Drug Transport and Delivery Research Group, Department of Pharmacy, University of Tromsø , Tromsø , Norway.
J Liposome Res. 2013 Dec;23(4):298-310. doi: 10.3109/08982104.2013.805338. Epub 2013 Jun 13.
Improving tumor delivery of lipophilic drugs through identifying advanced drug carrier systems with efficient carrier potency is of high importance. We have performed an investigative approach to identify parameters that affect liposomes' ability to effectively deliver lipophilic camptothecin (CPT) to target cells. CPT is a potent anticancer drug, but its undesired physiological properties are impairing its therapeutic use. In this study, we have identified parameters influencing incorporation and retention of lipophilic CPT in liposomes, evaluating the effect of lipid composition, lipid chemical structure (head and tail group variations, polymer inclusion), zeta potential and anisotropy. Polyethyleneglycol (PEG) surface decoration was included to avoid liposome fusing and increase the potential for prolonged in vivo circulation time. The in vitro effect of the different carrier formulations on cell cytotoxicity was compared and the effect of active targeting of one of the formulations was evaluated. We found that a combination of liposome surface charge, lipid headgroup and carbon chain unsaturation affect CPT incorporation. Retention in liposomes was highly dependent on the liposomal surroundings and liposome zeta potential. Inclusion of lipid tethered PEG provided stability and prevented liposome fusing. PEGylation negatively affected CPT incorporation while improving retention. In vitro cell culture testing demonstrated that all formulations increased CPT potency compared to free CPT, while cationic formulations proved significantly more toxic to cancer cells that healthy cells. Finally, antibody mediated targeting of one liposome formulation further enhanced the selectivity towards targeted cancer cells, rendering normal cells fully viable after 1 hour exposure to targeted liposomes.
提高亲脂性药物向肿瘤的传递效率，通过鉴定具有高效载体效力的先进药物载体系统非常重要。我们采用了一种研究方法来确定影响脂质体有效将亲脂性喜树碱（CPT）递送至靶细胞的能力的参数。CPT 是一种有效的抗癌药物，但它不理想的生理特性使其治疗用途受到限制。在这项研究中，我们确定了影响亲脂性 CPT 掺入和保留在脂质体中的参数，评估了脂质组成、脂质化学结构（头基和尾基变化、聚合物包含）、zeta 电位和各向异性的影响。聚乙二醇（PEG）表面修饰被包括在内，以避免脂质体融合并增加延长体内循环时间的潜力。比较了不同载体配方对细胞细胞毒性的体外影响，并评估了其中一种配方的主动靶向效果。我们发现，脂质体表面电荷、脂质头基和碳链不饱和性的组合影响 CPT 的掺入。脂质体中保留率高度依赖于脂质体环境和脂质体 zeta 电位。连接脂质的 PEG 的包含提供了稳定性并防止脂质体融合。PEG 化对 CPT 掺入有负面影响，但对保留有积极影响。体外细胞培养测试表明，与游离 CPT 相比，所有配方均增加了 CPT 的效力，而阳离子配方对癌细胞的毒性明显高于健康细胞。最后，一种脂质体配方的抗体介导靶向进一步增强了对靶癌细胞的选择性，使靶向脂质体暴露 1 小时后，正常细胞完全存活。
