Pharmaceutics Research Laboratory, Dept. of Pharmaceutical Sciences, Dr. H. S. Gour University, Sagar (MP) 470 003, India.
Eur J Pharm Sci. 2013 Mar 12;48(4-5):668-79. doi: 10.1016/j.ejps.2012.12.027. Epub 2013 Jan 5.
The present investigation was aimed at exploring dual targeting of anti-HIV drug, zidovudine (ZDV) via sialic acid conjugated-mannosylated poly(propyleneimine) (PPI) dendritic nano-constructs. Fourth generation PPI dendrimers, sialic acid conjugated PPI dendrimers (SPPI), mannose conjugated PPI dendrimers (MPPI) and dual ligand system i.e. sialic acid conjugated-mannosylated PPI dendrimers (SMPPI) were synthesized and characterized by FT-IR and (1)H NMR spectroscopies and were further confirmed by size exclusion chromatography and differential scanning calorimetry. Various parameters like drug loading, pH dependent in vitro release, hemolytic toxicity, macrophage uptake and cytotoxicity concerning PPI, SPPI, MPPI and SMPPI dendrimers were evaluated. ZDV loaded SMPPI, SPPI and MPPI have shown reduced hemolytic toxicity, cytotoxicity and in vitro drug release at pH 7.4. Extremely significant (P<0.001) increase in cellular uptake of ZDV by macrophage cells was observed in case of SMPPI as compared to PPI and free drug. The in vivo blood level and tissue distribution studies in albino rats also demonstrated potential of dual targeted system towards sialoadhesin and carbohydrate receptors. The drug concentration in lymph nodes was increased to about 28 times in case of SMPPI (1335 ± 17.6 ng/g) as compared to free drug (48 ± 5.8 ng/g) at 6th hr. The results suggested that such dual ligand dendritic system (SMPPI) hold potential to enhance biocompatibility and site specific delivery of antiretroviral drug, ZDV.
本研究旨在探索通过唾液酸偶联甘露糖化聚（丙烯亚胺）（PPI）树枝状纳米结构实现抗 HIV 药物齐多夫定（ZDV）的双重靶向。第四代 PPI 树枝状大分子、唾液酸偶联 PPI 树枝状大分子（SPPI）、甘露糖化 PPI 树枝状大分子（MPPI）和双配体系统即唾液酸偶联甘露糖化 PPI 树枝状大分子（SMPPI）均通过傅里叶变换红外光谱（FT-IR）和（1）H 核磁共振光谱（NMR）进行了合成和表征，并通过尺寸排阻色谱和差示扫描量热法进一步进行了确认。评估了 PPI、SPPI、MPPI 和 SMPPI 树枝状大分子的载药量、pH 值依赖性体外释放、溶血毒性、巨噬细胞摄取和细胞毒性等各种参数。负载 ZDV 的 SMPPI、SPPI 和 MPPI 在 pH 7.4 时显示出降低的溶血毒性、细胞毒性和体外药物释放。与 PPI 和游离药物相比，SMPPI 显著增加了巨噬细胞对 ZDV 的细胞摄取（P<0.001）。在白化大鼠的体内血液水平和组织分布研究中，也证明了双靶向系统对唾液酸黏附素和碳水化合物受体的潜力。与游离药物（48±5.8ng/g）相比，SMPPI（1335±17.6ng/g）在第 6 小时时淋巴结中的药物浓度增加了约 28 倍。结果表明，这种双配体树枝状系统（SMPPI）具有增强抗逆转录病毒药物齐多夫定（ZDV）的生物相容性和靶向递药的潜力。
