Reduction-Sensitive Liposomes from a Multifunctional Lipid Conjugate and Natural Phospholipids: Reduction and Release Kinetics and Cellular Uptake
Reduction-Sensitive Liposomes from a Multifunctional Lipid Conjugate and Natural Phospholipids: Reduction and Release Kinetics and Cellular Uptake
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DOI：
10.1021/la201160y
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发表时间：
2011-09-06
期刊：
影响因子：
3.9
通讯作者：
Arbuzova, Anna
中科院分区：
文献类型：
--
作者：
Goldenbogen, Bjoern;Brodersen, Nicolai;Arbuzova, Anna
靶向和可重复递送系统的开发与抗癌疗法高度相关。我们在这里报告的还原敏感的脂质体组成的一种新的多功能lipidlike共轭物，含有二硫键和生物素部分，和天然磷脂。二硫键共轭物的掺入囊泡和动力学的还原进行了研究，使用丹磺酰标记的共轭物1中使用丹磺酰荧光环境灵敏度和福斯特共振能量转移从丹磺酰罗丹明标记的磷脂。二硫键的断裂（例如，通过三（2-羧乙基）膦（TCEP）、二硫苏糖醇（DTT）、L-半胱氨酸或谷胱甘肽（GSH））除去缀合物的亲水性头基，从而改变膜组织，导致捕获分子的释放。当巨噬细胞非特异性摄取囊泡时，由二硫键缀合物和磷脂组成的还原敏感脂质体释放钙黄绿素比仅由磷脂组成的还原不敏感脂质体更有效。链霉亲和素与缀合物的结合不干扰缀合物的二硫键的随后还原或捕获分子的释放。过表达HER 2受体的乳腺癌细胞系BT-474显示出对用生物素标记的抗HER 2抗体功能化的还原敏感的负载阿霉素的脂质体的高摄取。观察到细胞内捕获的货物的释放，这意味着使用我们的系统进行主动靶向和递送的潜力。
The development of targeted and triggerable delivery systems is of high relevance for anticancer therapies. We report here on reduction-sensitive liposomes composed of a novel multifunctional lipidlike conjugate, containing a disulfide bond and a biotin moiety, and natural phospholipids. The incorporation of the disulfide conjugate into vesicles and the kinetics of their reduction were studied using dansyl-labeled conjugate 1 in using the dansyl fluorescence environmental sensitivity and the Forster resonance energy transfer from dansyl to rhodamine-labeled phospholipids. Cleavage of the disulfide bridge (e.g., by tris(2-carboxyethyl)phosphine (TCEP), dithiothreitol (DTT), L-cysteine, or glutathione (GSH)) removed the hydrophilic headgroup of the conjugate and thus changed the membrane organization leading to-the release of entrapped molecules. Upon nonspecific uptake of vesicles by macrophages, calcein release from reduction sensitive liposomes consisting of the disulfide conjugate and phospholipids was more efficient than from reduction insensitive liposomes composed only of phospholipids. The binding of Streptavidin to the conjugates did not interfere with either the subsequent reduction of the disulfide bond of the conjugate or the release of entrapped molecules. Breast cancer cell line BT-474, overexpressing the HER2 receptor, showed a high uptake of the reduction sensitive doxorubicin-loaded liposomes functionalized with the biotin-tagged anti-HER2 antibody. The release of the entrapped cargo inside the cells was observed, implying the potential of using our system for active targeting and delivery.