Pharmaceutics Division, CSIR-Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226001, India.
J Antimicrob Chemother. 2012 Nov;67(11):2650-60. doi: 10.1093/jac/dks286. Epub 2012 Aug 7.
The purpose of this study was to explore the applicability, targeting potential and drug delivery to specialized phagocytes via phosphatidylserine (PS)-specific ligand-anchored nanocapsules (NCs) bearing doxorubicin.
The layer-by-layer method was utilized to prepare NCs having a nanoemulsion core loaded with doxorubicin (NCs-DOX), which was further grafted with PS. PS-coated NCs (PS-NCs-DOX) were compared with NCs-DOX for in vitro targeting ability by studying uptake by macrophages, intracellular localization, in vivo pharmacokinetics and organ distribution studies. The in vivo antileishmanial activity of free doxorubicin, NCs-DOX and PS-NCs-DOX was tested against visceral leishmaniasis in Leishmania donovani-infected hamsters.
Flow cytometric data revealed 1.75-fold enhanced uptake of PS-NCs-DOX in J774A.1 macrophage cell lines compared with NCs-DOX. In vivo organ distribution studies in Wistar rats demonstrated a significantly higher extent of accumulation of PS-NCs-DOX compared with NCs-DOX in macrophage-rich organs, particularly in liver and spleen. Highly significant antileishmanial activity (P < 0.05 compared with NCs) was observed with PS-NCs-DOX, causing 85.23% ± 4.49% inhibition of splenic parasitic burden. NCs-DOX and free doxorubicin caused only 72.88% ± 3.87% and 42.85% ± 2.11% parasite inhibition, respectively, in Leishmania-infected hamsters (P < 0.01 for PS-NCs-DOX versus free doxorubicin and NCs-DOX versus free doxorubicin).
We conclude that the PS targeting moiety can provide a new insight for efficient drug delivery to specialized macrophages and thus may be developed for effective use in macrophage-specific delivery systems, especially for leishmaniasis.
本研究旨在探讨通过载有多柔比星的磷脂酰丝氨酸（PS）特异性配体锚定的纳米胶囊（NCs）将药物递送至特化吞噬细胞的适用性、靶向潜力和药物传递。
采用层层法制备载有多柔比星的纳米乳液核心负载的纳米胶囊（NCs-DOX），并进一步接枝 PS。通过研究巨噬细胞摄取、细胞内定位、体内药代动力学和器官分布研究，比较 PS 包被的 NCs（PS-NCs-DOX）与 NCs-DOX 的体外靶向能力。用游离多柔比星、NCs-DOX 和 PS-NCs-DOX 对感染利什曼原虫的仓鼠内脏利什曼病进行体内抗利什曼原虫活性测试。
流式细胞术数据显示，与 NCs-DOX 相比，J774A.1 巨噬细胞系中 PS-NCs-DOX 的摄取增加了 1.75 倍。在 Wistar 大鼠体内器官分布研究中，与 NCs-DOX 相比，PS-NCs-DOX 在富含巨噬细胞的器官，特别是肝脏和脾脏中的积累程度明显更高。与 NCs 相比，PS-NCs-DOX 表现出显著的抗利什曼原虫活性（与 NCs 相比，P<0.05），导致脾脏寄生虫负荷抑制率为 85.23%±4.49%。NCs-DOX 和游离多柔比星分别导致感染利什曼原虫的仓鼠的寄生虫抑制率为 72.88%±3.87%和 42.85%±2.11%（与 PS-NCs-DOX 相比，游离多柔比星和 NCs-DOX 与游离多柔比星相比，P<0.01）。
我们得出结论，PS 靶向部分可为高效递送至特化巨噬细胞的药物提供新的见解，因此可能被开发用于巨噬细胞特异性递药系统，特别是用于利什曼病。
