GnRH介导MLT纳米微粒靶向治疗前列腺癌

前列腺癌的治疗现状仍不令人满意,尤其是当癌细胞转化成去势抵抗性时,雄激素全阻断治疗的疗效甚微。国内外的实验研究已表明蜂毒蛋白（MLT）对前列腺癌细胞有杀伤、抑制和细胞毒作用。本课题拟将MLT经磷脂纳米载体包裹制成MLT纳米微粒，然后用化学耦联的方法将促性腺激素释放激素（GnRH）结合到该纳米微粒表面，使其具有GnRH介导的高度靶向性。因前列腺癌细胞无论雄激素依赖性或去势抵抗性，均高表达GnRH受体，GnRH介导的MLT纳米微粒能特异性地和前列腺癌细胞结合，通过蜂毒蛋白四聚体洞穿细胞膜而造成癌细胞的崩解。此外，纳米技术的应用使得该纳米微粒更易通过血脑屏障和血睾屏障，破坏脑垂体及睾丸中高表达GnRH受体的细胞，提高其与GnRH受体的结合率，形成永久性的药物去势，有望为前列腺癌，特别是晚期前列腺癌、去势抵抗性前列腺癌探索出一种新的治疗方法。

The current treatments for the advanced prostate cancer are still far from satisfactory, especially when progress to castrate-resistant prostate cancers (CRPC), they fail to respond to androgen-deprivation therapy (ADT). Both the domestic and foreign researches have shown that the melittin (MLT), derived from honeybee venom protein, has cytotoxicity to prostate cancer cells. This project explores a novel target therapy for prostate cancer with melittin (MLT) nano-particles derived from honeybee venom protein. MLT nano-particles are prepared from MLT proteins encapsulated by the phospholipids nanometer carrier and subsequently coated with gonadotropin releasing hormone (GnRH) by chemical conjugation method. Because GnRH receptors are highly expressed in both androgen-dependent and castrate-resistant prostate cancers, the MLT nano-particles can specifically target all prostate cancers regardless of androgen status. After binding to GnRH receptors on the cell membrane, the MLT tetramers penetrate the cell membrane and cause cancer cells disintegration and death. Moreover, the application of nanotechnology makes it much easier for the MLT particles to transverse the blood barriers and dramatically increases the efficacy of the treatment. The MLT nano-particles can also specifically target the cells containing GnRH receptors in the pituitary and testis, therefore, results in a permanent medical castration. Our study may identify MLT nano-particles as a novel targeted therapy for prostate cancers, particularly the advanced and castrate-resistant prostate cancers.