Biomedical Engineering Center, College of Chemistry and Chemical Engineering, and State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China.
Bioconjug Chem. 2009 Dec;20(12):2214-21. doi: 10.1021/bc8003809.
We have synthesized a series of novel prodrugs consisting of amphiphilic heparin-paclitaxel conjugates. Each prodrug in the series consists of a succinylated-heparin carrier conjugated to paclitaxel via a single amino acid spacer, either valine, leucine, or phenylalanine (prodrug1, prodrug2, and prodrug3, respectively). Unlike physically encapsulated drugs, these prodrugs can self-assemble to form nanoparticles in aqueous solution while still maintaining structural integrity for loading parent drug due to the dual hydrophilic/hydrophobic nature of the carrier and drug compound. The structure of prodrugs has been characterized by 1H NMR, FT-IR, and GPC. Their morphology has been investigated by SEM. Our results show that these self-assembled nanoparticles have a narrow size distribution (140-180 nm) and form an approximately spherical shape composed of a paclitaxel core and carrier shell. The anticoagulant activity of all the prodrugs is sharply decreased compared to that of heparin, as measured by activated partial thromboplastin time (aPTT), thereby reducing the risk of severe hemorrhagic complication during systemic administration. Furthermore, the prodrugs exhibit better in vitro cell inhibition for MCF-7 cells than free paclitaxel. Flow cytometric analyses (FCM) have shown that MCF-7 cells treated with prodrugs are arrested in the G(2)/M phase of the cell cycle. Meanwhile, these three prodrugs each exhibit unique hydrolysis properties under various physiological or plasma conditions. In particular, prodrug2 with leucine spacer may result in favorable hydrolysis of the ester bond between the amino acid and paclitaxel under physiological conditions. In mice, prodrug2 shows a similar ovarian tumor growth inhibition as paclitaxel and induces no obvious body weight loss. Hence, the prepared nanoscale prodrugs are expected not only to render structural integrity to the parent drug, but also enhance targeting capacity to solid tumors.
我们合成了一系列新型前药，这些前药由两亲性肝素-紫杉醇缀合物组成。该系列中的每个前药均由通过单个氨基酸间隔物（缬氨酸、亮氨酸或苯丙氨酸）连接的琥珀酰肝素载体与紫杉醇缀合而成（分别为前药 1、前药 2 和前药 3）。与物理包封的药物不同，这些前药可以在水溶液中自组装形成纳米颗粒，同时由于载体和药物化合物的双重亲水性/疏水性，仍然保持载药的结构完整性。前药的结构已通过 1H NMR、FT-IR 和 GPC 进行了表征。通过 SEM 研究了它们的形态。我们的结果表明，这些自组装的纳米颗粒具有较窄的粒径分布（140-180nm），并形成由紫杉醇核和载体壳组成的近似球形。与肝素相比，所有前药的抗凝血活性均明显降低，这是通过活化部分凝血活酶时间（aPTT）测量的，从而降低了全身给药时严重出血并发症的风险。此外，与游离紫杉醇相比，前药在体外对 MCF-7 细胞的抑制作用更好。流式细胞术分析（FCM）表明，用前药处理的 MCF-7 细胞被阻滞在细胞周期的 G2/M 期。同时，这三种前药在各种生理或血浆条件下均表现出独特的水解特性。特别是，具有亮氨酸间隔物的前药 2 可能导致在生理条件下氨基酸和紫杉醇之间的酯键发生有利的水解。在小鼠中，前药 2 表现出与紫杉醇相似的卵巢肿瘤生长抑制作用，并且不会引起明显的体重减轻。因此，所制备的纳米级前药不仅有望赋予母体药物结构完整性，而且还增强了对实体瘤的靶向能力。
