Université Paris-Sud , Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry cedex, France.
Bioconjug Chem. 2013 Nov 20;24(11):1840-9. doi: 10.1021/bc400210x. Epub 2013 Oct 17.
A new paclitaxel (Ptx) prodrug was designed by coupling a single terpene unit (MIP) to the hydroxyl group in position 2' of the drug molecule. Using a squalene derivative of polyethylene glycol (SQ-PEG) as surface active agent, the resulting bioconjugate (PtxMIP) self-assembled in water leading to the formation of stable nanoparticles (PtxMIP_SQ-PEG NPs) with an impressively high drug loading (82%). In vivo, the anticancer activity of this novel Ptx nanoassembled prodrug was compared to the conventional Cremophor-containing formulation (Taxol) on a murine model of breast cancer lung metastasis induced by intravenous injection of 4T1 tumor cells, genetically modified to stably express firefly luciferase. Cell growth was assessed noninvasively by bioluminescence imaging (BLI) which enabled monitoring tumor metastatic burden in the same animals. PtxMIP_SQ-PEG nanoparticles slowed metastatic spread and were better tolerated than the Cremophor-containing formulation (i.e., free drug), thus demonstrating the potential of terpene-based nanoassembled prodrugs in the improvement of the therapeutic index of Ptx in balb/c mice.
设计了一种新型紫杉醇（Ptx）前药，通过将单萜单元（MIP）与药物分子 2'位的羟基连接来实现。使用聚乙二醇的角鲨烯衍生物（SQ-PEG）作为表面活性剂，所得生物缀合物（PtxMIP）在水中自组装，形成具有令人印象深刻的高载药量（82%）的稳定纳米颗粒（PtxMIP_SQ-PEG NPs）。在体内，通过静脉注射经基因修饰稳定表达萤火虫荧光素酶的 4T1 肿瘤细胞诱导的乳腺癌肺转移的小鼠模型，将这种新型 Ptx 纳米组装前药的抗癌活性与含有 Cremophor 的常规制剂（Taxol）进行了比较。通过生物发光成像（BLI）进行非侵入性细胞生长评估，从而能够在同一动物中监测肿瘤转移负担。PtxMIP_SQ-PEG 纳米颗粒减缓了转移扩散，并且比含有 Cremophor 的制剂（即游离药物）更耐受，因此证明了基于萜类的纳米组装前药在提高 Ptx 在 Balb/c 小鼠中的治疗指数方面的潜力。
