Affram Kevin, Udofot Ofonime, Singh Mandip, Krishnan Sunil, Reams Renee, Rosenberg Jens, Agyare Edward
College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida, United States of America.
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2017 Sep 21;12(9):e0185116. doi: 10.1371/journal.pone.0185116. eCollection 2017.
In numerous studies, liposomes have been used to deliver anticancer drugs such as doxorubicin to local heat-triggered tumor. Here, we investigate: (i) the ability of thermosensitive liposomal nanoparticle (TSLnp) as a delivery system to deliver poorly membrane-permeable anticancer drug, gemcitabine (Gem) to solid pancreatic tumor with the aid of local mild hyperthermia and, (ii) the possibility of using gadolinium (Magnevist®) loaded-TSLnps (Gd-TSLnps) to increase magnetic resonance imaging (MRI) contrast in solid tumor. In this study, we developed and tested gemcitabine-loaded thermosensitive liposomal nanoparticles (Gem-TSLnps) and gadolinium-loaded thermosensitive liposomal nanoparticles (Gd-TSLnps) both in in-vitro and in-vivo. The TSLnps exhibited temperature-dependent release of Gem, at 40-42°C, 65% of Gem was released within 10 min, whereas < 23% Gem leakage occurred at 37°C after a period of 2 h. The pharmacokinetic parameters and tissue distribution of both Gem-TSLnps and Gd-TSLnps were significantly greater compared with free Gem and Gd, while Gem-TSLnps plasma clearance was reduced by 17-fold and that of Gd-TSLpns was decreased by 2-fold. Area under the plasma concentration time curve (AUC) of Gem-TSLnps (35.17± 0.04 μghr/mL) was significantly higher than that of free Gem (2.09 ± 0.01 μghr/mL) whereas, AUC of Gd-TSLnps was higher than free Gd by 3.9 fold high. TSLnps showed significant Gem accumulation in heated tumor relative to free Gem. Similar trend of increased Gd-TSLnps accumulation was observed in non-heated tumor compared to that of free Gd; however, no significant difference in MRI contrast enhancement between free Gd and Gd-TSLnps ex-vivo tumor images was observed. Despite Gem-TSLnps dose being half of free Gem dose, antitumor efficacy of Gem-TSLnps was comparable to that of free Gem(Gem-TSLnps 10 mg Gem/kg compared with free Gem 20 mg/kg). Overall, the findings suggest that TSLnps may be used to improve Gem delivery and enhance its antitumor activity. However, the formulation of Gd-TSLnp needs to be fully optimized to significantly enhance MRI contrast in tumor.
在众多研究中，脂质体已被用于将阿霉素等抗癌药物递送至局部热触发肿瘤。在此，我们研究：（i）热敏脂质体纳米颗粒（TSLnp）作为一种递送系统，借助局部轻度热疗将膜通透性差的抗癌药物吉西他滨（Gem）递送至实体胰腺肿瘤的能力，以及（ii）使用负载钆（马根维显®）的TSLnp（Gd-TSLnp）来增加实体肿瘤磁共振成像（MRI）对比度的可能性。在本研究中，我们在体外和体内开发并测试了负载吉西他滨的热敏脂质体纳米颗粒（Gem-TSLnp）和负载钆的热敏脂质体纳米颗粒（Gd-TSLnp）。TSLnp表现出Gem的温度依赖性释放，在40-42°C时，10分钟内65%的Gem被释放，而在37°C下2小时后Gem泄漏率<23%。与游离Gem和Gd相比，Gem-TSLnp和Gd-TSLnp的药代动力学参数和组织分布均显著更高，而Gem-TSLnp的血浆清除率降低了17倍，Gd-TSLnp的血浆清除率降低了2倍。Gem-TSLnp的血浆浓度时间曲线下面积（AUC）（35.17±0.04μghr/mL）显著高于游离Gem（2.09±0.01μghr/mL），而Gd-TSLnp的AUC比游离Gd高3.9倍。相对于游离Gem，TSLnp在加热的肿瘤中显示出显著的Gem积累。与游离Gd相比，在未加热的肿瘤中观察到Gd-TSLnp积累增加的类似趋势；然而，在体外肿瘤图像中，游离Gd和Gd-TSLnp之间的MRI对比度增强没有显著差异。尽管Gem-TSLnp的剂量是游离Gem剂量的一半，但Gem-TSLnp的抗肿瘤疗效与游离Gem相当（Gem-TSLnp为10mg Gem/kg，游离Gem为20mg/kg）。总体而言，研究结果表明TSLnp可用于改善Gem递送并增强其抗肿瘤活性。然而，Gd-TSLnp的制剂需要充分优化，以显著增强肿瘤中的MRI对比度。
