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基于共抑制 RELA/P65 和 EGFR 的刺激响应型肽/siRNA 纳米颗粒作为脑胶质母细胞瘤治疗的增敏剂。

Stimuli-Responsive Peptide/siRNA Nanoparticles as a Radiation Sensitizer for Glioblastoma Treatment by Co-Inhibiting RELA/P65 and EGFR.

机构信息

Department of Radiation Oncology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China.

Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.

出版信息

Int J Nanomedicine. 2024 Nov 9;19:11517-11537. doi: 10.2147/IJN.S483252. eCollection 2024.

DOI:10.2147/IJN.S483252
PMID:39539970
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11559232/
Abstract

PURPOSE

To develop a novel approach for increasing radiosensitivity in glioblastoma (GBM) by using targeted nanoparticles to deliver siRNA aimed at silencing the EGFR and RELA/P65 genes, which are implicated in radioresistance.

PATIENTS AND METHODS

We engineered biodegradable, tumor-targeted, self-assembled, and stimuli-responsive peptide nanoparticles for efficient siRNA delivery. We evaluated the nanoparticles' ability to induce gene silencing and enhance DNA damage under radiation in vitro and in vivo. The nanoparticles were designed to exhibit pH-responsive endosomal escape and αvβ3 integrin targeting, allowing for preferential accumulation at tumor sites and traversal of the blood-brain tumor barrier.

RESULTS

The application of these nanoparticles resulted in significant gene silencing, increased apoptosis, and decreased cell viability. The treatment impaired DNA repair mechanisms, thereby enhancing radiosensitivity in GBM cells. In a GBM mouse model, the combination of nanoparticle treatment with radiotherapy notably prolonged survival without apparent toxicity.

CONCLUSION

Our findings suggest that nanoparticle-mediated dual gene silencing can effectively overcome GBM radioresistance. This strategy has the potential to improve clinical outcomes in GBM treatment, proposing a promising therapeutic avenue for this challenging malignancy.

摘要

目的

通过使用靶向纳米颗粒递送针对 EGFR 和 RELA/P65 基因的 siRNA，开发一种新的方法来提高胶质母细胞瘤（GBM）的放射敏感性，这两个基因与放射抵抗有关。

患者和方法

我们设计了可生物降解、肿瘤靶向、自组装和刺激响应的肽纳米颗粒，以实现高效的 siRNA 递送。我们评估了纳米颗粒在体外和体内诱导基因沉默和增强放射诱导的 DNA 损伤的能力。这些纳米颗粒被设计为表现出 pH 响应的内涵体逃逸和 αvβ3 整合素靶向，允许优先在肿瘤部位积累并穿透血脑肿瘤屏障。

结果

应用这些纳米颗粒导致显著的基因沉默、增加的细胞凋亡和降低的细胞活力。该治疗破坏了 DNA 修复机制，从而增强了 GBM 细胞的放射敏感性。在 GBM 小鼠模型中，纳米颗粒治疗与放疗的联合显著延长了无明显毒性的存活期。

结论

我们的研究结果表明，纳米颗粒介导的双重基因沉默可以有效地克服 GBM 的放射抵抗。这种策略有可能改善 GBM 治疗的临床结果，为这种具有挑战性的恶性肿瘤提出了一种有前途的治疗途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/cd2418087932/IJN-19-11517-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/fad86bea5f7d/IJN-19-11517-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/028017b9e7f6/IJN-19-11517-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/ac00ba0ac861/IJN-19-11517-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/5a151554770e/IJN-19-11517-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/a9f9a665188d/IJN-19-11517-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/cd2418087932/IJN-19-11517-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/fad86bea5f7d/IJN-19-11517-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/028017b9e7f6/IJN-19-11517-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/ac00ba0ac861/IJN-19-11517-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/5a151554770e/IJN-19-11517-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/a9f9a665188d/IJN-19-11517-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa52/11559232/cd2418087932/IJN-19-11517-g0006.jpg

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