Multifunctional Indomethacin Conjugates for the Development of Nanosystems Targeting Cancer Treatment.

IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY
International Journal of Nanomedicine Pub Date : 2024-11-27 eCollection Date: 2024-01-01 DOI:10.2147/IJN.S477512
Vaikunthavasan Thiruchenthooran, Marta Świtalska, Gabriela Maciejewska, Anna Palko-Łabuz, Lorena Bonilla-Vidal, Joanna Wietrzyk, Eliana B Souto, Elena Sánchez-López, Anna Gliszczyńska
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引用次数: 0

Abstract

Purpose: It is well known that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (IND) exhibits significant anticancer potential reported not only by in vitro and in vivo studies, but also in clinical trials. Despite promising results, IND is not widely used as an adjunctive agent in cancer therapy due to the occurrence of several gastrointestinal side effects, primarily after oral administration. Therefore, this study aimed to develop a nanosystem with reduced toxicity and risk of side effects for the delivery of IND for cancer treatment.

Methods: IND was encapsulated in nanostructured lipid carriers (NLC) in the form of a phospholipid conjugate, where a covalent bond exists between the drug and phosphatidylcholine skeleton. For this purpose, seven new hybrid molecules were synthesized, and subsequently evaluated as anticancer agents in an in vitro model against selected cancer cell lines.

Results: Biological studies demonstrated that the synthesized conjugates possessed excellent antiproliferative effects, exhibiting a 2.7-fold to even 100-fold higher activity against selected cancer cells, while remaining non-toxic to healthy cells. Based on biological studies and molecular calculations, heterosubstituted phosphatidylcholine containing IND and oleic acid (IND-OA-PC) in the sn-1 and sn-2 positions, respectively, was identified as the most potent molecule. Subsequently, IND-OA-PC was encapsulated in nanostructured lipid carriers (IND-OA-PC-NLC). The results revealed that IND-OA-PC-NLC has a spherical shape with an average diameter of 155 nm and a negatively charged surface (-17.4 ± 0.49 mV). In this study, it was proven that the encapsulated conjugate of indomethacin with PC exhibits high activity against triple-negative (TNBC, Her2-, PR-, and ER-) breast cancer cells MDA-MB-468. While free IND was active at a concentration of 270.5 μM, in the form of the phospholipid conjugate (IND-OA-PC), it inhibited the growth of cancer cells at 67.5 μM and after conjugate encapsulation (IND-OA-PC-NLC) it was effective at only 10.3 μM.

Conclusion: Our study revealed that the conjugation of NSAID with phosphatidylcholine and its combination with nanotechnology techniques create opportunities to repurpose well-known drugs from this group for new therapeutic applications.

多功能吲哚美辛缀合物用于肿瘤靶向治疗纳米系统的开发。
目的:非甾体抗炎药吲哚美辛(indomethacin, IND)在体外和体内研究以及临床试验中均显示出显著的抗癌潜力。尽管有很好的结果,IND并没有被广泛用作癌症治疗的辅助药物,因为发生了一些胃肠道副作用,主要是口服给药后。因此,本研究旨在开发一种具有降低毒性和副作用风险的纳米系统,用于癌症治疗的IND递送。方法:将IND以磷脂缀合物的形式包裹在纳米结构脂质载体(NLC)中,其中药物与磷脂酰胆碱骨架之间存在共价键。为此,合成了7种新的杂交分子,并随后在体外模型中对选定的癌细胞系进行了抗癌评价。结果:生物学研究表明,合成的偶联物具有良好的抗增殖作用,对选定的癌细胞表现出2.7倍甚至100倍的活性,同时对健康细胞无毒。基于生物学研究和分子计算,分别在sn-1和sn-2位置上含有IND和油酸的杂取代磷脂酰胆碱(IND- oa - pc)被确定为最有效的分子。随后,将IND-OA-PC封装在纳米结构脂质载体(IND-OA-PC- nlc)中。结果表明:IND-OA-PC-NLC呈球形,平均直径为155 nm,表面带负电荷(-17.4±0.49 mV);本研究证实,吲哚美辛与PC包封的偶联物对三阴性(TNBC、Her2-、PR-和ER-)乳腺癌细胞MDA-MB-468具有较高的活性。游离IND在270.5 μM的浓度下具有活性,在67.5 μM的浓度下以磷脂缀合物(IND- oa - pc)的形式抑制癌细胞的生长,在10.3 μM的浓度下经缀合物包封(IND- oa - pc - nlc)有效。结论:我们的研究表明,非甾体抗炎药与磷脂酰胆碱的结合及其与纳米技术的结合为这组已知药物的新治疗应用创造了机会。
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来源期刊
International Journal of Nanomedicine
International Journal of Nanomedicine NANOSCIENCE & NANOTECHNOLOGY-PHARMACOLOGY & PHARMACY
CiteScore
14.40
自引率
3.80%
发文量
511
审稿时长
1.4 months
期刊介绍: The International Journal of Nanomedicine is a globally recognized journal that focuses on the applications of nanotechnology in the biomedical field. It is a peer-reviewed and open-access publication that covers diverse aspects of this rapidly evolving research area. With its strong emphasis on the clinical potential of nanoparticles in disease diagnostics, prevention, and treatment, the journal aims to showcase cutting-edge research and development in the field. Starting from now, the International Journal of Nanomedicine will not accept meta-analyses for publication.
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