Second generation antiandrogens have improved overall survival for men with metastatic castrate resistant prostate cancer; however, the antiandrogens result in suppression of androgen receptor (AR) activity in all tissues resulting in dose limiting toxicity. We sought to overcome this limitation through encapsulation in a prostate specific membrane antigen (PSMA)–conjugated nanoparticle. We designed and characterized a novel nanoparticle containing an antiandrogen, enzalutamide. Selectivity and enhanced efficacy was achieved through coating the particle with PSMA. The PSMA-conjugated nanoparticle was internalized selectively in AR expressing prostate cancer cells. It did not elicit an inflammatory effect. The efficacy of enzalutamide was not compromised through insertion into the nanoparticle; in fact, lower systemic drug concentrations of enzalutamide resulted in comparable clinical activity. Normal muscle cells were not impacted by the PSMA-conjugated containing antiandrogen. This approach represents a novel strategy to increase the specificity and effectiveness of antiandrogen treatment for men with castrate resistant prostate cancer. The ability to deliver higher drug concentrations in prostate cancer cells may translate into improved clinical end points including overall survival.

中文翻译：

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治疗功效的改善和细胞毒性的减少：新型抗PSMA共轭杂化抗雄激素纳米粒子的介绍。

第二代抗雄激素可改善转移性去势抵抗性前列腺癌男性的总生存期。但是，抗雄激素药会抑制所有组织中的雄激素受体（AR）活性，从而导致剂量限制性毒性。我们试图通过封装在前列腺特异性膜抗原（PSMA）偶联的纳米颗粒中来克服这一限制。我们设计和表征了一种新型的含有抗雄激素恩杂鲁胺的纳米粒子。通过用PSMA包覆颗粒，实现了选择性和增强的功效。PSMA共轭的纳米粒子被选择性地内化表达AR的前列腺癌细胞。它没有引起炎症作用。恩杂鲁胺的功效不会因插入纳米颗粒而受到损害；实际上，较低的恩杂鲁胺全身药物浓度可导致相当的临床活动。正常的肌肉细胞不受PSMA结合的抗雄激素的影响。这种方法代表了一种新的策略，可以提高去势抵抗性前列腺癌男性的抗雄激素治疗的特异性和有效性。在前列腺癌细胞中递送较高药物浓度的能力可以转化为改善的临床终点，包括总体存活率。