高转变温度磷脂对提高氧化还原敏感性多柔比星脂质体在结肠癌模型中疗效的影响

IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Elaheh Mirhadi , Anis Askarizadeh , Leila Farhoudi , Mohammad Mashreghi , Saeed Behboodifar , Seyedeh Hoda Alavizadeh , Leila Arabi , Mahmoud Reza Jaafari
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引用次数: 0

摘要

本研究以 10,10′-二壬二基双癸酸(DDA)有机硒化合物作为 RS 分子,开发了一种氧化还原敏感(RS)多柔比星脂质体制剂。因此,使用 DOPE、HSPC、DDA、mPEG2000-DSPE 和胆固醇制备了多种 RS 脂质体制剂。利用 pH 梯度和柠檬酸复合物原位装载药物,RS 脂质体的药物脂质比和包封效率都很高(100%)。对脂质体制剂的尺寸、表面电荷和形态、载药量、释放特性、细胞摄取和细胞毒性以及对携带 C26 肿瘤细胞的 BALB/c 小鼠的疗效进行了表征。制剂的平均粒径为 200 nm,粒度分布较窄(PDI <0.3),表面负电荷从 -6 mV 到 -18.6 mV 不等。我们的研究证实,脂质体中的 DDA 化合物对 0.1 % w/v 的过氧化氢高度敏感,可导致高达 40 % 的显著猝发释放。对携带 C26 结肠癌的 BALB/c 小鼠进行的体内疗效研究证实,RS 脂质体在肿瘤微环境中具有良好的功能,从而延长了中位生存时间(MST)。氢化大豆磷脂酰胆碱(HSPC)具有较高的转变温度(Tm:52-53.5 °C),与对RS不敏感的Caelyx(PEG脂质体Dox)(39天)相比,加入氢化大豆磷脂酰胆碱(HSPC)后,我们的F14(DOPE/HSPC/DDA)三组分配方的中位生存时间延长至60天。总之,含有对 RS 敏感的分子的 HSPC 脂质体提高了对结肠癌的体外和体内疗效。这一成果明确强调了高活性磷脂,尤其是 HSPC 在显著增强脂质体在血液中稳定性方面的关键作用。此外,RS 脂质体还能利用肿瘤细胞的氧化还原环境按需释放药物,从而增强制剂的疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The impact of phospholipids with high transition temperature to enhance redox-sensitive liposomal doxorubicin efficacy in colon carcinoma model

The impact of phospholipids with high transition temperature to enhance redox-sensitive liposomal doxorubicin efficacy in colon carcinoma model

In this study, we have developed a redox-sensitive (RS) liposomal doxorubicin formulation by incorporating 10,10′-diselanediylbis decanoic acid (DDA) organoselenium compound as the RS moiety. Hence, several RS liposomal formulations were prepared by using DOPE, HSPC, DDA, mPEG2000-DSPE, and cholesterol. In situ drug loading using a pH gradient and citrate complex yielded high drug to lipid ratio and encapsulation efficiency (100 %) for RS liposomes. Liposomal formulations were characterized in terms of size, surface charge and morphology, drug loading, release properties, cell uptake and cytotoxicity, as well as therapeutic efficacy in BALB/c mice bearing C26 tumor cells. The formulations showed an average particle size of 200 nm with narrow size distributions (PDI < 0.3), and negative surface charges varying from −6 mV to −18.6 mV. Our study confirms that the presence of the DDA compound in liposomes is highly sensitive to hydrogen peroxide at 0.1 % w/v, resulting in a significant burst release of up to 40 %. The in vivo therapeutic efficacy study in BALB/c mice bearing C26 colon carcinoma confirmed the promising function of RS liposomes in the tumor microenvironment which led to a prolonged median survival time (MST). The addition of hydrogenated soy phosphatidylcholine (HSPC) with a high transition temperature (Tm: 52–53.5 °C) extended the MST of our 3-component formulation of F14 (DOPE/HSPC/DDA) to 60 days in comparison to Caelyx (PEGylated liposomal Dox), which is not RS-sensitive (39 days). Overall, HSPC liposomes bearing RS-sensitive moiety enhanced therapeutic efficacy against colon cancer in vitro and in vivo. This achievement unequivocally underscores the criticality of high-TM phospholipids, particularly HSPC, in significantly enhancing liposome stability within the bloodstream. In addition, RS liposomes enable the on-demand release of drugs, leveraging the redox environment of tumor cells, thereby augmenting the efficacy of the formulation.

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来源期刊
Chemistry and Physics of Lipids
Chemistry and Physics of Lipids 生物-生化与分子生物学
CiteScore
7.60
自引率
2.90%
发文量
50
审稿时长
40 days
期刊介绍: Chemistry and Physics of Lipids publishes research papers and review articles on chemical and physical aspects of lipids with primary emphasis on the relationship of these properties to biological functions and to biomedical applications. Accordingly, the journal covers: advances in synthetic and analytical lipid methodology; mass-spectrometry of lipids; chemical and physical characterisation of isolated structures; thermodynamics, phase behaviour, topology and dynamics of lipid assemblies; physicochemical studies into lipid-lipid and lipid-protein interactions in lipoproteins and in natural and model membranes; movement of lipids within, across and between membranes; intracellular lipid transfer; structure-function relationships and the nature of lipid-derived second messengers; chemical, physical and functional alterations of lipids induced by free radicals; enzymatic and non-enzymatic mechanisms of lipid peroxidation in cells, tissues, biofluids; oxidative lipidomics; and the role of lipids in the regulation of membrane-dependent biological processes.
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