Xu Yanyun, Meng Haijing, Du Fang, Lu Wei, Liu Shiyuan, Huang Jin, Yu Jiahui
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China; Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw 01-224, Poland.
Int J Pharm. 2015 Nov 30;495(2):792-7. doi: 10.1016/j.ijpharm.2015.09.030. Epub 2015 Sep 26.
Our recent publication showed that VES-dFdC nanocapsules in pure water could be obtained via the self-assembling of VES-dFdC prodrug synthesized by coupling gemcitabine (dFdC) with vitamin E succinate (VES). To prepare the intravenous injection nanoformulation, we present here a novel strategy to improve the stability and drug concentration of VES-dFdC nanoformulation in PBS or isotonic solution. Particularly, D-α-tocopheryl polyethylene glycol succinate (TPGS), usually used as drug solubilizer and coincidentally contains the same VES moiety as VES-dFdC prodrug and PEG chain, is selected to co-assemble with VES-dFdC prodrug. The zeta potentials of all the TPGS/VES-dFdC co-assemblies were close to 0 mV, and their particle size measured by dynamic light scattering (DLS) decreased from 113 to 36 nm with increasing TPGS/VES-dFdC molar ratios from 0.15 to 1.5. Stable colloidal suspensions were obtained without aggregates in PBS at 4 °C in one month or isotonic solution at 37 °C in one week, and the weight concentration of VES-dFdC prodrug increased from 7 to 17 mg/mL when the molar ratios of TPGS/VES-dFdC ranged from 0.5/1 to 1.5/1. The concentration of VES-dFdC prodrug was high enough to be used as intravenous injection nanoformulation in nude mice. Interestingly, along with the increase of TPGS/VES-dFdC molar ratios from 0.3/1 to 1.5/1, the morphology of TPGS/VES-dFdC co-assemblies changed from loose nanocapsule to compact micelle revealed by transmission electron microscope (TEM). Finally, the co-assembly of TPGS/VES-dFdC (TPGS/VES-dFdC: 1/1) was selected as intravenous injection nanoformulation to evaluate the antitumor activity. Compared with native dFdC, TPGS/VES-dFdC nanoformulation with 0.2mmol/kg of dosage showed similar low toxicity in vivo, but 4.7 times high of tumor inhibition rate in nude mice with pre-established BxPC-3 tumors.
我们最近的研究表明，通过将吉西他滨（dFdC）与维生素E琥珀酸酯（VES）偶联合成的VES-dFdC前药自组装，可以得到纯水中的VES-dFdC纳米胶囊。为了制备静脉注射纳米制剂，我们在此提出一种新策略，以提高VES-dFdC纳米制剂在磷酸盐缓冲液（PBS）或等渗溶液中的稳定性和药物浓度。特别地，通常用作药物增溶剂且巧合地含有与VES-dFdC前药相同的VES部分和聚乙二醇（PEG）链的D-α-生育酚聚乙二醇琥珀酸酯（TPGS），被选择与VES-dFdC前药共同组装。所有TPGS/VES-dFdC共组装体的zeta电位均接近0 mV，并且随着TPGS/VES-dFdC摩尔比从0.15增加到1.5，通过动态光散射（DLS）测量的它们的粒径从113 nm减小到36 nm。在4℃下于PBS中一个月或在37℃下于等渗溶液中一周内均获得了无聚集体的稳定胶体悬浮液，并且当TPGS/VES-dFdC的摩尔比范围为0.5/1至1.5/1时，VES-dFdC前药的重量浓度从7 mg/mL增加到17 mg/mL。VES-dFdC前药的浓度足够高，可用于裸鼠的静脉注射纳米制剂。有趣的是，随着TPGS/VES-dFdC摩尔比从0.3/1增加到1.5/1，透射电子显微镜（TEM）显示TPGS/VES-dFdC共组装体的形态从松散的纳米胶囊变为致密的胶束。最后，选择TPGS/VES-dFdC（TPGS/VES-dFdC：1/1）的共组装体作为静脉注射纳米制剂来评估其抗肿瘤活性。与天然dFdC相比，剂量为0.2mmol/kg的TPGS/VES-dFdC纳米制剂在体内显示出相似的低毒性，但在预先建立BxPC-3肿瘤的裸鼠中具有高4.7倍的肿瘤抑制率。
