Optimal Hydrophobicity of Lipoid Gene Delivery Agents

描述（由申请人提供）：阳离子脂质样化合物通常在体外和体内用于将DNA递送至细胞以表达外源基因。许多临床试验表明这些药物用于基因治疗的前景，然而基于脂质的递送仍然不如替代病毒载体有效。尽管如此，在最初的配方上已经有了很大的改进，脂质样药物比修饰的病毒具有重要的安全优势。Avanti Lipids一直在销售一种不寻常的阳离子脂质，这种脂质基于天然脂质磷脂酰胆碱，在体外表现出低细胞毒性。通过简单的化学修饰，磷脂酰胆碱被转化为阳离子化合物，与DNA形成复合物，是有效的转染剂。这些化合物最初是由西北大学开发的，最近发现它们在混合物中具有很强的协同作用;例如，两种这样的化合物的混合物比单独使用任何一种化合物都有效。此外，最佳组合物取决于条件和细胞。这些发现指出了一种全新的增强基因（可能还有药物）传递的方法，表明这些分子的疏水部分可能对这些阳离子脂质样药物的功效至关重要。本建议的目的是调查各种阳离子磷脂酰胆碱，具有不寻常的疏水部分，这将是困难或不可能在任何其他阳离子类脂类合成。脂质将由Avanti合成，并在Northwestern测试转染活性和相关物理性质。预期活性比目前化合物高50倍的化合物或混合物将立即商业化，尽管预期将发现具有更高活性的化合物。所有提出的方法都已发表。

DESCRIPTION (provided by applicant): Cationic lipid-like compounds are commonly used in vitro and in vivo to deliver DNA to cells for the purposes of expressing exogenous genes. A number of clinical trials have indicated the promise of these agents for gene therapy, however lipid-based delivery remains less effective than the alternative viral vectors. Nevertheless, vast improvements have been made over the initial formulations and lipid-like agents have an important safety advantage over modified viruses. Avanti Lipids has been marketing an unusual category of cationic lipoids that are based on the natural lipid phosphatidylcholine and which, in vitro exhibit low cell toxicity. Through a simple chemical modification, the phosphatidyl cholines are converted to cationic compounds that form complexes with DNA and are effective transfection agents. These compounds, originally developed at Northwestern University, have recently been found to give very strong synergy in mixtures; for example, a mixture of 2 such compounds is much more effective than either compound separately. Furthermore, the optimal composition depends on conditions and cells. These findings point to an entirely new approach for enhancing gene (and probably drug) delivery, suggesting that the hydrophobic portions of these molecules maybe critical for the efficacy these cationic lipid-like agents. The aim of this proposal is to survey a variety of cationic phosphatidylcholines that have unusual hydrophobic moieties that would be difficult or impossible to synthesize in any other cationic lipoid class. The lipids will be synthesized by Avanti and tested for transfection activity and characterized with respect to relevant physical properties at Northwestern. Immediate commercialization is anticipated for compounds or mixtures with 50X higher activity than current compounds, although the expectation is that compounds with even higher activity will be discovered. All proposed methods have been previously published.