Hariri Waseem, Sudha Thangirala, Bharali Dhruba J, Cui Huadong, Mousa Shaker A
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, New York, 12144, USA.
Pharm Res. 2015 Aug;32(8):2764-74. doi: 10.1007/s11095-015-1662-x. Epub 2015 Mar 12.
Estrogen Receptor-α (ERα) expression is increased in prostate cancer and acts as an oncogene. We propose that blocking of estrogen hormone binding to ERα using the ERα blocker toremifene will reduce the tumorigenicity of prostate cancer, and nano-targeted delivery of toremifene will improve anticancer efficacy. We report the synthesis and use in an orthotopic mouse model of PLGA-PEG nanoparticles encapsulating toremifene and nanoparticles encapsulating toremifene that are also conjugated to anti-PSMA for targeted prostate tumor delivery.
Human prostate cancer cell line PC3M and a nude mouse model were used to test efficacy of nano-targeted and nano-encapsulated toremifene versus free toremifene on the growth and differentiation of tumor cells.
Treatment with free toremifene resulted in a significant reduction in growth of prostate tumor and proliferation, and its nano-targeting resulted in greater reduction of prostate tumor growth, greater toremifene tumor uptake, and enhanced tumor necrosis. Tumors from animals treated with nano-encapsulated toremifene conjugated with anti-PSMA showed about a 15-fold increase of toremifene compared to free toremifene.
Our data provide evidence that blocking ERα by toremifene and targeting prostate cancer tissues with anti-PSMA antibody on the nanoparticles' surface repressed the tumorigenicity of prostate cancer cells in this mouse model.
雌激素受体-α（ERα）在前列腺癌中的表达增加，并作为一种癌基因发挥作用。我们提出，使用ERα阻滞剂托瑞米芬阻断雌激素与ERα的结合将降低前列腺癌的致瘤性，并且托瑞米芬的纳米靶向递送将提高抗癌疗效。我们报告了包裹托瑞米芬的PLGA-PEG纳米颗粒以及还与抗前列腺特异性膜抗原（PSMA）偶联以实现前列腺肿瘤靶向递送的包裹托瑞米芬的纳米颗粒的合成及其在原位小鼠模型中的应用。
使用人前列腺癌细胞系PC3M和裸鼠模型来测试纳米靶向和纳米包裹的托瑞米芬与游离托瑞米芬对肿瘤细胞生长和分化的疗效。
游离托瑞米芬治疗导致前列腺肿瘤生长和增殖显著降低，其纳米靶向导致前列腺肿瘤生长进一步降低、托瑞米芬在肿瘤中的摄取增加以及肿瘤坏死增强。与游离托瑞米芬相比，用与抗PSMA偶联的纳米包裹托瑞米芬治疗的动物的肿瘤中托瑞米芬含量增加了约15倍。
我们的数据提供了证据，表明在该小鼠模型中，托瑞米芬阻断ERα以及纳米颗粒表面的抗PSMA抗体靶向前列腺癌组织可抑制前列腺癌细胞的致瘤性。
