人胶质母细胞瘤衍生的细胞膜纳米囊泡：一种新的、细胞特异性的硼中子俘获治疗脑肿瘤的策略-动脉网

Human glioblastoma-derived cell membrane nanovesicles: a novel, cell-specific strategy for boron neutron capture therapy of brain tumors

Nature 等信源发布 2024-08-20 12:19

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AbstractGlioblastoma (GBM), one of the deadliest brain tumors, accounts for approximately 50% of all primary malignant CNS tumors, therefore novel, highly effective remedies are urgently needed. Boron neutron capture therapy, which has recently repositioned as a promising strategy to treat high-grade gliomas, requires a conspicuous accumulation of boron atoms in the cancer cells.

。硼中子俘获疗法最近被重新定位为治疗高级别神经胶质瘤的一种有前途的策略，它需要在癌细胞中明显积累硼原子。

With the aim of selectively deliver sodium borocaptate (BSH, a 12 B atoms-including molecule already employed in the clinics) to GBM cells, we developed novel cell membrane-derived vesicles (CMVs), overcoming the limits of natural extracellular vesicles as drug carriers, while maintaining their inherent homing abilities that make them preferable to fully synthetic nanocarriers.

为了选择性地将硼Captate钠（BSH，一种12 B原子，包括已经用于临床的分子）递送至GBM细胞，我们开发了新型细胞膜衍生囊泡（CMV），克服了天然细胞外囊泡作为药物载体的局限性，同时保持其固有的归巢能力，使其优于完全合成的纳米载体。

Purified cell membrane fragments, isolated from patient-derived GBM stem-like cell cultures, were used to prepare nanosized CMVs, which retained some membrane proteins specific of the GBM parent cells and were devoid of potentially detrimental genetic material. In vitro tests evidenced the targeting ability of this novel nanosystem and ruled out any cytotoxicity.

从患者来源的GBM干细胞样细胞培养物中分离出的纯化细胞膜片段用于制备纳米级CMV，该CMV保留了GBM亲本细胞特有的一些膜蛋白，并且没有潜在的有害遗传物质。体外测试证明了这种新型纳米系统的靶向能力，并排除了任何细胞毒性。

The CMVs were successfully loaded with BSH, by following two different procedures, i.e. sonication and electroporation, demonstrating their potential applicability in GBM therapy..

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IntroductionDiffuse gliomas are the most prevalent malignant and deadliest primary brain tumors in adults1. Glioblastoma IDH-wild type WHO 4 (GBM)2, accounting for approximately 50% of all primary malignant CNS tumors3, presents very poor prognosis and a median survival of about 15 months4; it is characterized by uncontrolled cell proliferation, diffuse infiltration and necrosis, and robust angiogenesis5, which largely depend on the presence and activity of cancer stem cells within the tumor mass2.

引言弥漫性胶质瘤是成人中最常见的恶性和致命的原发性脑肿瘤1。胶质母细胞瘤IDH野生型WHO 4（GBM）2约占所有原发性恶性中枢神经系统肿瘤的50%3，预后极差，中位生存期约为15个月4；它的特征是不受控制的细胞增殖，弥漫性浸润和坏死以及强大的血管生成5，这在很大程度上取决于肿瘤块内癌症干细胞的存在和活性2。

Usually, GBM patients at diagnosis display non-specific neurological symptoms, like headaches, seizures, focal neurologic deficits, memory loss, visual changes, personality changes, and vomiting1,6. Current standard treatment for GBM includes maximal surgical resection followed by concurrent radiotherapy with the alkylating drug temozolomide and further adjuvant temozolomide7.

通常，诊断时的GBM患者表现出非特异性神经系统症状，如头痛，癫痫发作，局灶性神经功能缺损，记忆力减退，视力改变，性格改变和呕吐1,6。目前GBM的标准治疗包括最大程度的手术切除，然后同时使用烷化药物替莫唑胺和进一步的辅助替莫唑胺7进行放疗。

Although few new drugs have recently been approved for GBM treatment, the outcome is still largely unsatisfactory, and more effective therapies are urgently needed. Indeed, many innovative therapeutic approaches, involving combinations of radiotherapy with immunotherapy or nanoparticle (NPs)-vehiculated drugs, are currently under study8.Exosomes, nanosized extracellular vesicles released by the majority of cell types, have been proposed as drug carriers due to their ability to shuttle biomolecules, their innate selectivity towards the parent cell of origin or cell type (i.e., homing ability), and their low immunogenicity9.

尽管最近很少有新药被批准用于GBM治疗，但结果仍然很不令人满意，迫切需要更有效的治疗方法。事实上，目前正在研究许多创新的治疗方法，包括放疗与免疫疗法或纳米颗粒（NPs）-载体药物的组合。外泌体是大多数细胞类型释放的纳米级细胞外囊泡，由于其穿梭生物分子的能力，其对起源或细胞类型的亲本细胞的先天选择性（即归巢能力）及其低免疫原性9，已被提议作为药物载体。

However, exosome purification and characterization are challenging, and their yield and loading efficiency are relatively poor, limiting their large-scale application in the clinics10. Therefore, the generation of bioinspired exosome-mimetics with higher yield and consistency is attra.

然而，外泌体的纯化和表征具有挑战性，它们的产量和负载效率相对较差，限制了它们在临床上的大规模应用10。因此，具有更高产量和一致性的生物启发外泌体模拟物的产生是必然的。

Table 1 Most abundant membrane proteins found with the proteomic analysis of a CMV sample.Full size tableSeveral of the identified membrane proteins have been reported in the literature as characteristic of GBM cells, including annexin A239, CD4440, HLA class I histocompatibility antigen A41 and adipocyte plasma membrane-associated protein42.

。在文献中已经报道了几种已鉴定的膜蛋白的全尺寸表作为GBM细胞的特征，包括膜联蛋白A239，CD4440，HLA I类组织相容性抗原A41和脂肪细胞质膜相关蛋白42。

In particular, the most abundant membrane protein found in the CMVs was annexin A2, a calcium-binding protein expressed on the surface of macrophages, mononuclear and endothelial cells, as well as in several types of cancer cells43. The expression of annexin A2 has been associated with cell dissemination and metastasis in many cancer types; it is overexpressed in GBM cells and positively correlated with tumor aggressiveness and progression sustaining cell invasion, angiogenesis, proliferation, matrix invasion and mesenchymal transition44,45.

特别是，在CMV中发现的最丰富的膜蛋白是膜联蛋白A2，一种在巨噬细胞，单核细胞和内皮细胞以及几种类型的癌细胞表面表达的钙结合蛋白43。膜联蛋白A2的表达与许多癌症类型的细胞传播和转移有关；它在GBM细胞中过表达，与肿瘤侵袭性和进展呈正相关，维持细胞侵袭，血管生成，增殖，基质侵袭和间充质转化44,45。

Interestingly, knockdown of annexin A2 decreased glioma cell migration in vitro and slowed down tumor progression in vivo, as evidenced by decreased proliferation, invasion, and angiogenesis46.To further investigate the presence of annexin A2 on the surface of the CMVs, the vesicles were incubated with a fluorescent labelled anti-annexin antibody and, after removal of the unbound ligands, a drop of suspension was observed through confocal microscopy.

有趣的是，膜联蛋白A2的敲低降低了体外神经胶质瘤细胞的迁移并减缓了体内肿瘤的进展，这可以通过增殖，侵袭和血管生成的减少来证明46。为了进一步研究膜联蛋白A2在CMV表面的存在，将囊泡与荧光标记的抗膜联蛋白抗体一起孵育，并且在去除未结合的配体后，通过共聚焦显微镜观察到一滴悬浮液。

As shown in Fig. 3, a co-localization of the red fluorescent signal, deriving from the CM-DiI-labeled CMVs, and of the green fluorescent signal deriving from the Alexa Fluor 488-labeled anti-annexin antibody, was highlighted.Figure 3Confocal images of CM-DiI-labeled CMVs after incubation with anti-annexin A2 antibody labeled with the Alexa Fluor 488 dye.

如图3所示，突出显示了源自CM-DiI标记的CMV的红色荧光信号和源自Alexa Fluor 488标记的抗膜联蛋白抗体的绿色荧光信号的共定位。图3与用Alexa Fluor 488染料标记的抗膜联蛋白A2抗体孵育后，CM-DiI标记的CMV的共聚焦图像。

(A) Red fluorescent signal deriving from CM-DiI-labelled CMVs (λex = 561 nm); (B) Green fluores.

（A）来自CM-DiI标记的CMV的红色荧光信号（λex=561 nm）；（B）绿色荧光。

Table 2 EE% and drug loading results obtained from the two different loading procedures. Results are expressed as mean ± standard deviation (n = 3).Full size tableNoteworthy, in most literature works reporting the loading of exosomes and other biomimetic nanosystems with active molecules, drug loading is expressed as amount of drug/amount of proteins; however, we decided to express it also in terms of µg BSH/number of CMVs, which might be more informative in the case of clinical application.Since both loading procedures might impair vesicle integrity, the mean size and PDI of CMVs was monitored after the loading and purification processes.

表2从两种不同的加载程序获得的EE%和药物加载结果。结果表示为平均±标准偏差（n=3）。全尺寸表值得注意的是，在大多数报道外泌体和其他具有活性分子的仿生纳米系统负载的文献中，药物负载量表示为药物量/蛋白质量；但是，我们决定也以µg BSH/CMV数量表示，这在临床应用中可能会提供更多信息。由于两种加载程序都可能损害囊泡的完整性，因此在加载和纯化过程后监测CMV的平均大小和PDI。

As shown in Fig. 4, the sonication procedure did not significantly affect the mean size and PDI; on the contrary, the electroporation procedure led to a significant increase in CMV mean size (from 125 ± 2 nm to 176 ± 3 nm), accompanied by a PDI increase (from 0.1 ± 0.1 to 0.4 ± 0.2), possibly due to a little extent of aggregation phenomena caused by the electric field49.

如图4所示，超声处理程序对平均大小和PDI没有显着影响；相反，电穿孔过程导致CMV平均大小显着增加（从125±2 nm到176±3 nm），伴随着PDI增加（从0.1±0.1到0.4±0.2），这可能是由于电场引起的聚集现象程度较小49。

However, even if significantly enlarged, the CMVs subjected to electroporation maintained their nanosized dimensions, acceptable for parenteral administration, and the PDI value is still indicating the presence of a monodisperse population.Figure 4Mean CMV size and PDI values before and after BSH loading, carried out by sonication and electroporation.

。图4通过超声处理和电穿孔进行BSH加载前后的平均CMV大小和PDI值。

Mean ± standard deviation (n = 3).Full size imageThe size and zeta potential of BSH-loaded CMVs did not significantly change (p < 0.05) over two-week storage at 4 °C, confirming the stability of the system at the storage conditions during this timeframe (Figs. 5A,B).Figure 5Stability of the BSH-loaded CMVs over 2 week storage at 4 °C, monitoring the size (A), zeta potential (B) and BSH content (C).Full size imageBSH leak.

平均±标准偏差（n=3）。全尺寸图像负载BSH的CMV的大小和zeta电位在4°C下储存两周后没有显着变化（p<0.05），证实了该时间段内系统在储存条件下的稳定性（图5A，B）。图5负载BSH的CMV在4°C下储存2周后的稳定性，监测尺寸（A），zeta电位（B）和BSH含量（C）。全尺寸imageBSH泄漏。

Data availability

数据可用性

The datasets generated during and/or analyzed during the current study are available from the corresponding authors on reasonable request.

在当前研究期间生成和/或分析的数据集可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsWork supported by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)—A Multiscale integrated approach to the study of the nervous system in health and disease (DN.

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1553 11.10.2022)Author informationAuthor notesThese authors contributed equally: Alice Balboni and Giorgia Ailuno.These authors jointly supervised this work: Tullio Florio and Gabriele Caviglioli.Authors and AffiliationsDepartment of Pharmacy, University of Genoa, 16148, Genoa, ItalyAlice Balboni, Giorgia Ailuno, Sara Baldassari, Giuliana Drava & Gabriele CaviglioliIRCCS Istituto Giannina Gaslini, 16147, Genoa, ItalyAndrea Petretto & Nicole GrinoveroDepartment of Physics, University of Genoa, 16146, Genoa, ItalyOrnella Cavalleri, Elena Angeli, Andrea Lagomarsino & Paolo CanepaDepartment of Internal Medicine, University of Genoa, 16132, Genoa, ItalyAlessandro Corsaro, Beatrice Tremonti, Federica Barbieri, Stefano Thellung, Paola Contini & Tullio FlorioDepartment of Experimental Medicine, University of Genoa, 16132, Genoa, ItalyKatia CorteseIRCCS Ospedale Policlinico San Martino, 16132, Genoa, ItalyTullio Florio & Gabriele CaviglioliAuthorsAlice BalboniView author publicationsYou can also search for this author in.

1553 11.10.2022）作者信息作者注意到这些作者做出了同样的贡献：爱丽丝·巴尔博尼和乔治·艾卢诺。这些作者共同监督了这项工作：Tullio Florio和Gabriele Caviglioli。作者和附属机构热那亚大学药学系，16148，热那亚，ItalyAlice Balboni，Giorgia Ailuno，Sara Baldassari，Giuliana Drava＆Gabriele CaviglioliIRCCS Istituto Giannina Gaslini，16147，热那亚，ItalyAndrea Petretto＆Nicole Grinovere热那亚大学物理系，16146，热那亚，ItalyOrnella Cavalleri，Elena Angeli，Andrea Lagomarsino＆Paolo Canepad热那亚大学内科，16132，热那亚，ItalyAlessandro Cor萨罗（Saro），比阿特丽斯·特雷蒙蒂（Beatrice Tremonti），费德里卡·巴比里（Federica Barbieri），斯特凡诺·塞隆（Stefano Thellung），保拉·康蒂尼（Paola Contini）和图利奥·弗洛里奥（Tullio Florio）热那亚大学实验医学系，16132，热那亚（Genoa），意大利科蒂西亚（ItalyKatia CorteseIRCCS Ospedale Policlinico San Martino），16132，热那亚（Genoa），意大利图利奥·弗洛里奥（ItalyTullio Florio）和加布里埃尔·卡维利奥（Gabriele CaviglioliAuthorsAlice BalboniView）作者出版物你也可以在。

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PubMed Google ScholarContributionsA.B. and G.A. equally contributed to this work and both should be considered as first author. T.F. and G.C. contributed equally to this work and both should be considered as last senior authors. A.B.: Conceptualization; Methodology; Investigation; Writing—Review and Editing; G.A.: Conceptualization; Methodology; Investigation; Writing—Original Draft; Writing—Review and Editing; S.B.: Methodology; Writing—Original Draft; Writing—Review and Editing; G.D.: Methodology; Investigation; Resources; Writing—Review and Editing; A.P.: Methodology; Investigation; Resources; N.G.: Investigation; O.C.: Methodology; Resources; Writing—Review and Editing; E.A.: Investigation; A.L.: Investigation; P.C.: Investigation; A.C.: Investigation; B.T.: Investigation; F.B.: Formal analysis; Investigation; Writing—Review and Editing; S.T.: Investigation; P.C.: Investigation; K.C.: Investigation; T.F.: Methodology; Resources; Writing—Review and Editing; Supervision; Funding acquisition; G.C.: Conceptualization; Methodology; Resources; Writing—Review and Editing; Supervision; Funding acquisition.

PubMed谷歌学术贡献。B、和G.A.对这项工作做出了同样的贡献，两者都应被视为第一作者。T、。A、 B.：概念化；方法论；调查；写作评论和编辑；G、 A：概念化；方法论；调查；撰写初稿；写作评论和编辑；S、 B.：方法论；撰写初稿；写作评论和编辑；G、 D.：方法论；调查；资源；写作评论和编辑；A、 P.：方法论；调查；资源；N、；O、 C.：方法论；资源；写作评论和编辑；E、 A.：调查；A、 L.：调查；P、 C.：调查；A、 C.：调查；B、 T.：调查；F、 B.：形式分析；调查；写作评论和编辑；S、 T.：调查；P、 C.：调查；K、 C.：调查；T、 F.：方法论；资源；写作评论和编辑；监督；资金获取；G、；方法论；资源；写作评论和编辑；监督；资金收购。

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Reprints and permissionsAbout this articleCite this articleBalboni, A., Ailuno, G., Baldassari, S. et al. Human glioblastoma-derived cell membrane nanovesicles: a novel, cell-specific strategy for boron neutron capture therapy of brain tumors.

转载和许可本文引用本文Balboni，A.，Ailuno，G.，Baldassari，S。等人。人类胶质母细胞瘤衍生的细胞膜纳米囊泡：一种用于脑肿瘤硼中子捕获治疗的新型细胞特异性策略。

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KeywordsCell membraneCancer treatmentBioinspired vesiclesCell internalizationProteomics

关键词细胞膜癌治疗生物激发的囊泡细胞内化蛋白质组学

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