School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.
Nanomedicine. 2012 Feb;8(2):185-93. doi: 10.1016/j.nano.2011.06.007. Epub 2011 Jun 24.
Novel nanostructured lipid-dextran sulfate hybrid carriers (NLDCs) were successfully developed for sustained delivery of water-soluble cationic mitoxantrone hydrochloride (MTO) and overcoming multidrug resistance. The introduction of negative polymer of dextran sulfate sodium significantly improved the encapsulation efficiency (97.4%) and sustained the release of MTO (86.9% at 72 hours). In vivo pharmacokinetics in rats after intravenous administration demonstrated that MTO-loaded NLDCs (MTO-NLDCs) had higher area under the curve and longer half-life than MTO solution (MTO-Sol). In the biodistribution study, NLDCs significantly improved the MTO levels in plasma, spleen, and brain, and decreased the distribution of MTO in heart and kidney. In comparison with MTO-Sol, MTO-NLDCs efficiently enhanced cytotoxicity through the higher accumulation of MTO in breast cancer resistance protein (BCRP)-overexpressing MCF-7/MX cells. MTO-NLDCs entered into the resistant cancer cells by the clathrin-mediated endocytosis pathway, which escaped the efflux induced by BCRP transporter and thereby overcame the multidrug resistance of MCF-7/MX cells.
In this study, novel nanostructured lipid-dextran sulfate hybrid carriers were synthesized and utilized for sustained delivery of mitoxantrone hydrochloride. The utilized methods successfully addressed multidrug resistance to this chemotherapy agent.
新型纳米结构脂质-硫酸葡聚糖杂化载体（NLDCs）成功开发，用于持续输送水溶性阳离子盐酸米托蒽醌（MTO）和克服多药耐药性。硫酸葡聚糖钠的引入显著提高了包封效率（97.4%），并持续释放 MTO（72 小时时为 86.9%）。大鼠静脉注射后的体内药代动力学研究表明，载有 MTO 的 NLDCs（MTO-NLDCs）比 MTO 溶液（MTO-Sol）具有更高的曲线下面积和更长的半衰期。在生物分布研究中，NLDCs 显著提高了 MTO 在血浆、脾脏和大脑中的水平，并降低了 MTO 在心脏和肾脏中的分布。与 MTO-Sol 相比，MTO-NLDCs 通过增加 BCRP 过表达 MCF-7/MX 细胞中 MTO 的积累，有效地增强了细胞毒性。MTO-NLDCs 通过网格蛋白介导的内吞作用途径进入耐药癌细胞，从而逃避了 BCRP 转运蛋白诱导的外排，从而克服了 MCF-7/MX 细胞的多药耐药性。
在这项研究中，新型纳米结构脂质-硫酸葡聚糖杂化载体被合成并用于持续输送盐酸米托蒽醌。所采用的方法成功解决了这种化疗药物的多药耐药性问题。
