Chemical and Life Science Engineering Department, Virginia Commonwealth University, Richmond, VA 23284, USA.
Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA.
Int J Mol Sci. 2020 Dec 5;21(23):9292. doi: 10.3390/ijms21239292.
The efficacy of paclitaxel (PTX) is limited due to its poor solubility, poor bioavailability, and acquired drug resistance mechanisms. Designing paclitaxel prodrugs can improve its anticancer activity and enable formulation of nanoparticles. Overall, the aim of this work is to improve the potency of paclitaxel with prodrug synthesis, nanoparticle formation, and synergistic formulation with lapatinib. Specifically, we improve potency of paclitaxel by conjugating it to α-tocopherol (vitamin E) to produce a hydrophobic prodrug (Pro); this increase in potency is indicated by the 8-fold decrease in half maximal inhibitory concentration (IC) concentration in ovarian cancer cell line, OVCA-432, used as a model system. The efficacy of the paclitaxel prodrug was further enhanced by encapsulation into pH-labile nanoparticles using Flash NanoPrecipitation (FNP), a rapid, polymer directed self-assembly method. There was an 1100-fold decrease in IC concentration upon formulating the prodrug into nanoparticles. Notably, the prodrug formulations were 5-fold more potent than paclitaxel nanoparticles. Finally, the cytotoxic effects were further enhanced by co-encapsulating the prodrug with lapatinib (LAP). Formulating the drug combination resulted in synergistic interactions as indicated by the combination index (CI) of 0.51. Overall, these results demonstrate this prodrug combined with nanoparticle formulation and combination therapy is a promising approach for enhancing paclitaxel potency.
由于紫杉醇（PTX）溶解度差、生物利用度低以及存在获得性耐药机制，其疗效受到限制。设计紫杉醇前药可以提高其抗癌活性并能够制成纳米颗粒。总的来说，这项工作的目的是通过前药合成、纳米颗粒形成以及与拉帕替尼的协同配方来提高紫杉醇的效力。具体来说，我们通过将紫杉醇与 α-生育酚（维生素 E）偶联来制备疏水性前药（Pro）来提高紫杉醇的效力，这通过作为模型系统的卵巢癌细胞系 OVCA-432 的半最大抑制浓度（IC）浓度降低 8 倍来表明。通过使用 Flash NanoPrecipitation（FNP）将紫杉醇前药包封到 pH 敏感的纳米颗粒中，进一步增强了前药的功效，FNP 是一种快速的、聚合物导向的自组装方法。将前药制成纳米颗粒后，IC 浓度降低了 1100 倍。值得注意的是，前药制剂比紫杉醇纳米颗粒有效 5 倍。最后，通过将前药与拉帕替尼（LAP）共包封进一步增强了细胞毒性作用。药物组合的配方导致协同相互作用，组合指数（CI）为 0.51。总的来说，这些结果表明，这种前药与纳米颗粒制剂和联合治疗相结合是提高紫杉醇效力的一种很有前途的方法。
