Reddy Lakkireddy Harivardhan, Adhikari Jawahar Singh, Dwarakanath Bilikere Srinirasa Rao, Sharma Rakesh Kumar, Murthy Rayasa Ramachandra
Drug Delivery Research Laboratory, Center of Relevance and Excellence in NDDS, Pharmacy Department, G. H. Patel Building, Donor's Plaza, M. S. University, Fatehgunj, Baroda-390002, Gujarat, India.
AAPS J. 2006 Apr 14;8(2):E254-62. doi: 10.1007/BF02854895.
The tumoricidal effects of etoposide incorporated into lipid nanoparticles after single-dose administration were investigated in Dalton's lymphoma ascites bearing mice. Etoposide and its nanoparticle formulations were administered intraperitoneally, and the cell cycle perturbation, cytogenetic damage, cell death (apoptosis), tumor regression, and animal survival were investigated as parameters of response with time. The tumor burden of mice treated with etoposide and its nanoparticle formulations decreased significantly (P < .001) compared with the initial up to 4 to 6 days, followed by an increase at later time intervals. Of the 3 different formulations, the survival time of mice was higher when treated with etoposide-loaded tripalmitin (ETP) nanoparticles, followed by etoposide-loaded glycerol monostearate (EGMS) (27.3%) and etoposide-loaded glycerol distearate (EGDS) (27.3%) compared with free etoposide. Cell cycle analysis revealed the hypodiploid peak (sub G0/G1 cell population) as well as G2 arrest in mice treated with etoposide and its nanoparticle formulations. The frequency of dead cells treated with the nanoparticle formulations remained high even after 8 days of treatment compared with free etoposide. The mice treated with nanoparticle formulations exhibited hypodiploid peaks and reduced S phase even 8 days after treatment, whereas the free etoposide-treated mice showed decrease in apoptosis after 3 days of treatment. The apoptotic frequency in cells 17 days after treatment was in the order of ETP > EGMS > EGDS > etoposide. The experimental results indicated that among the 3 nanoparticle formulations studied, the ETP nanoparticles showed greater and prolonged apoptotic induction properties, resulting in the higher increase in survival time of tumor bearing mice.
在荷Dalton淋巴瘤腹水的小鼠中研究了单剂量给药后依托泊苷掺入脂质纳米颗粒的杀瘤作用。依托泊苷及其纳米颗粒制剂通过腹腔注射给药，并研究细胞周期扰动、细胞遗传损伤、细胞死亡（凋亡）、肿瘤消退和动物存活情况，作为随时间变化的反应参数。与初始状态相比，接受依托泊苷及其纳米颗粒制剂治疗的小鼠肿瘤负荷在4至6天内显著降低（P <.001），随后在后期时间间隔有所增加。在3种不同制剂中，与游离依托泊苷相比，用载有依托泊苷的三棕榈酸甘油酯（ETP）纳米颗粒治疗的小鼠存活时间更长，其次是载有依托泊苷的单硬脂酸甘油酯（EGMS）（27.3%）和载有依托泊苷的二硬脂酸甘油酯（EGDS）（27.3%）。细胞周期分析显示，接受依托泊苷及其纳米颗粒制剂治疗的小鼠出现亚二倍体峰（亚G0/G1细胞群体）以及G2期阻滞。与游离依托泊苷相比，纳米颗粒制剂处理的死细胞频率即使在治疗8天后仍保持较高水平。用纳米颗粒制剂处理的小鼠即使在治疗8天后仍表现出亚二倍体峰且S期减少，而游离依托泊苷处理的小鼠在治疗3天后凋亡减少。治疗17天后细胞中的凋亡频率顺序为ETP > EGMS > EGDS >依托泊苷。实验结果表明，在所研究的3种纳米颗粒制剂中，ETP纳米颗粒表现出更强且持续时间更长的凋亡诱导特性，导致荷瘤小鼠存活时间有更高的增加。
