Department of Pharmaceutical Sciences, College of Pharmacy , University of Michigan , 1600 Huron Parkway, North Campus Research Complex, Building 520 , Ann Arbor , Michigan 48109 , United States.
Translational Development and Clinical Pharmacology , Celgene Corporation , 86 Morris Avenue , Summit , New Jersey 07901 , United States.
Mol Pharm. 2018 Oct 1;15(10):4505-4516. doi: 10.1021/acs.molpharmaceut.8b00527. Epub 2018 Sep 21.
Previous studies have shown that different paclitaxel formulations produce distinct anticancer efficacy and safety profiles in animals and humans. This study aimed to investigate the distinct pharmacokinetics and tissue distribution of various nanoformulations of paclitaxel, which may translate into potential differences in safety and efficacy. Four nanoparticle formulations ( nab-paclitaxel, mouse albumin nab-paclitaxel [m -nab-paclitaxel], micellar paclitaxel, and polymeric nanoparticle paclitaxel) as well as solvent-based paclitaxel were intravenously administered to mice. Seventeen blood and tissue samples were collected at different time points. The total paclitaxel concentration in each tissue specimen was measured with liquid chromatography-tandem mass spectrometry. Compared with solvent-based paclitaxel, all four nanoformulations demonstrated decreased paclitaxel exposure in plasma. All nanoformulations were associated with paclitaxel blood-cell accumulation in mice; however, m- nab-paclitaxel was associated with the lowest accumulation. Five minutes after dosing, the total paclitaxel in the tissues and blood was approximately 44% to 57% of the administered dose of all paclitaxel formulations. Paclitaxel was primarily distributed to liver, muscle, intestine, kidney, skin, and bone. Compared with solvent-based paclitaxel, the different nanocarriers altered the distribution of paclitaxel in all tissues with distinct paclitaxel concentration-time profiles. nab-paclitaxel was associated with increased delivery efficiency of paclitaxel in the pancreas compared with the other formulations, consistent with the demonstrated efficacy of nab-paclitaxel in pancreatic cancer. All the nanoformulations led to high penetration in the lungs and fat pad, which potentially points to efficacy in lung and breast cancers. Micellar paclitaxel and polymeric nanoparticle paclitaxel were associated with high paclitaxel accumulation in the heart; thus, the risk of cardiovascular toxicity with these formulations may warrant further investigation. The solvent-based formulation was associated with the poorest paclitaxel penetration in all tissues and the lowest tissue-to-plasma ratio. The different nanocarriers of paclitaxel were associated with distinct pharmacokinetics and tissue distribution, which largely align with the observed efficacy and toxicity profiles in clinical trials.
先前的研究表明，不同的紫杉醇制剂在动物和人类中产生不同的抗癌疗效和安全性特征。本研究旨在探讨各种紫杉醇纳米制剂的不同药代动力学和组织分布，这可能转化为安全性和疗效的潜在差异。四种纳米制剂（白蛋白结合型紫杉醇、鼠源白蛋白结合型紫杉醇[ m -nab-紫杉醇]、胶束紫杉醇和聚合物纳米粒紫杉醇）和溶剂型紫杉醇被静脉注射到小鼠体内。在不同时间点采集了 17 个血样和组织样本。用液相色谱-串联质谱法测定每个组织标本中的总紫杉醇浓度。与溶剂型紫杉醇相比，所有四种纳米制剂在血浆中的紫杉醇暴露均降低。所有纳米制剂均与小鼠体内的紫杉醇血细胞蓄积有关；然而， m -nab-紫杉醇的蓄积最低。给药后 5 分钟，所有紫杉醇制剂的组织和血液中的总紫杉醇约为给药剂量的 44%至 57%。紫杉醇主要分布于肝脏、肌肉、肠道、肾脏、皮肤和骨骼。与溶剂型紫杉醇相比，不同的纳米载体改变了紫杉醇在所有组织中的分布，具有不同的紫杉醇浓度-时间曲线。与其他制剂相比， nab-紫杉醇与胰腺中紫杉醇的递送效率增加有关，这与 nab-紫杉醇在胰腺癌中的疗效一致。所有纳米制剂均导致肺部和脂肪垫的高穿透性，这可能表明在肺癌和乳腺癌中具有疗效。胶束紫杉醇和聚合物纳米粒紫杉醇与心脏中紫杉醇的高蓄积有关；因此，这些制剂可能存在心血管毒性风险，需要进一步研究。溶剂型制剂与所有组织中紫杉醇的穿透性最差以及组织与血浆的比值最低有关。紫杉醇的不同纳米载体与不同的药代动力学和组织分布有关，这与临床试验中观察到的疗效和毒性特征基本一致。
