Thiruchenthooran Vaikunthavasan, Świtalska Marta, Maciejewska Gabriela, Palko-Łabuz Anna, Bonilla-Vidal Lorena, Wietrzyk Joanna, Souto Eliana B, Sánchez-López Elena, Gliszczyńska Anna
Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Poland.
Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.
Int J Nanomedicine. 2024 Nov 27;19:12695-12718. doi: 10.2147/IJN.S477512. eCollection 2024.
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.
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.
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 -1 and -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.
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.
众所周知，非甾体抗炎药吲哚美辛（IND）不仅在体外和体内研究中，而且在临床试验中都显示出显著的抗癌潜力。尽管取得了令人鼓舞的结果，但由于出现了多种胃肠道副作用，主要是口服给药后，IND并未广泛用作癌症治疗的辅助药物。因此，本研究旨在开发一种毒性和副作用风险降低的纳米系统，用于递送IND进行癌症治疗。
IND以磷脂共轭物的形式包裹在纳米结构脂质载体（NLC）中，药物与磷脂酰胆碱骨架之间存在共价键。为此，合成了七个新的杂化分子，随后在体外模型中针对选定的癌细胞系评估其作为抗癌剂的活性。
生物学研究表明，合成的共轭物具有优异的抗增殖作用，对选定的癌细胞表现出高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-1和-2位含有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包裹在纳米结构脂质载体（IND-OA-PC-NLC）中。结果显示，IND-OA-PC-NLC呈球形，平均直径为155nm，表面带负电荷（-17.4±0.49mV）。在本研究中，已证明吲哚美辛与PC的包封共轭物对三阴性（TNBC，Her2-、PR-和ER-）乳腺癌细胞MDA-MB-468具有高活性。游离IND在浓度为270.5μM时具有活性，以磷脂共轭物（IND-OA-PC）的形式，它在67.5μM时抑制癌细胞生长，共轭物包封后（IND-OA-PC-NLC）仅在10.3μM时有效。
我们的研究表明，非甾体抗炎药与磷脂酰胆碱的共轭及其与纳米技术的结合为将该类知名药物重新用于新的治疗应用创造了机会。
