Targeting Stealth Liposome for Cancer Gene Therapy

晚期前列腺癌倾向于对标准化疗药物相对难治，并且这种化学抗性与功能性p53的缺乏相关。我们的初步数据表明，癌细胞可以敏感的化疗通过p53替代使用肿瘤靶向脂质体传递系统。这些配体-脂质体的低稳定性和从循环中的快速清除是其临床应用的显著缺点。在阳离子脂质体中加入聚乙二醇（PEG）可以改善这两个参数。然而，在大多数情况下，PEG涂层可导致大尺寸复合物和/或可阻碍复合物的配体靶向潜力。我们开发了一种新的方法来制备配体导向的PEG稳定复合物作为靶向基因治疗的基因递送系统。由于PEG的存在，这些新型复合物具有比常规配体-脂质体复合物更长的循环时间和降低的毒性。此外，由于在与PEG的复合物中存在配体，这些复合物是组织靶向的。此外，它们保持其小尺寸，使得它们非常适合体内使用。这个I期项目，我们建议优化这种配体-PEG-脂质体-DNA复合物，用作前列腺癌的全身治疗，并证明其在裸鼠模型中的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-PEG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中最常见的癌症。超过一百万的美国男性现在生活在前列腺癌的诊断中，因此构成了新的前列腺癌治疗的重要标志。世界上最畅销的八种抗癌药物中有四种是前列腺药物（Casodex，Eulixin，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。

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.