Targeting Stealth Liposome for Cancer Gene Therapy

晚期前列腺癌对标准化疗药物往往相对耐药，这种化疗耐药性与缺乏功能性P53有关。我们的初步数据表明，癌细胞可以通过使用肿瘤靶向脂质体传递系统的P53替换来对化疗敏感。这些配体-脂质体的稳定性低，从循环中迅速清除是其临床应用的重大缺陷。在阳离子脂质体中加入聚乙二醇可以改善这两个参数。然而，在大多数情况下，聚乙二醇包覆会导致大尺寸的络合物和/或会阻碍络合物的配体靶向潜力。我们开发了一种新的方法来制备一种配体导向的、聚乙二醇稳定的络合物，作为靶向基因治疗的基因递送系统。由于聚乙二醇的存在，这些新型络合物比传统的配体-脂质体络合物具有更长的循环时间和更低的毒性。此外，由于与聚乙二醇络合物中配体的存在，这些络合物具有组织靶向性。此外，它们保留了它们的小尺寸，使它们非常适合在体内使用。在这个第一阶段的项目中，我们建议优化这种配体-聚乙二醇脂质体-DNA复合体，用于前列腺癌的系统治疗，并在裸鼠模型中证明其肿瘤和转移靶向潜力。该项目的长期目标是开发和销售一种更有效的前列腺癌治疗方法，使用配体-聚乙二醇稳定的脂质体介导的基因疗法与化疗相结合。建议的商业应用：前列腺癌是美国男性最常见的癌症。现在有100多万美国男性被诊断患有前列腺癌，因此构成了前列腺癌新疗法的重要标志。世界上最畅销的八种抗癌药物中有四种是前列腺癌药物(Casodex、Euliin、Lupron和Zoladex)。这些药物的年销售额合计为17亿美元，尽管它们只是治标不治本的事实。

Advanced prostate cancer tends to be relatively refractory to standard chemotherapeutic agents, and this chemoresistance correlates with a lack of functional p53. Our preliminary data indicate that cancer cells can be sensitize to chemotherapy via p53 replacement using a tumor-targeting liposomal delivery system. The low stability and rapid clearance from circulation of these ligand-liposomes are significant drawbacks for their clinical use. The addition of polyethylene glycol (PEG) to cationic liposomes can improve these two parameters. However, in most cases PEG coating can result in large size complexes and/or can impede the ligand-targeting potential of the complex. We have developed a novel method to prepare a ligand-directed, PEG stabilized complex as a gene delivery system for targeted gene therapy. Due to the presence of PEG these novel complexes have longer circulating times than conventional ligand-liposome complexes and reduced toxicities. In addition, due to the presence of the ligand in the complex with PEG, these complexes are tissue targeting. Furthermore, they retain their small size making them very desirable for in vivo use. This Phase I project we propose to optimize this ligand-PEG-liposome-DNA complex for use as a systemic therapy for prostate cancer, and demonstrate as Proof-of-Principle, its tumor and metastases targeting potential in nude mouse models. The longer-term aim of this project is development and marketing of a more effective treatment for prostate cancer using ligand-PEG stabilized, liposome-mediated gene therapy in combination with chemotherapy. PROPOSED COMMERCIAL APPLICATIONS: Prostate cancer is the most common cancer among American men. Over one million American men are now living with a diagnosis of prostate cancer and thus constitute a substantial marker for new prostate cancer therapies. Four of the world's eight top-selling anti-cancer drugs are prostate drugs (Casodex, Eulixin, Lupron, and Zoladex). These agents have combined annual sales of $1.7 billion, despite the fact that they are merely palliative.