Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, Maharashtra, India.
Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India.
Biomaterials. 2015 Jul;57:116-32. doi: 10.1016/j.biomaterials.2015.03.040. Epub 2015 Apr 24.
In the present work, we designed and synthesized a novel mono-guanidine heterolipid (MGH) and confirmed its structure by NMR and ESI-MS. The MGH was used as cationic lipid in developing etoposide loaded cationic self-microemulsifying drug delivery system (ECS) intended to be delivered by intratumoral route. The ECS exhibited size <50 nm and zeta potential +32.6 mV on dilution with various isotonic vehicles with no phase separation or drug precipitation. The ECS could be easily sterilized by membrane filtration method and showed excellent stability for 6 months. The ECS demonstrated excellent in vitro antiproliferative activity against B16F10 cells which is attributed to its high transfection efficiency and capability to cause prolonged drug release in cytosolic space. In vivo antitumor activity of ECS was conducted in B16F10 induced melanoma tumor model. ECS at 12 mg/kg dose showed superior tumor suppression ability and exhibited 100% survival compared to other formulations. Mice treated with ECS by intratumoral route, showed neither systemic side effect nor any evidences of hepatotoxicity and nephrotoxicity. In contrast, etoposide administered by intravenous route showed remarkable systemic toxicity, hepatotoxicity and nephrotoxicity.
在本工作中，我们设计并合成了一种新型的单胍基杂化脂质（MGH），并通过 NMR 和 ESI-MS 确认了其结构。MGH 被用作阳离子脂质，用于开发依托泊苷负载的阳离子自微乳给药系统（ECS），旨在通过瘤内途径给药。ECS 在与各种等渗载体稀释时表现出 <50nm 的粒径和 +32.6mV 的 zeta 电位，没有相分离或药物沉淀。ECS 可以通过膜过滤法轻松进行灭菌，并在 6 个月内表现出优异的稳定性。ECS 对 B16F10 细胞表现出优异的体外增殖抑制活性，这归因于其高转染效率和在细胞质空间中持续释放药物的能力。在 B16F10 诱导的黑色素瘤肿瘤模型中进行了 ECS 的体内抗肿瘤活性研究。在 12mg/kg 剂量下，ECS 表现出优异的肿瘤抑制能力，与其他制剂相比，显示出 100%的存活率。通过瘤内途径给予 ECS 的小鼠既没有表现出全身副作用，也没有肝毒性和肾毒性的迹象。相比之下，通过静脉途径给予依托泊苷表现出明显的全身毒性、肝毒性和肾毒性。
