Cytotoxic and antiangiogenic paclitaxel solubilized and permeation-enhanced by natural product nanoparticles.
Cytotoxic and antiangiogenic paclitaxel solubilized and permeation-enhanced by natural product nanoparticles.
复制标题
DOI：
10.1097/cad.0000000000000173
复制
发表时间：
2015-02
影响因子：
2.3
通讯作者：
Stout RW
中科院分区：
文献类型：
--
作者：
Liu Z;Zhang F;Koh GY;Dong X;Hollingsworth J;Zhang J;Russo PS;Yang P;Stout RW
紫杉醇（PTX）是迄今为止最有效的静脉化疗药物之一，但由于其溶解度和渗透性低，口服制剂一直存在问题。利用最近发现的鲁布苏苷（RUB）的增溶特性，我们研究了这种独特的PTX-RUB配方。用RUB将紫杉醇溶于水中，浓度为1.6 ~ 6.3 mg/mL，重量/体积比例为10 ~ 40%。这些纳米胶束PTX-RUB配合物被干燥成粉末，随后在生理溶液中重组。在胃液中2.5小时后，85%至99%的PTX-RUB仍可溶解，而在肠液中仍可溶解79至96%。PTX与RUB之间形成了平均直径为6.6 nm的水溶性球形纳米胶束，实现了PTX的增溶。与Taxol®相比，PTX-RUB纳米颗粒在Caco-2细胞单培养中的渗透性提高了近4倍。在与dmso溶解PTX的对比中，PTX- rub对三种人类癌细胞保持相同水平的细胞毒性，IC50值在4 nM至20 nM之间。此外，在低至5 nM的浓度下，huvec的管状形成和迁移受到抑制。PTX-RUB纳米颗粒所证明的这些化学和生物学特性可能会提高口服生物利用度，并使进一步的药代动力学、毒理学和功效研究成为可能。
Paclitaxel (PTX) is one of the most potent intravenous chemotherapeutic agents to date, yet an oral formulation has been problematic due to its low solubility and permeability. Using the recently discovered solubilizing properties of rubusoside (RUB), we investigated this unique PTX-RUB formulation. Paclitaxel was solubilized by RUB in water to levels of 1.6 to 6.3 mg/mL at 10 to 40% weight/volume. These, nanomicellar, PTX-RUB complexes were dried to a powder which was subsequently reconstituted in physiologic solutions. After 2.5 hrs in gastric fluid 85 to 99% of PTX-RUB remained soluble, while 79 to 96% remained soluble in intestinal fluid. The solubilization of PTX was mechanized by the formation of water-soluble spherical nanomicelles between PTX and RUB with an average diameter of 6.6 nm. Compared with Taxol®, PTX-RUB nanoparticles were nearly four times more permeable in Caco-2 cell monocultures. In a side-by-side comparison with DMSO-solubilized PTX, PTX-RUB maintained the same level of cytotoxicity against three human cancer cell lines with IC50 values ranging from 4 nM to 20 nM. Additionally, tubular formation and migration of HUVECs were inhibited at levels as low as 5 nM. These chemical and biological properties demonstrated by the PTX-RUB nanoparticles may improve oral bioavailability and enable further pharmacokinetic, toxicologic, and efficacy investigations.