Selective vascular disrupting therapy by lipid nanoparticle-mediated Fas ligand silencing and stimulation of STING

IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL
Rikito Endo , Tomoki Ueda , Takumi Nagaoki , Yusuke Sato , Nako Maishi , Kyoko Hida , Hideyoshi Harashima , Takashi Nakamura
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引用次数: 0

Abstract

Although recent therapeutic developments have greatly improved the outcomes of patients with cancer, it remains on ongoing problem, particularly in relation to acquired drug resistance. Vascular disrupting agents (VDAs) directly damage tumor blood vessels, thus promoting drug efficacy and reducing the development of drug resistance; however, their low molecular weight and resulting lack of selectivity for tumor endothelial cells (TECs) lead to side effects that can hinder their practical use. Here, we report a novel tumor vascular disrupting therapy using nucleic acid-loaded lipid nanoparticles (LNPs). We prepared two LNPs: a small interfering RNA (siRNA) against Fas ligand (FasL)-loaded cyclic RGD modified LNP (cRGD-LNP) to knock down FasL in TECs and a stimulator of interferon genes (STING) agonist-loaded LNP to induce systemic type I interferon (IFN) production. The combination therapy disrupted the tumor vasculature and induced broad tumor cell apoptosis within 48 h, leading to rapid and strong therapeutic effects in various tumor models. T cells were not involved in these antitumor effects. Furthermore, the combination therapy demonstrated a significantly superior therapeutic efficacy compared with conventional anti-angiogenic agents and VDAs. RNA sequencing analysis suggested that reduced collagen levels may have been responsible for TEC apoptosis. These findings demonstrated a potential therapeutic method for targeting the tumor vasculature, which may contribute to the development of a new class of anti-cancer drugs.

Abstract Image

脂质纳米颗粒介导的Fas配体沉默和刺激STING的选择性血管破坏治疗
尽管最近的治疗进展大大改善了癌症患者的预后,但它仍然是一个持续存在的问题,特别是在获得性耐药方面。血管干扰剂(VDAs)直接损伤肿瘤血管,促进药物疗效,减少耐药的发生;然而,它们的低分子量和对肿瘤内皮细胞(tec)缺乏选择性导致副作用,阻碍了它们的实际应用。在这里,我们报告了一种新的肿瘤血管破坏疗法,使用装载核酸的脂质纳米颗粒(LNPs)。我们制备了两种LNPs:一种是小干扰RNA (siRNA),可抑制Fas配体(FasL)负载的环状RGD修饰LNP (cRGD-LNP),可抑制TECs中的FasL;另一种是干扰素基因刺激剂(STING)激动剂负载LNP,可诱导全身I型干扰素(IFN)的产生。联合治疗可在48 h内破坏肿瘤血管,诱导肿瘤细胞广泛凋亡,对多种肿瘤模型均有快速而强的治疗效果。T细胞不参与这些抗肿瘤作用。此外,与常规抗血管生成药物和vda相比,联合治疗显示出明显优于常规抗血管生成药物的治疗效果。RNA测序分析表明,胶原蛋白水平降低可能是TEC细胞凋亡的原因。这些发现证明了一种潜在的靶向肿瘤血管的治疗方法,这可能有助于开发一类新的抗癌药物。
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来源期刊
Biomaterials
Biomaterials 工程技术-材料科学:生物材料
CiteScore
26.00
自引率
2.90%
发文量
565
审稿时长
46 days
期刊介绍: Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.
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