the peptide fragment responsive to matrix metalloproteinase 2 is selected from the group consisting of PLGLAG、GPLGVRG、GPLGVRGK、GPLGVRGC、GPLGVRGCA、PLGVR、PLGVRG、GPLGVRGGGG、CGPLGVRGK、PRCGV、SGAVRWLLTA、GPPGVVGEKGEQ; Preferably, the peptide fragment responsive to matrix metalloproteinase 9 is selected from SGKGPRQITA, GGKGPLGLPG, GPLGMWSRC, LGRMGLPG, LGPRSLSGK, SGAVRWLLTA, PLGLRSW, PLGVRGK.
  2. 2. Use according to claim 1, wherein the degree of polymerization of the polyamino acid is a number greater than or equal to 1, for example a number from 1 to 800, a number from 2 to 600, a number from 5 to 500 or a number from 10 to 300; preferably, the polyethylene glycol has a degree of polymerization of greater than or equal to 1, for example, a number from 1 to 800, a number from 2 to 600, a number from 5 to 500, or a number from 10 to 300. Preferably, the degree of grafting of the-E-PEG on the polyamino acid side chains is 0.01-0.3, for example 0.02-0.2,0.03-0.15,0.04-0.1.
  3. 3. The use according to any one of claims 1 to 3, wherein the main chain of the polyamino acid is polymerized from one amino acid or is copolymerized from two or more amino acids; preferably, the modified polyamino acid has a main chain polymerized from one or more amino acids selected from the group consisting of glutamic acid, aspartic acid, lysine, alanine, phenylalanine, valine, tyrosine, and cysteine.
  4. 4. The use according to any one of claims 1 to 4, wherein the modified polyamino acid comprises a repeating unit represented by the following formula (a) and a repeating unit represented by formula (B), optionally comprising one or more repeating units represented by formula (C): (A); (B) (C); wherein m is 0 or 1, n is a number greater than or equal to 1, x, y, z is a number greater than or equal to 1; R 1 are identical or different and are optionally selected from the following groups ：-CH 3 、-CH(CH 3 ) 2 、-CH 2 Ph-OH、-CH 2 Ph、-(CH 2 ) 4 NH 2 .
  5. 5. Use according to claim 5, wherein x is the degree of polymerization of the repeating unit of formula (a), for example a number from 1 to 100, a number from 1 to 50, a number from 1 to 30, a number from 1 to 20 or a number from 5 to 10; preferably, y is the degree of polymerization of the repeating unit represented by formula (B), for example, a number of 1 to 800, a number of 1 to 500, a number of 2 to 300, or a number of 5 to 200, for example, a number of 5 to 200; Preferably, z is the degree of polymerization of the repeating unit represented by formula (C), for example, a number of 1 to 500, a number of 1 to 300, a number of 2 to 200, a number of 5 to 100 or a number of 5 to 50; preferably, n is a number from 1 to 800, a number from 1 to 500, a number from 2 to 300, a number from 5 to 200, or a number from 50 to 150; Preferably, the molar ratio of the repeating units represented by the formula (A) to all the repeating units is 0.01 to 0.3, for example 0.02 to 0.2,0.03 to 0.15,0.04 to 0.1.
  6. 6. The use according to any one of claims 1 to 6, wherein the modified polyamino acid is selected from polymers of formula (I-a), formula (I-b) or formula (I-c) below: (I-a) (I-b) (I-c) R 1 , n, x, y, z are as defined in any one of claims 1 to 6, R 2 is C 1-10 alkyl.
  7. 7. The use according to any one of claims 1 to 6, wherein the modified polyamino acid is prepared by a process comprising polymerizing amino acid-benzyl ester-N-carboxycyclic anhydride and/or amino acid-N-carboxycyclic anhydride in the presence of an initiator to give polyamino acid, which is then reacted with polyethylene glycol having a peptide stretch responsive to matrix metalloproteinase, introducing-E-PEG in the side chains of the polyamino acid, wherein E and PEG are as defined in any one of claims 1 to 6.
  8. 8. The use according to any one of claims 1-7, wherein the modified polyamino acid is a nanoparticle.
  9. 9. Use according to any one of claims 1-8, wherein the modified polyamino acid kills tumor cells by microwave hyperthermia.
  10. 10. The use according to any one of claims 1-9, wherein the tumor is breast cancer, gastric cancer, prostate cancer, rectal cancer, lung cancer and ovarian cancer, such as triple negative breast cancer.

Description

Application of polyamino acid material in tumor microwave thermal therapy sensitization Technical Field The invention relates to the technical field related to application of polyamino acid materials, in particular to application of the polyamino acid materials in tumor microwave hyperthermia sensitization. Background Malignant tumors have become one of the major diseases that seriously threaten human health worldwide. The direct medical costs and indirect socioeconomic burden of cancer therapy have become one of the major public health problems. The cancer treatment means commonly used in clinic at present mainly comprise （Chinese Med J 2020, 133(10), 1166-1174; Lancet Oncol 2024, 25, 352-362; Lancet Oncol 2025, 26, 152-170）. of operation treatment, radiation treatment, chemical treatment, targeting treatment, immunotherapy and the like, wherein the tumor hyperthermia is taken as a physical treatment method, and the unique treatment mechanism of the tumor hyperthermia is widely paid attention in recent years. Hyperthermia can selectively kill tumor cells by localized heating (40-45 ℃) while enhancing the sensitivity of tumor tissue to radiation and chemotherapy (J Immunother Cancer 2020, 8, 000421). Particularly, the microwave hyperthermia technology has the advantages of large penetration depth, high heating efficiency and the like, and has good prospect in clinical application (Adv mate 2024, 36, 2309770). However, the main technical bottlenecks faced by traditional microwave hyperthermia are that 1) tumor specific heating is difficult to achieve, so that the temperature difference between a treatment area and normal tissues is insufficient, and 2) the heat dose is unevenly distributed, so that tumor residues and recurrence are easily caused (Cancers 2023, 15 (4) and 1200). To solve this problem, nano-enhanced microwave hyperthermia technology has been developed. The technology utilizes the unique Enhanced Penetration and Retention (EPR) effect of tumor tissues to achieve precise heating of tumor regions by selective enrichment of nanomaterials (ACS Nano 2024, 18, 3636-3650). However, the existing nano microwave thermal sensitization material still has the safety problems of poor biocompatibility, difficult metabolism and the like, and severely restricts the clinical application thereof. Therefore, the development of a novel nano microwave thermal sensitization material with high biological safety, excellent microwave thermal conversion efficiency and tumor targeting has important significance for breaking through the technical bottleneck of the current microwave thermal therapy. The ideal nano microwave heat sensitization material has the following characteristics of 1) good biocompatibility and degradability, 2) high-efficiency microwave heat conversion capability and 3) excellent tumor targeting enrichment performance. The technical breakthrough will obviously improve the specificity and the treatment effect of the microwave hyperthermia, and provide a new solution for clinical tumor treatment. Disclosure of Invention In order to solve the technical problems, the invention provides an application of modified polyamino acid in preparing a medicine for treating tumors, wherein the modified polyamino acid is a polyamino acid containing a structure shown as the following formula (I) in a side chain of the polyamino acid: -E-PEG, (I) wherein PEG is polyethylene glycol and E is a peptide segment which responds to matrix metalloproteinase. According to an embodiment of the invention, the peptide fragment responsive to a matrix metalloproteinase is a polypeptide sequence that specifically responds to a Matrix Metalloproteinase (MMP). For example selected from the group consisting of a peptide fragment responsive to matrix metalloproteinase 2 (MMP-2) or a peptide fragment responsive to matrix metalloproteinase 9 (MMP-9). According to an embodiment of the invention, the peptide fragment responsive to MMP-2 is selected, for example, from the group consisting of PLGLAG（SEQ ID NO:1）、GPLGVRG（SEQ ID NO:2）、GPLGVRGK（SEQ ID NO:3）、GPLGVRGC（SEQ ID NO:4）、GPLGVRGCA（SEQ ID NO:5）、PLGVR（SEQ ID NO:6）、PLGVRG（SEQ ID NO:7）、GPLGVRGGGG（SEQ ID NO:8）、CGPLGVRGK（SEQ ID NO:9）、PRCGV（SEQ ID NO:10）、SGAVRWLLTA（SEQ ID NO:11）、GPPGVVGEKGEQ（SEQ ID NO:12）. polypeptide fragments, each of which is known to be specifically responsive to MMP-2, e.g., PLGLAG represents Pro-Leu-Gly-Leu-Ala-Gly. According to an embodiment of the invention, the peptide stretch responsive to MMP-9 is for example selected from SGKGPRQITA（SEQ ID NO:13）、GGKGPLGLPG（SEQ ID NO:14）、GPLGMWSRC（SEQ ID NO:15）、LGRMGLPG（SEQ ID NO:16）、LGPRSLSGK（SEQ ID NO:17）、SGAVRWLLTA（SEQ ID NO:18）、PLGLRSW（SEQ ID NO:19）、PLGVRGK（SEQ ID NO:20）. According to an embodiment of the invention, the polyamino acid has a degree of polymerization of greater than or equal to 1, for example a number from 1 to 800, a number from 2 to 600, a number from 5 to 500 or a number from 10 to 300. According to an embodimen