Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Nanjing, People's Republic of China.
Int J Nanomedicine. 2013;8:641-52. doi: 10.2147/IJN.S38203. Epub 2013 Feb 12.
20(S)-protopanaxadiol (PPD), similar to several other anticancer agents, has low oral absorption and is extensively metabolized. These factors limit the use of PPD for treatment of human diseases.
In this study, we used cubic nanoparticles containing piperine to improve the oral bioavailability of PPD and to enhance its absorption and inhibit its metabolism. Cubic nanoparticles loaded with PPD and piperine were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel and verified using transmission electron microscopy and differential scanning calorimetry. We evaluated the in vitro release of PPD from these nanoparticles and its absorption across the Caco-2 cell monolayer model, and subsequently, we examined the bioavailability and metabolism of PPD and its nanoparticles in vivo.
The in vitro release of PPD from these nanoparticles was less than 5% at 12 hours. PPD-cubosome and PPD-cubosome loaded with piperine (molar ratio PPD/piperine, 1:3) increased the apical to basolateral permeability values of PPD across the Caco-2 cell monolayer from 53% to 64%, respectively. In addition, the results of a pharmacokinetic study in rats showed that the relative bioavailabilities of PPD-cubosome [area under concentration-time curve (AUC)(0-∞)] and PPD-cubosome containing piperine (AUC(0-∞)) compared to that of raw PPD (AUC(0-∞)) were 166% and 248%, respectively.
The increased bioavailability of PPD-cubosome loaded with piperine is due to an increase in absorption and inhibition of metabolism of PPD by cubic nanoparticles containing piperine rather than because of improved release of PPD. The cubic nanoparticles containing piperine may be a promising oral carrier for anticancer drugs with poor oral absorption and that undergo extensive metabolism by cytochrome P450.
20(S)-原人参二醇（PPD）与其他几种抗癌剂类似，口服吸收低且广泛代谢。这些因素限制了 PPD 在人类疾病治疗中的应用。
在这项研究中，我们使用含有胡椒碱的立方纳米粒子来提高 PPD 的口服生物利用度，并增强其吸收和抑制其代谢。载有 PPD 和胡椒碱的立方纳米粒子是通过甘油单油酸酯（GMO）/泊洛沙姆 407 块状立方凝胶的碎裂制备的，并通过透射电子显微镜和差示扫描量热法进行了验证。我们评估了这些纳米粒子中 PPD 的体外释放及其在 Caco-2 细胞单层模型中的吸收，随后，我们在体内研究了 PPD 及其纳米粒子的生物利用度和代谢。
这些纳米粒子中 PPD 的体外释放在 12 小时内小于 5%。PPD-立方纳米囊和载有胡椒碱的 PPD-立方纳米囊（PPD/胡椒碱摩尔比为 1:3）分别将 PPD 通过 Caco-2 细胞单层的顶侧到基底侧渗透率值从 53%增加到 64%。此外，大鼠药代动力学研究的结果表明，与 PPD 原药相比，PPD-立方纳米囊[浓度-时间曲线下面积（AUC）（0-∞）]和载有胡椒碱的 PPD-立方纳米囊（AUC（0-∞））的相对生物利用度分别为 166%和 248%。
载有胡椒碱的 PPD-立方纳米囊的生物利用度增加是由于立方纳米囊载有胡椒碱增加了 PPD 的吸收并抑制了其代谢，而不是由于 PPD 的释放得到改善。载有胡椒碱的立方纳米囊可能是一种有前途的口服载体，可用于口服吸收差且经细胞色素 P450 广泛代谢的抗癌药物。
