Idlas Pierre, Lepeltier Elise, Bastiat Guillaume, Pigeon Pascal, McGlinchey Michael J, Lautram Nolwenn, Vessières Anne, Jaouen Gerard, Passirani Catherine
Micro et Nanomédecines Translationnelles, MINT, Université Angers, INSERM 1066, CNRS 6021, Angers49100, France.
Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), Paris75005, France.
Langmuir. 2023 Feb 7;39(5):1885-1896. doi: 10.1021/acs.langmuir.2c02910. Epub 2023 Jan 24.
Ferrocifens, lipophilic organometallic complexes, comprise a biologically active redox motif [ferrocenyl-ene--phenol] which confers very interesting cytotoxic properties to this family. However, because of their highly lipophilic nature, a formulation stage is required before being administered . In recent decades, ferrocifen lipid nanocapsules (LNCs) have been successfully formulated and have demonstrated anticancer activity on multidrug-resistant cancers in several mice and rat models (glioblastoma, breast cancer, and metastatic melanoma). A recent family of ferrocifens (succinimidoalkyl-ferrociphenols, including ) appears to be most efficacious on several resistant cancer cell lines, with IC values in the nanomolar range together with promising results on murine ovarian cancer models. As LNCs are composed of an oily core (caprylic/capric triglycerides), modulation of the succinimido-ferrociphenol lipophilicity could be a valuable approach toward improving the drug loading in LNCs. As the drug loading of the diphenol in LNCs was low, it was structurally modified to increase its lipophilicity and thereby the payload in LNCs. Chemical modification led to a series of five succinimido-ferrocifens. Results confirmed that these slight structural modifications led to increased drug loading in LNCs for all ferrocifens, with no reduction of their cytotoxicity on the SKOV3 ovarian cancer cell line. Interestingly, encapsulation of two of the ferrocifens, diester and monophenolic ester , led to the formation of a gel. This was unprecedented behavior, a phenomenon that could be rationalized in terms of the positioning of ferrocifens in LNCs as shown by the decrease of interfacial tension measurements at the water/oil interface. Moreover, these results highlighted the importance of obtaining a gel of this particular motif, in which the acetylated phenolic ring and the succinimidoalkyl moieties are mutually cis relative to the central double bond. Promising perspectives to use these ferrocifen-loaded LNCs to treat glioblastoma could be readily envisaged by local application of the gel in the cavity after tumor resection.
二茂铁衍生物是亲脂性有机金属配合物,包含具有生物活性的氧化还原基序[二茂铁基-烯-苯酚],赋予了该家族非常有趣的细胞毒性特性。然而,由于它们具有高度亲脂性,在给药前需要进行制剂阶段。近几十年来,二茂铁脂质纳米囊(LNCs)已成功制备,并在几种小鼠和大鼠模型(胶质母细胞瘤、乳腺癌和转移性黑色素瘤)中对多药耐药癌症表现出抗癌活性。最近的一类二茂铁衍生物(琥珀酰亚胺烷基-二茂铁酚,包括 )似乎对几种耐药癌细胞系最有效,其IC值在纳摩尔范围内,并且在小鼠卵巢癌模型中也有令人鼓舞的结果。由于LNCs由油相核心(辛酸/癸酸甘油三酯)组成,调节琥珀酰亚胺-二茂铁酚的亲脂性可能是提高LNCs中药物载量的一种有价值的方法。由于二酚在LNCs中的药物载量较低,对其进行了结构修饰以增加其亲脂性,从而提高LNCs中的有效载荷。化学修饰产生了一系列五种琥珀酰亚胺-二茂铁衍生物。结果证实,这些轻微的结构修饰导致所有二茂铁衍生物在LNCs中的药物载量增加,同时对SKOV3卵巢癌细胞系的细胞毒性没有降低。有趣的是,两种二茂铁衍生物,二酯 和单酚酯 的包封导致形成了一种凝胶。这是前所未有的行为,这种现象可以根据二茂铁在LNCs中的定位来解释,如油水界面处界面张力测量值的降低所示。此外,这些结果突出了获得这种特定基序凝胶的重要性,其中乙酰化酚环和琥珀酰亚胺烷基部分相对于中心双键相互为顺式。通过在肿瘤切除后将凝胶局部应用于腔内,可以很容易地设想使用这些负载二茂铁的LNCs治疗胶质母细胞瘤的前景广阔。