乳铁蛋白-甘草酸偶联物用于胶质母细胞瘤治疗抑制肿瘤微环境中DAMP的作用。

IF 11.3 1区 医学 Q1 Medicine Biomaterials Research Pub Date : 2023-05-20 DOI:10.1186/s40824-023-00391-w
Hyung Shik Kim, Seok Chan Park, Hae Jin Kim, Dong Yun Lee
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引用次数: 2

摘要

背景:肿瘤微环境释放的高迁移率组框-1 (HMGB1)在肿瘤进展中起关键作用。HMGB1作为一种损伤相关分子模式(DAMP),诱导肿瘤血管生成及其发展。甘草酸(Glycyrrhizin, GL)是肿瘤释放的HMGB1的有效细胞内拮抗剂,但其药代动力学(PK)和向肿瘤部位的递送缺乏。为了解决这一缺点,我们开发了乳铁蛋白-甘草酸(Lf-GL)偶联物。方法:采用表面等离子体共振(SPR)结合亲和实验,评价Lf-GL与HMGB1之间的生物分子相互作用。通过体外、离体和体内综合评价Lf-GL减弱HMGB1在肿瘤微环境中的作用对肿瘤血管生成和发育的抑制作用。研究了Lf-GL在原位胶质母细胞瘤小鼠模型中的药动学研究和抗肿瘤作用。结果:Lf-GL与血脑屏障和GBM上表达的乳铁蛋白受体(LfR)相互作用,从而有效抑制肿瘤细胞质和细胞外区域的HMGB1。在肿瘤微环境方面,Lf-GL通过阻断坏死肿瘤释放的HMGB1,阻止血管内皮细胞的募集,抑制血管生成和肿瘤生长。此外,Lf-GL在GBM小鼠模型中使GL的PK特性提高了约10倍,并使肿瘤生长降低了32%。同时,肿瘤的各种生物标志物也从根本上减少。结论:总的来说,我们的研究表明HMGB1与肿瘤进展密切相关,提示Lf-GL可能是应对damp相关肿瘤微环境的潜在策略。HMGB1是肿瘤微环境中促肿瘤的DAMP。Lf-GL与HMGB1的高结合能力抑制肿瘤的级联进展,如肿瘤血管生成、发展和转移。Lf-GL通过与LfR的相互作用靶向GBM,并允许从肿瘤微环境中释放HMGB1。因此,Lf-GL可以通过调节HMGB1活性来治疗GBM。
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Inhibition of DAMP actions in the tumoral microenvironment using lactoferrin-glycyrrhizin conjugate for glioblastoma therapy.

Background: High-mobility group box-1 (HMGB1) released from the tumor microenvironment plays a pivotal role in the tumor progression. HMGB1 serves as a damaged-associated molecular pattern (DAMP) that induces tumor angiogenesis and its development. Glycyrrhizin (GL) is an effective intracellular antagonist of tumor released HMGB1, but its pharmacokinetics (PK) and delivery to tumor site is deficient. To address this shortcoming, we developed lactoferrin-glycyrrhizin (Lf-GL) conjugate.

Methods: Biomolecular interaction between Lf-GL and HMGB1 was evaluated by surface plasmon resonance (SPR) binding affinity assay. Inhibition of tumor angiogenesis and development by Lf-GL attenuating HMGB1 action in the tumor microenvironment was comprehensively evaluated through in vitro, ex vivo, and in vivo. Pharmacokinetic study and anti-tumor effects of Lf-GL were investigated in orthotopic glioblastoma mice model.

Results: Lf-GL interacts with lactoferrin receptor (LfR) expressed on BBB and GBM, therefore, efficiently inhibits HMGB1 in both the cytoplasmic and extracellular regions of tumors. Regarding the tumor microenvironment, Lf-GL inhibits angiogenesis and tumor growth by blocking HMGB1 released from necrotic tumors and preventing recruitment of vascular endothelial cells. In addition, Lf-GL improved the PK properties of GL approximately tenfold in the GBM mouse model and reduced tumor growth by 32%. Concurrently, various biomarkers for tumor were radically diminished.

Conclusion: Collectively, our study demonstrates a close association between HMGB1 and tumor progression, suggesting Lf-GL as a potential strategy for coping with DAMP-related tumor microenvironment. HMGB1 is a tumor-promoting DAMP in the tumor microenvironment. The high binding capability of Lf-GL to HMGB1 inhibits tumor progression cascade such as tumor angiogenesis, development, and metastasis. Lf-GL targets GBM through interaction with LfR and allows to arrest HMGB1 released from the tumor microenvironment. Therefore, Lf-GL can be a GBM treatment by modulating HMGB1 activity.

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来源期刊
Biomaterials Research
Biomaterials Research Medicine-Medicine (miscellaneous)
CiteScore
10.20
自引率
3.50%
发文量
63
审稿时长
30 days
期刊介绍: Biomaterials Research, the official journal of the Korean Society for Biomaterials, is an open-access interdisciplinary publication that focuses on all aspects of biomaterials research. The journal covers a wide range of topics including novel biomaterials, advanced techniques for biomaterial synthesis and fabrication, and their application in biomedical fields. Specific areas of interest include functional biomaterials, drug and gene delivery systems, tissue engineering, nanomedicine, nano/micro-biotechnology, bio-imaging, regenerative medicine, medical devices, 3D printing, and stem cell research. By exploring these research areas, Biomaterials Research aims to provide valuable insights and promote advancements in the biomaterials field.
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