School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
Int J Pharm. 2019 Apr 5;560:246-260. doi: 10.1016/j.ijpharm.2019.02.007. Epub 2019 Feb 12.
Liposomes have emerged as a fascinating nanocarriers for the delivery of cancer therapeutics. However, their efficacy for cancer therapy is reduced partially because of the serum-instability and incomplete drug release. In this study, a novel disulfide cross-linked liposomes (CLs) assembled from dimeric lipoic acid-derived glycerophosphorylcholine (di-LA-PC) conjugate was developed. The conjugate was synthesized by a facial esterification of lipoic acid (LA) and glycerophosphorylcholine (GPC) and characterized by MS, H NMR and C NMR. Featuring the enhanced serum-stability and intracellular drug release determined by in vitro stability and GSH-responsive behavior, CLs prepared with dried thin film technique following 10 % dithiothreitol (DTT) cross-linking can attain effective delivery of anticancer candidates. Notably, CLs stably encapsulated doxorubicin (Dox) in their vesicular structures and showed a remarkable thiol-sensitive release of payload upon cellular uptake by cancer cells, compared to that of uncross-linked liposomes (uCLs) or Doxil-like liposome (DLLs). The cell viability and apoptosis of Dox-loaded CLs worked the pronounced cytotoxic effects to MCF-7 cells with an IC value of 10.8 μg Dox equiv./mL comparable to free Dox and 2.8-fold higher than DLLs. More importantly, it is demonstrated that the nanoscale characteristics of Dox-loaded CLs could prevent the proliferation of adriamycin-resistant MCF-7/ADR cell line, highlighting their potential in reversal of drug resistance. Furthermore, the preliminary in vivo test (n = 3) showed that disulfide cross-linked liposomal formulation of Dox (Dox-CLs) improved the therapeutic efficacy compared to free Dox and DLLs in a human breast carcinoma xenograft mouse model. Therefore, the current thiol-responsive cross-linked liposome may provide a robust drug delivery platform for cancer therapy.
脂质体作为癌症治疗药物的递送载体，具有巨大的应用潜力。然而，由于其在血清中的不稳定性和不完全药物释放，其癌症治疗效果受到了一定的限制。在本研究中，开发了一种由二硫键交联的脂质体（CLs）组成的新型纳米载体，该脂质体由二硫键交联的二硫键连接的脂酰乳酸衍生的甘油磷酸胆碱（di-LA-PC）缀合物组装而成。该缀合物通过 LA 和 GPC 的酯化反应合成，并通过 MS、H NMR 和 C NMR 进行了表征。通过体外稳定性和 GSH 响应行为研究发现，该缀合物具有增强的血清稳定性和细胞内药物释放能力。采用干燥薄膜技术制备的 CLs，经 10%二硫苏糖醇（DTT）交联后，可有效递送至抗癌候选物。值得注意的是，CLs 在其囊泡结构中稳定地包封了阿霉素（Dox），并在被癌细胞摄取后表现出显著的对巯基敏感的载药释放，与未交联的脂质体（uCLs）或 Doxil 样脂质体（DLLs）相比。载有 Dox 的 CLs 的细胞活力和凋亡对 MCF-7 细胞表现出明显的细胞毒性作用，其 IC 值为 10.8μg Dox equiv./mL，与游离 Dox 相当，比 DLLs 高 2.8 倍。更重要的是，研究表明，载有 Dox 的 CLs 的纳米尺寸特征可防止阿霉素耐药 MCF-7/ADR 细胞系的增殖，突出了其在逆转耐药方面的潜力。此外，初步的体内试验（n=3）表明，与游离 Dox 和 DLLs 相比，载有 Dox 的二硫键交联脂质体（Dox-CLs）在荷人乳腺癌异种移植小鼠模型中提高了治疗效果。因此，当前的基于巯基响应的交联脂质体可为癌症治疗提供一个强大的药物递送平台。
