Oh Y K, Nix D E, Straubinger R M
Department of Pharmaceutics, University at Buffalo, State University of New York, Amherst 14260-1200, USA.
Antimicrob Agents Chemother. 1995 Sep;39(9):2104-11. doi: 10.1128/AAC.39.9.2104.
Mycobacterium avium is an intracellular pathogen that can invade and multiply within macrophages of the reticuloendothelial system. Current therapy is not highly effective. Particulate drug carriers that are targeted to the reticuloendothelial system may provide a means to deliver antibiotics more efficiently to M. avium-infected cells. We investigated the formulation of the antibiotics ciprofloxacin and azithromycin in liposomes and tested their antibacterial activities in vitro against M. avium residing within J774, a murine macrophage-like cell line. A conventional passive-entrapment method yielded an encapsulation efficiency of 9% for ciprofloxacin and because of aggregation mediated by the cationic drug, was useful only with liposomes containing < or = 50 mol% negatively charged phospholipid. In contrast, ciprofloxacin was encapsulated with > 90% efficiency, regardless of the content of negatively charged lipids, by a remote-loading technique that utilized both pH and potential gradients to drive drug into preformed liposomes. Both the cellular accumulation and the antimycobacterial activity of ciprofloxacin increased in proportion to the liposome negative charge; the maximal enhancement of potency was 43-fold in liposomes of distearoylphosphatidylglycerol-cholesterol (DSPG-Chol) (10:5). Azithromycin liposomes were prepared as a freeze-dried preparation to avoid chemical instability during storage, and drug could be incorporated at 33 mol% (with respect to phospholipid). Azithromycin also showed enhanced antimycobacterial effect in liposomes, and the potency increased in parallel to the moles percent of negatively charged lipids; azithromycin in DSPG-Chol (10:5) liposomes inhibited intracellular M. avium growth 41-fold more effectively than did free azithromycin. Thus, ciprofloxacin or azithromycin encapsulated in stable liposomes having substantial negative surface charge is superior to nonencapsulated drug in inhibition of M.avium growth within cultured macrophages and may provide more effective therapy of M.avium infections.
鸟分枝杆菌是一种细胞内病原体，可在网状内皮系统的巨噬细胞内侵袭和繁殖。目前的治疗方法效果不佳。靶向网状内皮系统的微粒药物载体可能提供一种更有效地将抗生素递送至鸟分枝杆菌感染细胞的方法。我们研究了环丙沙星和阿奇霉素在脂质体中的制剂，并在体外测试了它们对存在于鼠巨噬细胞样细胞系J774内的鸟分枝杆菌的抗菌活性。传统的被动包封方法对环丙沙星的包封效率为9%，并且由于阳离子药物介导的聚集作用，仅对含有≤50 mol%带负电荷磷脂的脂质体有用。相比之下，通过利用pH和电位梯度将药物驱动到预先形成的脂质体中的远程加载技术，无论带负电荷脂质的含量如何，环丙沙星的包封效率均>90%。环丙沙星的细胞摄取和抗分枝杆菌活性均与脂质体的负电荷成比例增加；在二硬脂酰磷脂酰甘油-胆固醇（DSPG-Chol）（10:5）脂质体中，效力的最大增强为43倍。阿奇霉素脂质体制备成冻干制剂以避免储存期间的化学不稳定性，并且药物可以以33 mol%（相对于磷脂）掺入。阿奇霉素在脂质体中也显示出增强的抗分枝杆菌作用，并且效力与带负电荷脂质的摩尔百分比平行增加；DSPG-Chol（10:5）脂质体中的阿奇霉素抑制细胞内鸟分枝杆菌生长的效果比游离阿奇霉素有效41倍。因此，封装在具有大量负表面电荷的稳定脂质体中的环丙沙星或阿奇霉素在抑制培养巨噬细胞内鸟分枝杆菌生长方面优于未封装的药物，并且可能提供更有效的鸟分枝杆菌感染治疗方法。
