纳米芬瑞汀在急性早幼粒细胞白血病细胞中表现出显著的活性-动脉网

Nano-fenretinide demonstrates remarkable activity in acute promyeloid leukemia cells

Nature 等信源发布 2024-06-14 16:32

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AbstractAcute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival.

摘要急性早幼粒细胞白血病（APL）的特征是视黄酸受体RARα的重排，这使得全反式视黄酸（ATRA）在治疗该疾病方面非常有效，诱导早幼粒细胞分化。目前基于ATRA联合三氧化二砷的治疗方法，无论有无化疗，均可提供高无事件生存率和总生存率。

However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL.

然而，在长期治疗中经常观察到由于ATRA代谢增加和RARα突变导致的药物活性下降。此外，如果疾病复发，可能会发生去分化。在这项研究中，我们评估了芬维a胺，一种半合成的ATRA衍生物，封装在纳米胶束（纳米芬维a胺）中，作为APL中ATRA的替代治疗方法。

Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy.

通过将芬维a胺包封在自组装磷脂混合物中制备纳米芬维a胺。通过dinamic光散射和分光光度法进行物理化学表征。通过MTT测定，流式细胞术和共聚焦激光扫描荧光显微镜评估生物活性。

Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90–100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies.

纳米芬维a胺通过早期增加活性氧和线粒体电位降低诱导急性早幼粒细胞白血病细胞（HL60）凋亡。诱导细胞活力降低90-100%的芬维a胺浓度在24小时时约为2.0µM，如先前的研究所示，当通过口服或静脉内途径给予纳米芬维a胺时，该浓度在体内很容易达到。

Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an.

纳米芬维a胺在阿霉素耐药的HL60细胞中也有效，尽管浓度略高，但与TK6淋巴母细胞的比较表明对正常细胞缺乏毒性。结果表明，纳米芬维A胺可以被认为是一种。

IntroductionFenretinide (4-hydroxyphenyl retinamide, FEN) is a semisynthetic derivative of ATRA endowed with antitumor activity and a low toxicity profile. The main adverse effect is represented by decreased night vision reversible upon treatment suspension1. FEN antitumor activity, largely proved in a wide range of solid tumors and hematologic malignancies2 is based on multiple mechanisms triggering apoptosis in tumor cells by reactive oxygen species (ROS) increase, unbalancement of ceramides/dehydroceramides ratio and RARβ induction3.Many studies reported FEN activity on non-APL, acute myeloid leukemia (AML) cells, without significant effect on normal counterparts4,5,6,7,8,9,10.However, in spite of its antitumor activity and low toxicity profile, FEN has not entered in clinical use because its scant bioavailability prevents the achievement of suitable plasma concentrations to elicit a therapeutic response.

简介芬维a胺（4-羟基苯基维a酰胺，FEN）是ATRA的半合成衍生物，具有抗肿瘤活性和低毒性。主要的不良反应表现为治疗中止后可逆的夜视下降1。FEN的抗肿瘤活性在广泛的实体瘤和血液系统恶性肿瘤中得到了广泛的证实2，其基于多种机制，通过活性氧（ROS）的增加，神经酰胺/脱氢神经酰胺比例的不平衡和RARβ的诱导来触发肿瘤细胞的凋亡3。许多研究报道FEN对非APL急性髓细胞白血病（AML）细胞的活性，对正常对照组没有显着影响4,5,6,7,8,9,10。然而，尽管FEN具有抗肿瘤活性和低毒性，但由于其生物利用度低，因此尚未进入临床使用，因为其生物利用度低，无法获得合适的血浆浓度以引发治疗反应。

The many attempts made over the years to increase FEN bioavailability produced only few formulations that entered in clinical trials but did not provide satisfying results either in solid tumors or in hematologic malignancies2,3.A FEN nanoformulation (NF) was obtained by FEN entrapment in supramolecular aggregates, formed in aqueous medium by spontaneous self-assembling of suitable amphiphilic phospholipid-based mixtures.

多年来为提高FEN生物利用度所做的许多尝试仅产生了少数进入临床试验的制剂，但在实体瘤或血液系统恶性肿瘤中均未提供令人满意的结果2,3。FEN纳米制剂（NF）是通过FEN包埋在超分子聚集体中获得的，该聚集体通过自发自组装合适的两亲性磷脂基混合物在水性介质中形成。

NF was studied in vitro and in vivo in a wide range of tumor models11,12,13,14,15,16. NF in vivo studies demonstrated a bioavailability and an antitumor activity much higher than free FEN, either by intravenous or oral administration11,12,13,14,15,16.In this study we evaluated the activity of this nanoformulation in APL cell lines.

NF在多种肿瘤模型中进行了体外和体内研究11,12,13,14,15,16。NF体内研究表明，通过静脉内或口服给药11,12,13,14,15,16，生物利用度和抗肿瘤活性远高于游离FEN。在这项研究中，我们评估了这种纳米制剂在APL细胞系中的活性。

AML is a malignant clonal disease where the presence of genetic alterations in myeloid cells causes inhibition of diff.

AML是一种恶性克隆性疾病，其中骨髓细胞中遗传改变的存在导致差异抑制。

Data availability

数据可用性

All data are available on request to the corresponding authors.

所有数据均可应要求提供给相应的作者。

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Download referencesAcknowledgementsThe project work was funded by the “Ministero dell’Università e della Ricerca” PRIN 2017, project n. 20175XBSX4 (Targeting Hedgehog pathway: Virtual screening identification and sustainable synthesis of novel Smo and Gli inhibitors and their pharmacological drug delivery strategies for improved therapeutic effects in tumors).Author informationAuthors and AffiliationsDepartment of Pharmacy and Biotechnology, University of Bologna, Via San Donato 19/2, 40127, Bologna, ItalyGiovanna Farruggia, Lorenzo Anconelli, Lucrezia Galassi, Manuela Voltattorni, Martina Rossi, Paolo Blasi & Isabella OrientiCenter for Applied Biomedical Research (CRBA), University of Bologna, 40126, Bologna, ItalyGiovanna Farruggia, Lucrezia Galassi, Martina Rossi & Paolo BlasiNational Institute of Biostructures and Biosystems, Via Delle Medaglie d’Oro 305, 00136, Rome, ItalyGiovanna FarruggiaSection of Endocrinology and Metabolic Diseases, Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, ItalyPietro LodesertoAuthorsGiovanna FarruggiaView author publicationsYou can also search for this author in.

下载参考文献致谢该项目工作由“Ministero dell'Universitàe della Ricerca”于2017年4月资助，项目编号20175XBSX4（靶向刺猬通路：新型Smo和Gli抑制剂的虚拟筛选鉴定和可持续合成及其药理药物递送策略，以改善肿瘤的治疗效果）。作者信息作者和附属机构博洛尼亚大学药学与生物技术系，Via San Donato 19/240127，博洛尼亚，ItalyGiovanna Farruggia，Lorenzo Anconelli，Lucrezia Galassi，Manuela Volattorni，Martina Rossi，Paolo Blasi&Isabella OrientiCenter for Applied Biomedical Research（CRBA），博洛尼亚大学，40126，博洛尼亚，ItalyGiovanna Farruggia，Lucrezia Galassi，Martina Rossi&Paolo BlasiNational Institute of Biostructures and Biosystems，Via Delle Medaglie d'Oro 30500136，罗马，ItalyGiovanna Farruggia罗马大学系统医学系内分泌和代谢疾病科Tor Vergata，00133，罗马，ItalyPietro LodesertoAuthorsGiovanna FarruggiaView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarLorenzo AnconelliView author publicationsYou can also search for this author in

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PubMed Google ScholarPietro LodesertoView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsG.F., I.O. conceptualization, writing, original draft preparation, review and editing, supervision; L.A. methodology, software, validation, formal analysis and investigation; L.G. methodology, software, validation, formal analysis and investigation; M.V.

PubMed谷歌学术贡献。F、，即概念化，写作，原稿准备，审查和编辑，监督；五十、 A.方法、软件、验证、正式分析和调查；五十、 G.方法、软件、验证、正式分析和调查；M、五。

formal analysis and investigation; M.R., P.L. methodology, writing, original draft preparation, review and editing; PB: Conceptualization, writing, original draft preparation, review and editing, supervision, funding acquisition.Corresponding authorsCorrespondence to.

形式分析和调查；M、 R.，P.L.方法论，写作，原稿准备，审查和编辑；PB：概念化，写作，原稿准备，审查和编辑，监督，资金获取。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleFarruggia, G., Anconelli, L., Galassi, L. et al. Nano-fenretinide demonstrates remarkable activity in acute promyeloid leukemia cells.

转载和许可本文引用本文Farruggia，G.，Anconelli，L.，Galassi，L。等人。纳米芬维A胺在急性早幼粒细胞白血病细胞中表现出显着的活性。

Sci Rep 14, 13737 (2024). https://doi.org/10.1038/s41598-024-64629-wDownload citationReceived: 15 December 2023Accepted: 26 March 2024Published: 14 June 2024DOI: https://doi.org/10.1038/s41598-024-64629-wShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsAPL4-Hydroxyphenyl retinamide

关键词APL4-羟基苯基视黄酰胺

All-trans retinoic acidAntitumor activityMitochondrial membrane potentialReactive oxygen speciesHL60HL60RTK6

全反式维甲酸抗肿瘤活性线粒体膜电位活性氧物种HL60HL60RTK6

Subjects

主题

Acute myeloid leukaemiaCancerHaematological cancerLeukaemia

急性髓系白血病癌症白血病

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