Panyam Jayanth, Labhasetwar Vinod
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA.
Mol Pharm. 2004 Jan 12;1(1):77-84. doi: 10.1021/mp034002c.
Efficient cytoplasmic delivery of therapeutic agents is especially important for drugs with an intracellular site of action for elicitation of a maximal therapeutic effect. In this study, we demonstrate the efficacy of biodegradable nanoparticles for cytoplasmic delivery of dexamethasone, a glucocorticoid, whose site of action is intracellular. Equal doses of two formulations of drug-loaded nanoparticles releasing different doses of the encapsulated drug were tested for antiproliferative activity in vascular smooth muscle cells. The antiproliferative activity of the drug was significantly greater and sustained with nanoparticles that released a higher dose of the drug than with nanoparticles which released a lower dose of the drug. The greater antiproliferative activity of the nanoparticles that released a higher dose of the drug correlated with sustained and higher intracellular drug levels. The antiproliferative activity of the drug in solution was lower and relatively transient compared to that with drug-loaded nanoparticles. The mechanism of inhibition of cell proliferation was mediated through inhibition of cell-cycle progression with a relatively higher percentage of cells in the G0/G1 arrest phase in the group that was treated with drug-loaded nanoparticles compared to that treated with the drug in solution. Results of the study thus suggest that the dose and duration of a drug's availability at the intracellular site of action determine its therapeutic efficacy. In conclusion, biodegradable nanoparticles could be used as an effective delivery mechanism for sustained intracellular delivery of different therapeutic agents.
对于作用位点在细胞内的药物，为了发挥最大治疗效果，将治疗剂高效递送至细胞质尤为重要。在本研究中，我们证明了可生物降解纳米颗粒用于将地塞米松（一种糖皮质激素，其作用位点在细胞内）递送至细胞质的有效性。测试了两种载药纳米颗粒制剂，它们释放不同剂量的包封药物，将等剂量的这两种制剂用于检测对血管平滑肌细胞的抗增殖活性。与释放较低剂量药物的纳米颗粒相比，释放较高剂量药物的纳米颗粒的药物抗增殖活性显著更高且持续时间更长。释放较高剂量药物的纳米颗粒具有更强的抗增殖活性，这与细胞内持续且更高的药物水平相关。与载药纳米颗粒相比，溶液中药物的抗增殖活性较低且相对短暂。抑制细胞增殖的机制是通过抑制细胞周期进程介导的，与用溶液中的药物处理的组相比，用载药纳米颗粒处理的组中处于G0/G1期停滞的细胞百分比相对更高。因此，该研究结果表明，药物在细胞内作用位点的可用剂量和持续时间决定了其治疗效果。总之，可生物降解纳米颗粒可作为一种有效的递送机制，用于不同治疗剂在细胞内的持续递送。
