Yu Na, Li Jun, Zhang Yuan, Ding Dan, Li Xiaolin, Xu Huae
Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University Nanjing 210029 China
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials Ministry of Education and College of Life Sciences Nankai University Tianjin 300071 China.
RSC Adv. 2020 Mar 31;10(22):12999-13005. doi: 10.1039/d0ra01117g. eCollection 2020 Mar 30.
Paclitaxel (Ptx), a microtubule depolymerization inhibitor, is one of the first-line regimens in lung cancer chemotherapy. However, the poor solubility of Ptx, as well as hypersensitivity of the solvent Cremphor EL, severely limits its clinical application. Here we developed a drug-polymer conjugate of Ptx-SA-PEG, in which amphiphilic copolymers poly(ethylene glycol) (PEG) and Ptx were conjugated by succinic acid (SA). The Ptx-SA-PEG polymers self-assemble into nanoparticles (Ptx-NPs) for efficient delivery of Ptx; cell count kit-8 assay and clonogenic assay were used to analyze the antitumor effect of Ptx-NPs. Acridine orange/ethidium bromide double staining, apoptosis analysis and western blot were measured to explore the apoptotic cell death after Ptx-NPs or free Ptx treatment. Subcutaneous xenograft models were practiced to estimate its tumor cytotoxicity and nonspecific side effects . Immunohistochemistry was used to analyze the effects of apoptosis and proliferation in tumor tissue; studies demonstrated that Ptx-NPs treatment exhibited more tumor inhibitory activity compared with free Ptx, especially at the lower doses. Moreover, Ptx-NPs activated apoptotic proteins. Animal experiments showed Ptx-NPs induced less weight loss and organ damage than free Ptx. Moreover, tumor growth was slower after Ptx-NPs treatment, indicating the superior antitumor effect and slight side effect of Ptx-NPs over free Ptx. Conjugation of Ptx-SA-PEG provides a feasible way to acquire self-assembled supramolecular Ptx-loaded nanoparticles with higher drug loading efficiency, less non-specific toxicity and more stable and durable antitumor effect of Ptx, providing a potential strategy to meliorate its clinical therapeutic efficacy.
紫杉醇（Ptx）是一种微管解聚抑制剂，是肺癌化疗的一线方案之一。然而，Ptx的低溶解度以及溶剂聚氧乙烯蓖麻油（Cremphor EL）的高致敏性严重限制了其临床应用。在此，我们研发了一种Ptx-SA-PEG药物-聚合物偶联物，其中两亲性共聚物聚乙二醇（PEG）和Ptx通过琥珀酸（SA）偶联。Ptx-SA-PEG聚合物自组装成纳米颗粒（Ptx-NPs）以实现Ptx的高效递送；采用细胞计数试剂盒-8法和克隆形成试验分析Ptx-NPs的抗肿瘤作用。通过吖啶橙/溴化乙锭双重染色、凋亡分析和蛋白质免疫印迹法来探究Ptx-NPs或游离Ptx处理后的细胞凋亡死亡情况。建立皮下异种移植模型以评估其肿瘤细胞毒性和非特异性副作用。采用免疫组织化学法分析肿瘤组织中凋亡和增殖的影响；研究表明，与游离Ptx相比，Ptx-NPs治疗表现出更强的肿瘤抑制活性，尤其是在较低剂量时。此外，Ptx-NPs激活了凋亡蛋白。动物实验表明，与游离Ptx相比，Ptx-NPs引起的体重减轻和器官损伤更小。此外，Ptx-NPs处理后肿瘤生长较慢，表明Ptx-NPs比游离Ptx具有更好的抗肿瘤效果和轻微的副作用。Ptx-SA-PEG偶联物提供了一种可行的方法，可获得具有更高载药效率、更低非特异性毒性以及更稳定持久抗肿瘤效果的自组装超分子载Ptx纳米颗粒，为改善其临床治疗效果提供了一种潜在策略。
