Terrence Donnelly Centre for Cellular and Biomolecular Research, Department of Chemical Engineering & Applied Chemistry, Institute of Biomaterials & Biomedical Engineering, University of Toronto, Room 514, 160 College Street, Toronto, ON M5S 3E1, Canada.
Medicinal Chemistry, Ontario Institute for Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
Biomaterials. 2017 Apr;123:39-47. doi: 10.1016/j.biomaterials.2017.01.026. Epub 2017 Jan 26.
We developed a novel taxane-binding peptide (TBP) modified, biodegradable polymeric micelle that overcomes limitations of drug loading and poor serum stability typically seen with particle delivery, leading to enhanced pharmacokinetics and tumor distribution of docetaxel (DTX). The use of the taxane-binding peptide to increase docetaxel loading is particularly compelling as it takes advantage of a known intracellular binding mechanism in a new way. Docetaxel is a potent chemotherapeutic with a therapeutic index often limited by the toxicity of the excipients that are necessary to enhance its solubility for intravenous delivery. Our polymeric micelle has terminal furan groups that enable facile antibody Fab conjugation by Diels-Alder chemistry for targeted delivery. Compared to the conventional ethanolic polysorbate 80 formulation (Free DTX), our nanoparticle (NP DTX) formulation exhibited a two-fold increase in exposure and tumor accumulation. Notably, the reduced toxicity of the NP DTX formulation increased the therapeutic index and allowed for higher dosing regimens, with a maximum tolerated dose (MTD) 1.6-fold higher than that of the Free DTX formulation, which is significant and similar to enhancements observed in clinical products for docetaxel and other drugs. These improved properties led to enhanced mouse survival in an orthotopic model of breast cancer; however, the targeted formulation of Fab-NP DTX did not further improve efficacy. Together, these results clearly demonstrate the benefits of the TBP-modified polymeric micelles as promising carriers for docetaxel.
我们开发了一种新型的紫杉醇结合肽（TBP）修饰的、可生物降解的聚合物胶束，克服了通常与颗粒递送相关的载药能力有限和血清稳定性差的限制，从而增强了多西他赛（DTX）的药代动力学和肿瘤分布。使用 taxane-binding 肽来增加 docetaxel 的载药量特别有吸引力，因为它以新的方式利用了已知的细胞内结合机制。多西他赛是一种有效的化疗药物，其治疗指数通常受到增强其静脉内递送溶解度所需的赋形剂毒性的限制。我们的聚合物胶束具有末端呋喃基团，可通过 Diels-Alder 化学轻松进行抗体 Fab 缀合，实现靶向递送。与传统的乙醇聚山梨醇酯 80 制剂（游离 DTX）相比，我们的纳米颗粒（NP DTX）制剂表现出暴露量和肿瘤积累增加了两倍。值得注意的是，NP DTX 制剂的毒性降低提高了治疗指数，并允许更高的剂量方案，最大耐受剂量（MTD）比游离 DTX 制剂高 1.6 倍，这是显著的，类似于临床产品中观察到的多西他赛和其他药物的增强。这些改善的特性导致在乳腺癌的原位模型中增强了小鼠的存活；然而，Fab-NP DTX 的靶向制剂并没有进一步提高疗效。总之，这些结果清楚地表明，TBP 修饰的聚合物胶束作为多西他赛有前途的载体的好处。
