School of Life Sciences, Jilin University, Changchun, Jilin, China,
Acalanes High School, Lafayette, CA, USA.
Int J Nanomedicine. 2018 Dec 21;14:135-148. doi: 10.2147/IJN.S181296. eCollection 2019.
We previously developed cabazitaxel (CTX)-loaded human serum albumin nanoparticles (NPs-CTX) via a self-assembly method, and these NPs showed efficacy in prostate cancer therapy. Many studies have shown that the levels of folic acid (FA) receptor on the surface of various tumor cells are high. Therefore, FA-modified NPs-CTX may have enhanced antitumor effects compared with unmodified NPs-CTX.
NPs-CTX were first prepared via self-assembly, and FA was conjugated on the surface of NPs-CTX through the -NH groups of the NPs to produce FA-NPs-CTX. The FA-NPs-CTX were evaluated in tumor cells with high FA receptor (FR) expression in vitro and in vivo.
Both NPs-CTX and FA-NPs-CTX exhibited good stability and morphology. Drug release from the NPs was not affected by FA conjugation. Compared with CTX dissolved in a mixture of Tween 80 and 13% ethanol (w/w) at a ratio of 1:4 (v/v) (Tween-CTX), the two nanoformulations had lower lytic activity against normal red blood cells. However, FA-NPs-CTX showed greater inhibition of tumor cells with overexpressed FR, compared with NPs-CTX, in the cytotoxicity experiments. Moreover, the cellular uptake of FA-NPs-CTX was enhanced through FR-mediated endocytosis in HeLa cells in vitro and HeLa xenograft tumors in vivo. Although Tween-CTX exhibited tumor growth inhibition similar to FA-NPs-CTX in vivo, this inhibition also caused adverse side effects; the median lethal dose (LD50) of Tween-CTX to mice was 5.68 mg/kg, while FA-NPs-CTX-treated mice survived at doses exceeding 400 mg/kg.
The results showed that FA-NPs-CTX caused inhibition of tumor growth in a manner similar to that of Tween-CTX; however, the safety and tolerability of CTX were greatly improved by FA conjugation compared with those of Tween-CTX. In summary, FA-NPs-CTX have great potential in CTX delivery, and this formulation is a promising candidate for the treatment of cancers with high FR levels.
我们之前通过自组装方法开发了载紫杉醇（CTX）的人血清白蛋白纳米颗粒（NPs-CTX），这些纳米颗粒在前列腺癌治疗中显示出疗效。许多研究表明，各种肿瘤细胞表面的叶酸（FA）受体水平较高。因此，与未修饰的 NPs-CTX 相比，FA 修饰的 NPs-CTX 可能具有增强的抗肿瘤作用。
首先通过自组装制备 NPs-CTX，然后通过 NPs 的-NH 基团将 FA 接枝到 NPs-CTX 表面，生成 FA-NPs-CTX。在体外和体内具有高 FA 受体（FR）表达的肿瘤细胞中评估 FA-NPs-CTX。
NPs-CTX 和 FA-NPs-CTX 均表现出良好的稳定性和形态。FA 接枝不影响 NPs 的药物释放。与 CTX 溶解在 Tween 80 和 13%乙醇（w/w）按 1:4（v/v）比例混合的混合物（Tween-CTX）相比，两种纳米制剂对正常红细胞的溶血性活性较低。然而，与 NPs-CTX 相比，FA-NPs-CTX 在细胞毒性实验中对 FR 过表达的肿瘤细胞具有更大的抑制作用。此外，FA-NPs-CTX 通过 HeLa 细胞中的 FR 介导的内吞作用增强了细胞摄取，在体外和体内 HeLa 异种移植肿瘤中均如此。虽然 Tween-CTX 在体内表现出与 FA-NPs-CTX 相似的肿瘤生长抑制作用，但这种抑制也引起了不良反应；Tween-CTX 对小鼠的半数致死剂量（LD50）为 5.68mg/kg，而 FA-NPs-CTX 治疗组的小鼠在超过 400mg/kg 的剂量下存活。
结果表明，FA-NPs-CTX 以类似于 Tween-CTX 的方式抑制肿瘤生长；然而，与 Tween-CTX 相比，FA 接枝大大提高了 CTX 的安全性和耐受性。总之，FA-NPs-CTX 在 CTX 递送上具有巨大潜力，并且该制剂是治疗 FR 水平较高的癌症的有前途的候选药物。
