Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Mol Pharm. 2010 Feb 1;7(1):177-86. doi: 10.1021/mp900201v.
Block copolymer micelles (BCMs) can improve the payload delivery of therapeutic agents to tumors. Our aim was to construct hEGF-modified BCMs for the delivery of 111In to tumor cells for Auger electron-emission radiotherapy of EGFR-positive breast cancer (BC). Multifunctional nanosized BCMs were prepared from MePEG(2500)-b-PCL(1200) and 111In-DTPA-PEG(3000)-b-PCL(1600) with or without hEGF-PEG(2900)-b-PCL(1400) (111In-hEGF-BCMs or 111In-BCMs). The resulting BCMs were analyzed by dynamic light scattering and transmission electron microscopy. Cellular uptake and nuclear importation were assessed in MDA-MB-468, MDA-MB-231 and MCF-7 BC cells with decreasing EGFR density. In vitro antiproliferative effects were evaluated using the WST-1 assay after 48 h with 111In-hEGF-BCMs, and the clonogenic assay was used to determine the survival fraction (SF) after a 21 h exposure. Results were compared with 111In-DTPA-hEGF, an established Auger electron-emitting radiotherapeutic that is currently in clinical development. Cell uptake and nuclear importation of 111In-hEGF-BCMs decreased in the following order: MDA-MB-468 > MDA-MB-231 > MCF-7. Cellular uptake of 111In-hEGF-BCMs was less than 111In-DTPA-hEGF (P < 0.05) but was 4-fold higher than for 111In-BCMs (P < 0.001). There was a significant growth inhibition of MDA-MB-468 cells by 111In-hEGF-BCMs (6-fold inhibition, P < 0.05) while the growth of MDA-MB-231 and MCF-7 were not significantly inhibited. The SF of MDA-MB-468 cells was decreased to 2.6% while that for MCF-7 cells was 132.7%. 111In-DTPA-hEGF reduced the SF of MDA-MB-468 cells to 0.4%. Nontargeted 111In-BCMs had minimal effect on the SF of BC cells. Therefore, the 111In-hEGF-BCMs were bound, internalized and transported to the nuclei of EGFR-positive BC cells, where the Auger electron emissions were lethal. The 111In-hEGF-BCMs are a promising delivery system for targeted radiotherapy of BC.
嵌段共聚物胶束 (BCMs) 可以提高治疗剂对肿瘤的有效载荷传递。我们的目的是构建 hEGF 修饰的 BCMs，用于将 111In 递送至肿瘤细胞，用于 EGFR 阳性乳腺癌 (BC) 的电子俘获放射治疗。多功能纳米级 BCMs 由 MePEG(2500)-b-PCL(1200) 和 111In-DTPA-PEG(3000)-b-PCL(1600) 与或不与 hEGF-PEG(2900)-b-PCL(1400) 制成（111In-hEGF-BCMs 或 111In-BCMs）。通过动态光散射和透射电子显微镜分析所得 BCMs。在 EGFR 密度降低的 MDA-MB-468、MDA-MB-231 和 MCF-7 BC 细胞中评估细胞摄取和核导入。使用 WST-1 测定法在 48 h 后评估 111In-hEGF-BCMs 的体外抗增殖作用，并使用克隆形成测定法确定 21 h 暴露后的存活分数 (SF)。将结果与目前正在临床开发中的已建立的电子俘获放射治疗剂 111In-DTPA-hEGF 进行比较。111In-hEGF-BCMs 的细胞摄取和核导入按以下顺序降低：MDA-MB-468> MDA-MB-231> MCF-7。111In-hEGF-BCMs 的细胞摄取低于 111In-DTPA-hEGF（P < 0.05），但比 111In-BCMs 高 4 倍（P < 0.001）。111In-hEGF-BCMs 对 MDA-MB-468 细胞的生长有显著抑制作用（6 倍抑制，P < 0.05），而 MDA-MB-231 和 MCF-7 的生长未受到显著抑制。MDA-MB-468 细胞的 SF 降低至 2.6%，而 MCF-7 细胞的 SF 降低至 132.7%。111In-DTPA-hEGF 将 MDA-MB-468 细胞的 SF 降低至 0.4%。非靶向 111In-BCMs 对 BC 细胞的 SF 几乎没有影响。因此，111In-hEGF-BCMs 与 EGFR 阳性 BC 细胞结合、内化并转运至细胞核，在那里电子俘获发射是致命的。111In-hEGF-BCMs 是一种有前途的 BC 靶向放射治疗的递药系统。
